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Inflammatory bowel diseases (IBD) include Crohn's disease and ulcerative colitis. Several studies relate eating habits to different aspects of IBD, such as progression and worsening of the clinical condition. Therefore, many natural products (NPs) such as polyphenols and carotenoids have been identified as promising agents in supporting IBD. An interesting source for obtaining bioactive NPs is the by-products of the food industry. The present study evaluated the potential beneficial effect of a standardized extract (CAE) obtained from cashew apple bagasse in the dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice. This was the first time that CAE had been evaluated in this experimental model. Chemical evaluation of CAE identified carotenoids (96.28 ± 0.15 mg/100 g), phenolic compounds (37.49 ± 0.64 mg/100 g), and a mixture of anacardic acids (C15:3 = 94.2 ± 0.6 mg/100 g; C15:2 = 108.4 ± 0.1 mg/100 g; C15:1 = 214.8 ± 0.2 mg/100 g). Administration of CAE (500 mg/kg, 4 days, p.o.) after DSS challenge was more effective in delaying disease progression compared with prior treatment (500 mg/kg, 30 days, p.o.), according to the disease activity index. However, no treatment strategy with CAE was able to prevent or inhibit disease progression, since all parameters evaluated (macroscopic, biochemical, and histopathological) in CAE-treated animals were similar to those observed in DSS-challenged animals. Despite the high dose (500 mg/kg), the standardized extract (CAE) did not result in an effective concentration of carotenoids. Furthermore, as some anacardic acids have been reported as histone acetyltransferases inhibitors, there could be a possible antagonistic relationship between carotenoids and anacardic acids. Complementary research will be necessary to test the hypothesis of antagonism. Thus, an optimized extract, with an even higher concentration of carotenoids, obtained from cashew apple bagasse, can be developed as a possible adjuvant food supplement for inflammatory bowel diseases. [ABSTRACT FROM AUTHOR]

The rising of diseases caused by multidrug‐resistant bacteria has encouraged researchers to explore more antimicrobial substances, as well as chemicals capable of potentiating the action of existing ones against multidrug‐resistant bacteria. Anacardium occidentale produces a fruit known as cashew nut, filled with a dark, almost black, caustic, and flammable liquid called cashew nutshell liquid (CNSL). The goal of the study was to evaluate the intrinsic antimicrobial activity of the major compounds present in CNSL, called anacardic acids (AA), as well as their possible modulatory action as an adjuvant of Norfloxacin against a Staphylococcus aureus strain overproducing the NorA efflux pump (SA1199B). Microdilution assays were performed to determine the minimum inhibitory concentration (MIC) of AA against different microbial species. Norfloxacin and Ethidium Bromide (EtBr) resistance modulation assays were performed in the presence or absence of AA against SA1199‐B. AA showed antimicrobial activity against Gram‐positive bacterial strains tested but no activity against Gram‐negative bacteria or yeast strains. At subinhibitory concentration, AA reduced the MIC values for Norfloxacin and EtBr against the SA1199‐B strain. Furthermore, AA increased the intracellular accumulation of EtBr in this NorA overproducer strain, indicating that AA are NorA inhibitors. Docking analysis showed that AA probably modulates Norfloxacin efflux by spatial impediment at the same binding site of NorA. [ABSTRACT FROM AUTHOR]

The human myeloid leukemia cell differentiation protein (hMcl-1) is an anti-apoptotic multi-partner protein, belonging to the B-cell lymphoma-2 (Bcl-2) family of proteins. Studies have linked hMcl-1 alleviated expression with resistance to hemopoietic chemotherapeutics, which makes it a key drug target in blood cancers. However, most of the developed small- to medium-sized hMcl-1 inhibitors have typical off-target activity towards other members of the Bcl-2 family. To improve the hMcl-1 inhibitor design, especially exploring a suitable scaffold with pharmacophoric features, we focused on natural hMcl-1 inhibitors. To date, seven classes of natural compounds have been isolated, which display a low micromolar affinity for hMcl-1 and have limited biophysical studies. We screened hMcl-1 co-crystal structures, and identified nine co-crystal structures of hMcl-1 protein, which were later evaluated by multiple receptor conformations (which indicates that the differences between hMcl-1 in crystal structures are low (RMSD values between 0.52 and 1.13 Å, average RMSD of 0.638–0.888 Å, with a standard deviation of 0.102–0.185Å)), and multiple ligand conformations (which led to the selection of the PDB structure, 3WIX (RMSD value = 0.879 Å, standard deviation 0.116 Å), to accommodate various Mcl-1 ligands from a range of co-crystal PDB files) methods. Later, the three adopted docking methods were assessed for their ability to reproduce the conformation bound to the crystal as well as predict trends in Ki values based on calculated RMSD and docking energies. Iterative docking and clustering of the docked pose within ≤1.0 Å was used to evaluate the reproducibility of the adopted docking methods and compared with their experimentally determined hMcl-1 affinity data.

Recently, natural antioxidants for the food industry have become an important focus. Cashew nut-shell liquid (CNSL) is composed of compounds that can act as natural antioxidants in food systems. The aim of this work was to evaluate the potential of CNSL and its components to act as natural antioxidants in a bulk oil system. CNSL was treated with calcium hydroxide to obtain two fractions [cardol/cardanols acid fraction (CCF) and anacardic acid fraction (AF)]. CNSL, FF and AF were analyzed by thin-layer chromatography and Fourier-transform infrared spectroscopy. The protective effects of CNSL, CCF and AF were tested in terms of the peroxide value of bulk soybean oil in accelerated assays and were compared against controls with and without synthetic antioxidants (CSA and CWA). CNLS, CCF, AF and CSA were tested at 200 mg/kg soybean oil by incubation at 30, 40, 50 and 60 °C for five days. The activation energy (Ea) for the production of peroxides was calculated by using the linearized Arrhenius equation. Thin-layer chromatography and Fourier-transform infrared spectroscopy revealed that (i) CNSL contained cardanols, anacardic acids, and cardols; (ii) CCF contained cardanols and cardols; and (iii) AF contained anacardic acids. CSA (Ea 35,355 J/mol) was the most effective antioxidant, followed by CCF (Ea 31,498 J/mol) and by CNSL (Ea 26,351 J/mol). AF exhibited pro-oxidant activity (Ea 8339 J/mol) compared with that of CWA (Ea 15,684 J/mol). Therefore, cardols and cardanols from CNSL can be used as a natural antioxidant in soybean oil. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBD) include Crohn’s disease and ulcerative colitis. Several studies relate eating habits to different aspects of IBD, such as progression and worsening of the clinical condition. Therefore, many natural products (NPs) such as polyphenols and carotenoids have been identified as promising agents in supporting IBD. An interesting source for obtaining bioactive NPs is the by-products of the food industry. The present study evaluated the potential beneficial effect of a standardized extract (CAE) obtained from cashew apple bagasse in the dextran sulfate sodium (DSS)-induced ulcerative colitis model in mice. This was the first time that CAE had been evaluated in this experimental model. Chemical evaluation of CAE identified carotenoids (96.28 ± 0.15 mg/100 g), phenolic compounds (37.49 ± 0.64 mg/100 g), and a mixture of anacardic acids (C15:3 = 94.2 ± 0.6 mg/100 g; C15:2 = 108.4 ± 0.1 mg/100 g; C15:1 = 214.8 ± 0.2 mg/100 g). Administration of CAE (500 mg/kg, 4 days, p.o.) after DSS challenge was more effective in delaying disease progression compared with prior treatment (500 mg/kg, 30 days, p.o.), according to the disease activity index. However, no treatment strategy with CAE was able to prevent or inhibit disease progression, since all parameters evaluated (macroscopic, biochemical, and histopathological) in CAE-treated animals were similar to those observed in DSS-challenged animals. Despite the high dose (500 mg/kg), the standardized extract (CAE) did not result in an effective concentration of carotenoids. Furthermore, as some anacardic acids have been reported as histone acetyltransferases inhibitors, there could be a possible antagonistic relationship between carotenoids and anacardic acids. Complementary research will be necessary to test the hypothesis of antagonism. Thus, an optimized extract, with an even higher concentration of carotenoids, obtained from cashew apple bagasse, can be developed as a possible adjuvant food supplement for inflammatory bowel diseases.

Herein, anacardic acid was applied for the preparation of nanosized cellulose using three different treatment conditions including ultrasonication, microwave irradiation, and reflux. Physico-chemical characterization was undertaken using FTIR, TEM, SEM, and XRD. FTIR, TEM, and SEM analyses confirm the preparation of nanosized cellulose with similar chemical but different physical properties as the cellulose starting material. In addition, calculated degrees of crystallinities from XRD data revealed crystallinities of 53.9, 54.4, and 54.7% for the nanosized cellulose prepared by ultrasonication (UNC), microwave irradiation (MNC), and reflux (RNC) respectively, which all are higher than the 53.3% of the precursor cellulose. Overall, the study shows that anacardic acid holds potential for the preparation of nanosized cellulose. [ABSTRACT FROM AUTHOR]

The human myeloid leukemia cell differentiation protein (hMcl-1) is an anti-apoptotic multi-partner protein, belonging to the B-cell lymphoma-2 (Bcl-2) family of proteins. Studies have linked hMcl-1 alleviated expression with resistance to hemopoietic chemotherapeutics, which makes it a key drug target in blood cancers. However, most of the developed small- to medium-sized hMcl-1 inhibitors have typical off-target activity towards other members of the Bcl-2 family. To improve the hMcl-1 inhibitor design, especially exploring a suitable scaffold with pharmacophoric features, we focused on natural hMcl-1 inhibitors. To date, seven classes of natural compounds have been isolated, which display a low micromolar affinity for hMcl-1 and have limited biophysical studies. We screened hMcl-1 co-crystal structures, and identified nine co-crystal structures of hMcl-1 protein, which were later evaluated by multiple receptor conformations (which indicates that the differences between hMcl-1 in crystal structures are low (RMSD values between 0.52 and 1.13 Å, average RMSD of 0.638–0.888 Å, with a standard deviation of 0.102–0.185Å)), and multiple ligand conformations (which led to the selection of the PDB structure, 3WIX (RMSD value = 0.879 Å, standard deviation 0.116 Å), to accommodate various Mcl-1 ligands from a range of co-crystal PDB files) methods. Later, the three adopted docking methods were assessed for their ability to reproduce the conformation bound to the crystal as well as predict trends in Ki values based on calculated RMSD and docking energies. Iterative docking and clustering of the docked pose within ≤1.0 Å was used to evaluate the reproducibility of the adopted docking methods and compared with their experimentally determined hMcl-1 affinity data. [ABSTRACT FROM AUTHOR]

Anacardic Acids (AcA) have been documented to have particularly important pathogenic properties. AcA and its complexes are being investigated in this article for their antimicrobial activities through in vitro and in silico assay methods. AcA from the cashew nut shell oil (CNSO) was isolated and Fourier-transform infrared spectroscopy (FTIR) and Proton nuclear magnetic resonance (1HNMR) were used to characterise the compound. AcA complexes were synthesised with hydrated metal (II) ions of Cobalt and Copper in a ratio of 1:1 using a modified method by Mendes et al. The antifungal activities of these AcA metal complexes were tested against five fungi. While AcA showed no antifungal activity, its complexes showed interesting results. Anacardic acid complex of cobalt (AcA-Co) showed activities against three of the five fungi; the best activity was against Penicillium citrinum (30±7.07 mm); a better result than clotrimazole (12.5±0.71 mm) which was the reference standard drug used. Anacardic acid complex of copper (AcA-Cu) also showed activities against all fungi tested against except Aspergillus flavus with the best activity also against Penicillium citrinum (15±2.83 mm). Standard precision (SP) and extra precision (XP) docking of AcA with 1Y54 revealed that it inhibits Enterococcus spp. better than standard drugs (Streptomycin and Tetracycline) as shown by docking scores and degree of binding affinities. These results of AcA and its complexes suggest additional studies which could lead to the development of new antifungal and antibacterial agents. [ABSTRACT FROM AUTHOR]

Diseases, such as cancer, peptic ulcers, and diabetes, as well as those caused by drug-resistant infectious agents are examples of some of the world's major public health problems. Amphipterygium adstringens (Schltdl.) Schiede ex Standl is an endemic tree to Mexico. Its stem bark has been used medicinally since pre-Hispanic times, but in recent decades it has been scientifically proven that it has properties that help counteract some diseases; extracts with organic solvents of the plant are outstanding for their anticancer, gastroprotective, and antimicrobial properties; terpenes and long-chain phenols have been identified as the main active compounds. Currently, overharvesting is causing a sharp reduction in natural populations due to an increase in demand for the stem bark by people seeking to improve their health and by national and transnational companies seeking to market it. Because of the growing interest of the world population and the scientific community, we reviewed recent studies on the bioactive properties of A. adstringens. Through the orderly and critical compendium of the current knowledge of A. adstringens, we provide a reference for future studies aimed at the rational use and protection of this valuable endemic natural resource. [ABSTRACT FROM AUTHOR]

Emerging antibiotic resistance among pathogenic bacteria is an issue of great clinical importance, and new approaches to therapy are urgently needed. Anacardic acid, the primary active component of cashew nut shell extract, is a natural product used in the treatment of a variety of medical conditions, including infectious abscesses. Here, we investigate the effects of this natural product on the function of human neutrophils. We find that anacardic acid stimulates the production of reactive oxygen species and neutrophil extracellular traps, two mechanisms utilized by neutrophils to kill invading bacteria. Molecular modeling and pharmacological inhibitor studies suggest anacardic acid stimulation of neutrophils occurs in a PI3K-dependent manner through activation of surface-expressed G protein-coupled sphingosine-1-phosphate receptors. Neutrophil extracellular traps produced in response to anacardic acid are bactericidal and complement select direct antimicrobial activities of the compound.

Recently, natural antioxidants for the food industry have become an important focus. Cashew nut-shell liquid (CNSL) is composed of compounds that can act as natural antioxidants in food systems. The aim of this work was to evaluate the potential of CNSL and its components to act as natural antioxidants in a bulk oil system. CNSL was treated with calcium hydroxide to obtain two fractions [cardol/cardanols acid fraction (CCF) and anacardic acid fraction (AF)]. CNSL, FF and AF were analyzed by thin-layer chromatography and Fourier-transform infrared spectroscopy. The protective effects of CNSL, CCF and AF were tested in terms of the peroxide value of bulk soybean oil in accelerated assays and were compared against controls with and without synthetic antioxidants (CSA and CWA). CNLS, CCF, AF and CSA were tested at 200 mg/kg soybean oil by incubation at 30, 40, 50 and 60 °C for five days. The activation energy (Ea) for the production of peroxides was calculated by using the linearized Arrhenius equation. Thin-layer chromatography and Fourier-transform infrared spectroscopy revealed that (i) CNSL contained cardanols, anacardic acids, and cardols; (ii) CCF contained cardanols and cardols; and (iii) AF contained anacardic acids. CSA (Ea 35,355 J/mol) was the most effective antioxidant, followed by CCF (Ea 31,498 J/mol) and by CNSL (Ea 26,351 J/mol). AF exhibited pro-oxidant activity (Ea 8339 J/mol) compared with that of CWA (Ea 15,684 J/mol). Therefore, cardols and cardanols from CNSL can be used as a natural antioxidant in soybean oil.

Diseases, such as cancer, peptic ulcers, and diabetes, as well as those caused by drug-resistant infectious agents are examples of some of the world’s major public health problems. Amphipterygium adstringens (Schltdl.) Schiede ex Standl is an endemic tree to Mexico. Its stem bark has been used medicinally since pre-Hispanic times, but in recent decades it has been scientifically proven that it has properties that help counteract some diseases; extracts with organic solvents of the plant are outstanding for their anticancer, gastroprotective, and antimicrobial properties; terpenes and long-chain phenols have been identified as the main active compounds. Currently, overharvesting is causing a sharp reduction in natural populations due to an increase in demand for the stem bark by people seeking to improve their health and by national and transnational companies seeking to market it. Because of the growing interest of the world population and the scientific community, we reviewed recent studies on the bioactive properties of A. adstringens. Through the orderly and critical compendium of the current knowledge of A. adstringens, we provide a reference for future studies aimed at the rational use and protection of this valuable endemic natural resource.

The n-hexane extract of Knema pachycarpa fruits (Myristicaceae family), exhibiting strong anti-acetylcholinesterase activity, was investigated by gas chromatography/mass spectrometry and then purified by column chromatography. Guided by GC/MS profiling and bioassay, chromatographic separations led to the isolation of five new compounds: two anacardic acid derivatives 1–2, two cardanol derivatives 3–4 and a cardol derivative 5, along with mixtures of known phenolic lipids 6–9. The chemical structures were determined by various spectroscopic methods. New isolated compounds 1–5 were evaluated for their cytotoxicity and anti-acetylcholinesterase activity. Cardanol 3 and cardol 5 were the most active compounds in the acetylcholinesterase inhibitory assay with IC50 values of 2.60 ± 0.24 µM and 2.46 ± 0.23 µM, respectively. Cardanol 4 and cardol 5 showed moderate cytotoxicity against Hela and MCF-7 cancer cell lines with IC50 values ranging from 31.36 ± 0.41 µM to 41.30 ± 2.49 µM. [ABSTRACT FROM AUTHOR]

The recurrence of coronavirus disease and bacterial resistant strains has drawn attention to naturally occurring bioactive molecules that can demonstrate broad-spectrum efficacy against bacteria as well as viral strains. The drug-like abilities of naturally available "anacardic acids" (AA) and their derivatives against different bacterial and viral protein targets through in-silico tools were explored. Three viral protein targets [P DB: 6Y2E (SARS-CoV-2), 1AT3 (Herpes) and 2VSM (Nipah)] and four bacterial protein targets [P DB: 2VF5 (Escherichia coli), 2VEG (Streptococcus pneumoniae), 1JIJ (Staphylococcus aureus) and 1KZN (E. coli)] were selected to evaluate the activity of bioactive AA molecules. The potential ability to inhibit the progression of microbes has been discussed based on the structure, functionality and interaction ability of these molecules on the selected protein targets for multi-disease remediation. The number of interactions, full-fitness value and energy of the ligand-target system were determined from the docked structure in SwissDock and Autodock Vina. In order to compare the efficacy of these active derivatives to that of commonly used drugs against bacteria and viruses, a few of the selected molecules were subjected to 100 ns long MD simulations. It was found that the phenolic groups and alkyl chains of AA derivatives are more likely to bind with microbial targets, that could be responsible for the improved activity against these targets. The results suggest that the proposed AA derivatives have demonstrated potential to become active drug ingredients against microbial protein targets. Further, experimental investigations are essential for clinical verification of the drug-like abilities of AA derivatives.Communicated by Ramaswamy H. Sarma.

Hypertension represents one of the most common maladies of western civilizations caused by bad dietary practices and lack of exercise. Angiotensin-I-converting enzyme inhibitors (ACEi) have been shown to be very efficient in the prevention of hypertension. ACEi are also implicated (by their ability to reduce the product of ACE activity namely angiotensin-II levels, which has oncogenic and increased cell proliferation effects) to be efficient anticancer agents. Therefore, we evaluated the potential antihypertension capacities of anacardic acids purified from Cashew (Anacardium occidentale Linn.) nut shell liquid by inhibition of ACE using analytical reverse-phase high performance liquid chromatography. The ability to inhibit ACE showed the following relation: anacardic-3 (IC50 = 12 µM) > anacardic acid-4 (IC50 = 20 µM) > anacardic acid-2 (IC50 = 33 µM) > anacardic acid-1 (IC50 = 39 µM) as compared to the positive control captopril (IC50 = 6.85 nM). Salicylic acid lacking a phytyl side chain was negative. The capacity of purified anacardic acids to inhibit ACE thereby represents the most potent naturally available plant chemicals described so far, as a potential means of reducing hypertension. The inhibition of angiotensin II production indicated that anacardic acids could also have utility in cancer prevention and recurrence, and reduction of cardiotoxicity during chemotherapy.

Cashew nut shell liquid (CNSL) was obtained from Anacardium occidentale L. plant, is a natural resource of phenolic lipid. It was obtained as natural (n) and technical (t), based on its mode of extraction, with unique structural features, such as phenolic hydroxyl, carboxyl, aromatic ring and long alkyl chain that identify it as good platform for chemical transformation into valuable products. The main constituents of CNSL are anacardic acid, cardanol and cardol. Copper (Cu) has been extensively used in bacteriostatic and bactericidal applications since ages. Copper incorporated CNSL combinations from technical CNSL (Cu-tCNSL) are expected to exhibit good antibacterial activity. The aim of this research is to prepare Cu-tCNSL, by simple, solvent-free, cost-effective and less timeconsuming approach following "Green Chemistry" protocol, to study the antibacterial activity of Cu-tCNSL, and to investigate the possibility of formulation of ointments therefrom. The structure and morphology of Cu-tCNSL were investigated by FTIR, NMR and TEM analyses, and homogeneity of ointments was studied by homogenization test. The antibacterial activity was investigated against Staphylococcus aureus and Pseudomonas aeruginosa. Our studies revealed that Cu-tCNSL showed antibacterial activity by Gram-positive Staphylococcus aureus only and can be well formulated into ointments. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) induced by environmental toxins involves a multifactorial cascade of harmful factors, thus motivating the search for therapeutic agents able to act on the greatest number of molecular targets. This study evaluated the efficacy of 50 mg/kg purified anacardic acids (AAs), isolated from cashew nut shell liquid, on multiple steps of oxidative stress and inflammation induced by rotenone in the substantia nigra (SN) and striatum. Adult mice were divided into four groups: Control, rotenone, AAs + rotenone, and AAs alone. Lipoperoxidation, nitric oxide (NO) levels, and reduced glutathione (GSH)/oxidized gluthatione (GSSG) ratio were evaluated. NF‐kB‐p65, pro‐IL‐1β, cleaved IL‐1β, metalloproteinase‐9, Tissue Inhibitory Factor‐1 (TIMP‐1), tyrosine hydroxylase (TH), and glial fibrillary acidic protein (GFAP) levels were assessed by Western blot. In silico studies were also made using the SwissADME web tool. Rotenone increased lipoperoxidation and NO production and reduced TH levels and GSH/GSSG ratio in both SN and striatum. It also enhanced NF‐kB‐p65, pro, and cleaved IL‐1β, MMP‐9, GFAP levels compared to control and AAs groups. The AAs alone reduced pro‐IL‐1β in the striatum while they augmented TIMP1 and reduced MMP‐9 amounts in both regions. AAs reversed rotenone‐induced effects on lipoperoxidation, NO production, and GSH/GSSG ratio, as well as increased TH and attenuated pro‐IL‐1β and MMP‐9 levels in both regions, NF‐kB‐p65 in the SN and GFAP in the striatum. Altogether, the in vivo and in silico analysis reinforced multiple and defined molecular targets of AAs, identifying that they are promising neuroprotective drug candidates for PD, acting against oxidative and inflammatory conditions induced by rotenone. [ABSTRACT FROM AUTHOR]

Summary: Pistachio (Pistacia vera L.) is an important cultivated plant in the Southeastern Anatolia region and its fruits are widely used in the food industry. The previous studies mostly focused on the food minerals and components. However, there is no study on chemical components and biological activity of the soft hulls of the pistachio fruits. In this study, it was focused on the acetone and water extracts of the soft hulls of pistachio fruits. Hence, the acetone extract was subjected to sephadex LH-20 column chromatography and fractioned into five fractions (Frs. A-E) according to molecular weight of components. A triterpen compound isolated from the Fr. B by crystallation method and its chemical structure was characterized as masticadienonic acid by spectroscopic methods. The fractions contain a mixture of the anacardic acids 13:1, 15:2, 15:1 and 17:1 and their derivatives according to their spectroscopic data and GC-MS analysis. Shikimic acid used in the synthesis of the oseltamivir, antiviral agent was also purified at high yield (14.36%) from the water extract of the soft hulls of pistachio fruits. In order to explore the antidiabetic properties of the pure compounds, the extracts and the fractions, their inhibition effects were determined on the activities of digestive enzymes (α-glucosidase and α-amylase). All of the extracts, masticadienonic acid and the fractions containing the anacardic acids strongly inhibited the α-glucosidase activity much more than acarbose. However, all applications exhibited much weaker inhibitory properties againts α-amylase, as compaired to the inhibition effect of the acarbose. Furthermore, the treatments of mesocarps of Pistachio fruits acted as much weaker inhibitors against AChE, whereas the acetone extract and its fractions containing different rates of anacardic acids were powerful agents against BChE as strong as neostigmine and galantamine. The cytotoxic activities of the extracts and the compounds against HUVEC, A549 and H1299 cells were also determined using the MTT analysis method and it was determined that the acetone extract and the compounds, masticadienonic and shikimic acids showed cytotoxic effects on the cells. [ABSTRACT FROM AUTHOR]

Ellagic acid, known for its various biological activities, is widely used. Ellagic acid from pomegranate peels is safe for consumption, while that from gallnuts is only suitable for external use. However, there is currently no effective method to confirm the source of ellagic acid. Therefore, this study establishes an analysis method using ultra-high-performance liquid chromatography-electrospray ionization-high-resolution mass spectrometry (UHPLC-ESI-HR-MS) to identify the components of crude ellagic acid extracts from pomegranate peels and gallnuts. The analysis revealed that there was a mix of components in the crude extracts, such as ellagic acid, palmitic acid, oleic acid, stearic acid, and 9(10)-EpODE. Furthermore, it could be observed that ellagic acid extracted from gallnuts contained toxic substances such as anacardic acid and ginkgolic acid (15:1). These components could be used to effectively distinguish the origin of ellagic acid from pomegranate peels or gallnuts. Additionally, a rapid quantitative analysis method using UHPLC-ESI-MS with multiple reaction monitoring (MRM) mode was developed for the quality control of ellagic acid products, by quantifying anacardic acid and ginkgolic acid (15:1). It was found that one of three ellagic acid health care products contained ginkgolic acid (C15:1) and anacardic acid at more than 1 ppm.

Amphipterygium adstringens (cuachalalate) contains anacardic acids (AAs) such as 6-pentadecyl salicylic acid (6SA) that show immunomodulatory and antitumor activity with minimal or no secondary adverse effects. By contrast, most chemotherapeutic agents, such as 5-fluorouracil (5-FU) and carboplatin (CbPt), induce myelosuppression and leukopenia. Here, we investigated the myeloprotective and antineoplastic potential of an AA extract or the 6SA as monotherapy or in combination with commonly used chemotherapeutic agents (5-FU and CbPt) to determine the cytoprotective action of 6SA on immune cells. Treatment of Balb/c breast tumor-bearing female mice with an AA mixture or 6SA did not induce the myelosuppression or leukopenia observed with 5-FU and CbPt. The co-administration of AA mixture or isolated 6SA with 5-FU or CbPt reduced the apoptosis of circulating blood cells and bone marrow cells. Treatment of 4T1 breast tumor-bearing mice with the AA mixture or 6SA reduced tumor growth and lung metastasis and increased the survival rate compared with monotherapies. An increased effect was observed in tumor reduction with the combination of 6SA and CbPt. In conclusion, AAs have important myeloprotective and antineoplastic effects, and they can improve the efficiency of chemotherapeutics, thereby protecting the organism against the toxic effects of drugs such as 5-FU and CbPt.

Aedes aegypti and Culex quinquefasciatus are vectors of diseases that constitute public health problems. The discovery of products capable of inhibiting their development which are less harmful to the environment would have a huge impact on vector control. Here, natural cashew nut shell liquid (CNSL), technical CNSL, anacardic acid, cardanol, and cardol were isolated from Anacardium occidentale and evaluated for larvicidal and pupicidal activity against Ae. aegypti and Cx. quinquefasciatus under laboratory and field conditions. The activities of phenol, resorcinol, salicylic acid, and pentadecane, commercial chemicals similar in structure to nut shell derivatives, were also evaluated. All of the fractions extracted from A. occidentale oil exerted larvicidal effects against both mosquito species (LC50 5.4-22.6 mg/L), and two of the aforementioned were effective against pupae (LC50 90.8-109.7 mg/L). Of all the fractions tested, cardol demonstrated the strongest larvicidal and pupicidal effects and presented the most prolonged residual activity against the larvae and pupae of Ae. aegypti and Cx. quinquefasciatus under field conditions. This study suggests that A. occidentale nut shell derivatives are sustainable and promising candidates for the development of novel insecticides to overcome the problem of harmful chemical insecticides. [ABSTRACT FROM AUTHOR]

Objective: Over the last years, vitrification has been widely used for oocyte cryopreservation, in animals and humans; however, it frequently causes minor and major epigenetic modifications. The effect of oocyte vitrification on levels of acetylation of histone H4 at lysine 12 (AcH4K12), and histone acetyltransferase (Hat) expression, was previously assessed; however, little is known about the inhibition of Hat expression during oocyte vitrification. This study evaluated the effect of anacardic acid (AA) as a Hat inhibitor on vitrified mouse oocytes. Materials and Methods: In this experimental study, 248 mouse oocytes at metaphase II (MII) stage were divided in three experimental groups namely, fresh control oocytes (which were not affected by vitrification), frozen/thawed oocytes (vitrified) and frozen/thawed oocytes pre-treated with AA (treatment). Out of 248 oocytes, 173 oocytes were selected and from them, 84 oocytes were vitrified without AA (vitrified group) and 89 oocytes were pretreated with AA, and then vitrified (treatment group). Fresh MII mouse oocytes were used as control group. Hat expression and AcH4K12 levels were assessed by using real-time quantitative polymerase chain reaction (PCR) and immunofluoresce staining, respectively. In addition, survival rate was determined in vitrified and treatment oocytes. Results: Hat expression and AcH4K12 modification significantly increased [4.17 ± 1.27 (P≤0.001) and 97.57 ± 6.30 (P<0.001), respectively] in oocytes that were vitrified, compared to the fresh oocytes. After treatment with AA, the Hat mRNA expression and subsequently H4K12 acetylation levels were significantly reduced [0.12 ± 0.03 (P≤0.001) and 89.79 ± 3.20 (P≤0.05), respectively] in comparison to the vitrified group. However, the survival rate was not significantly different between the vitrified (90.47%) and treatment (91.01%) groups (P>0.05). Conclusion: The present study suggests that AA reduces vitrification risks caused by epigenetic modifications, but does not affect the quality of vitrification. In fact, AA as a Hat inhibitor was effective in reducing the acetylation levels of H4K12. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • DTX loaded AA functionalized liposomes (DTX-AA-PEG-Liposomes) were developed. • In-vitro studies showed high cell uptake and cytotoxicity of DTX-AA-PEG-Liposomes. • Efficient nuclear co-localization was observed in case of AA modified Liposomes. • DTX-AA-PEG-Liposomes showed higher DTX bioavailability as compared to Taxotere®. • DTX-AA-PEG-Liposomes showed potential tumor targeting with minimal side effects. Abstract Potential toxicity due to nonspecific distribution is one of the major challenges with currently available chemotherapeutics. In the present report we have developed Docetaxel (DTX) loaded Anacardic acid (AA) functionalized liposomes (DTX-AA-PEG-Liposomes) to have the advantage of selective distribution to cancer cells due to recognition and enhanced uptake by VEGF receptors. AA dual conjugate (AA-PEG-AA) was synthesized by using carbodiimide chemistry and further used to formulate the AA functionalized DTX loaded liposomes by using film hydration method. Extensive optimization of different process variables resulted in the formation of liposomes with particle size 126.4 ± 6.2 nm and PDI 0.239 ± 0.03. The freeze dried DTX-AA-PEG-Liposomes demonstrated sustained release for up to 24 h and excellent stability at accelerated storage stability conditions. Qualitative cell uptake studies demonstrated remarkably higher cellular uptake of Coumarin-6 (C-6) loaded liposomes, while quantitative determination revealed 2.64 and 2.88-fold higher uptake of DTX-AA-PEG-Liposomes in comparison with free DTX. Cell culture studies in MCF-7 to determine cellular uptake mechanism demonstrated clathrin and caveolae mediated internalization of liposomes, independent of Organic Anion Transporting Polypeptides (OATPs) transporters. Moreover, developed liposomes demonstrated relatively higher cell inhibition and apoptosis in MCF-7 cells as compared to free DTX. Furthermore, in vivo pharmacokinetics demonstrated 3.7 and 4.5-fold increase in AUC and t 1/2 value of DTX-AA-PEG-Liposomes as compared to Taxotere®, respectively. Moreover, DTX-AA-PEG-Liposomes demonstrated significant reduction in tumor volume and toxicity in comparison with marketed formulation (Taxotere®), confirming enhanced efficacy and safety of the developed formulation. [ABSTRACT FROM AUTHOR]

[Display omitted] • Anacardic acids (AnAs) of dried pistachio shells were extracted and investigated. • A green extraction procedure from agrifood waste was applied. • Epoxidation and tandem MS analysis were used to distinguish positional isomers of AnAs. • Epoxidated and native AnAs were separated using a C30 column. • The procedure is informative, simple, and effective and can be extended to other samples. Anacardic acids (AnAs) are important secondary metabolites that occur primarily in plants of the Anacardiaceae family, such as pistachio (Pistacia vera L.). Some AnAs have been associated with health benefits, and the position of the C C double bonds is a crucial feature of these metabolites. Herein, we propose a new strategy based on RPLC separation and detection by ESI-MS/MS, preceded by an epoxidation reaction. The procedure was applied to the green extracts of lignified pistachio shells, and a mixture of AnAs bearing alkyl chains 13:0, 15:0, and 17:1 emerged as prevailing. As positional isomers of AnA 15:1 (Δ8 and Δ6) and AnAs 17:1 (Δ10 and Δ8) were identified for the first time, their discovery paves the way to the systematic study of their potential health-beneficial effects. The developed method was validated and applied to quantify AnAs in pistachio ethanolic extract, showing contents higher than 10 mg/ 100 g of biomass. [ABSTRACT FROM AUTHOR]

Aim: The effect of anacardic acid impregnation on catheter surfaces for the prevention of Staphylococcus aureus attachments and biofilm formations were evaluated. Methods and Results: Silicon catheter tubes were impregnated using different concentrations of anacardic acids (0·002–0·25%). Anacardic acids are antibacterial phenolic lipids from cashew nut (Anacardium occidentale) shell oil. Anacardic acid‐impregnated silicon catheters revealed no significant haemolytic activity and were cytocompatible against fibroblast cell line (L929). Sustained release of anacardic acids was observed for 4 days. Anacardic acid‐impregnated silicon catheters efficiently inhibited S. aureus colonization and the biofilm formation on its surface. The in vivo antibiofilm activity of anacardic acid‐impregnated catheters was tested in an intraperitoneal catheter‐associated medaka fish infection model. Significant reduction in S. aureus colonization on anacardic acid‐impregnated catheter tubes was observed. Conclusions: Our data suggest that anacardic acid‐impregnated silicon catheters may help in preventing catheter‐related staphylococcal infections. Significance and Impact of the Study: This study opens new directions for designing antimicrobial phytochemical‐coated surfaces with ideal antibiofilm properties and could be of great interest for biomedical research scientists. [ABSTRACT FROM AUTHOR]

Abstract Anacardic acid, which is abundant in nutshell of Anacardium occidentale , has multiple pharmacological activities. In this study, we examined the therapeutic potential of anacardic acid in treating rheumatoid arthritis (RA). We explored the effects of anacardic acid on collagen-induced arthritis (CIA) in mice and on the proliferation and invasion of RA fibroblast-like synoviocytes (RA-FLSs). The underlying molecular mechanism was investigated. Anacardic acid treatment markedly suppressed paw swelling, joint destruction, and arthritis scores in CIA mice. The serum levels of tumor necrosis factor alpha (TNF- α) and interleutkin-1beta (IL- 1β) were significantly lowered by anacardic acid. In vitro assays demonstrated that anacardic acid impaired the proliferation and invasion abilities of RA-FLSs in the presence of TNF- α or IL- 1β. Western blot analysis revealed the reduction of Akt protein expression and phoshporylation in RA-FLSs by anacardic acid. However, the mRNA level of Akt remained unchanged. Anacardic acid treatment significantly increased the expression of miR-633 in RA-FLSs. Akt was identified as a novel target of miR-633. Overexpression of miR-633 significantly inhibited the proliferation and invasion of RA-FLSs, which was rescued by enforced expression of Akt. Depletion of miR-633 prevented anacardic acid-mediated suppression of proliferation and invasion of RA-FLSs, which was accompanied by increased expression of Akt protein. In conclusion, anacardic acid may serve as a promising agent in the treatment of RA. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disease affecting people of all ages worldwide. Side effects of antiepileptic drugs and their association with oxidative stress stimulate the search for new drugs, which would be more affordable with fewer adverse effects. Accordingly, the aim of the present work is to evaluate the anticonvulsant effect of anacardic acid (AA), a natural compound extracted from cashew liquid ( Anacardium occidentalis ), in murine models, as well as its antioxidant actions in Saccharomyces cerevisiae . AA (>90% purity) was tested, in vivo , in male Swiss mice (25–30 g) with four convulsive models, (1) pentylenetetrazole, (2) pilocarpine, (3) electroshock, and (4) kainic acid, at doses of 25, 50, and 100 mg/kg, body weight (B.W.) Additionally, the effective dose, toxic dose, and protective index studies were also performed. Results revealed that AA exhibits anticonvulsive effects in models 1, 3, and 4, with a mean effective dose (ED 50 ) of 39.64 (model 1) >100 mg/kg, B.W. (model 2), and 38.36 (model 3); furthermore, AA displays a protection index of 1.49 (model 1), <0.6 (model 2, and 1.54 (model 3). In addition, AA showed antioxidant activities in S. cerevisiae mutated for superoxide dismutases (SOD). In conclusion, these results show that AA exhibits significant anticonvulsant and antioxidant activities and may be used as a promising natural product for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Anacardic acids (AAs) are alkyl phenols mainly presenting in cashew nuts. The antioxidant effects of these compounds have been an area of interest in recent research, with findings suggesting potential therapeutic use for certain diseases. Nevertheless, none of these studies were performed in order to test the hypothesis of whether anacardic acids are capable of preventing behavioral changes and oxidative stress induced by the pesticide rotenone in experimental model of Parkinson’s disease. In our research, adult male rats were treated orally with AAs (1, 3, 10, 25, 50, or 100 mg/kg/day) 1 h before rotenone (3 mg/kg; s.c.) for five consecutive days. The behavioral testing strategies, including tests for general locomotor activity (open field), motor coordination (rotarod), and spatial memory performance (elevated T-maze), were carried out. Lipoperoxidation levels and total superoxide dismutase (t-SOD) activity, as well as cytoplasmic and mitochondrial SOD gene expression, were assessed in the substantia nigra (SN), striatum, and cerebral cortex. The results showed that AAs dose-dependently prevented the rotenone-induced learning and motor impairment from 10 mg/kg/day. AAs also precluded rotenone-induced lipoperoxidation in all doses, acting directly on the mitochondria, and improved the t-SOD activity in the doses 25-100 mg/kg/day. AAs per se (100 mg/kg/day) increased SOD gene expression and t-SOD activity. Our findings indicate that the oral administration of AAs prevents rotenone-induced behavioral changes and oxidative stress, in part due to a modulatory action on the mitochondria and SOD gene expression. These data suggest that AAs have promising neuroprotective action against degenerative changes in Parkinson’s disease. [ABSTRACT FROM AUTHOR]

Pistachio hulls, important by-products of pistachio processing, were extracted using an environmentally friendly process with subcritical water (SCW) at a pressure of 6.9 MPa in the range of 110 and 190 °C, and a flow rate of 4 ml/min. Detailed HPLC-DAD-ESI/MS n analyses allowed the identification of 49 phenolic compounds in the SCW extracts. Total gallotannin yields up to 33 g/kg were reached at 150–170 °C, where gallic acid (22.2 g/kg) and penta- O -galloyl- β - d -glucose (9.77 g/kg) levels were 13.2- and 10.6-fold higher than those in the aqueous methanol extracts. Flavonols were also effectively extracted at 110–150 °C (4.37–5.65 g/kg), while anacardic acid recovery was poor (1.13–2.77 g/kg). Accordingly, high amounts of anacardic acids (up to 50.7 g/kg) were retained in the extraction residue, revealing that SCW extraction allowed selective extraction of gallotannins and flavonols. Antioxidant capacities ranged from 0.68 to 1.20 mmol Trolox equivalents (TE)/g for SCW extracts increasing with temperature up 190 °C. [ABSTRACT FROM AUTHOR]

In the present study, we have modified bovine serum albumin (BSA) by covalently conjugating with anacardic acid (AA) and gemcitabine (GEM) and further used for development of docetaxel (DTX) loaded nanoparticles (AA-GEM-BSA NPs). AA is supposed to provide tumor targeting through VEGF receptors overexpressed in tumors, while the combination of GEM and DTX is supposed to provide synergistic activity by targeting multiple pathways. The conjugate was synthesized via carbodiimide chemistry and characterized by 1 H NMR, FTIR, MALDI-TOF and elemental analysis. Conformational changes owing to conjugation of AA and GEM were estimated via fluorescence, Raman and CD spectroscopy, while changes in physiochemical properties were studied by differential scanning calorimetry (DSC), thermogravimetry (TGA) and contact angle goniometry (CAG). Synthesized conjugate was further transformed into DTX loaded NPs and freeze dried. Scanning Electron Microscopy (SEM) and Atomic Force Microscopy (AFM) demonstrated formation of spherical NPs having particle size, 163 ± 8 nm, PDI, 0.13 ± 0.09 and ZP, −27 ± 1 mV. Cellular uptake in MCF-7 and MDA-MB-231 revealed hNTs, OATP1B3 independent, clathrin mediated internalization followed via nuclear co-localization of C-6 loaded AA-GEM-BSA NPs, responsible for significantly higher apoptosis index. Pharmacokinetic profile of DTX loaded AA-GEM-BSA NPs revealed 6.12 and 3.27-fold and 6.28 and 8.9-fold higher AUC and T 1/2 values of DTX and GEM as compared to Taxotere® and Gemzar®, respectively. Interestingly, the developed NPs were found safe with no marked effect on RBCs, lower hepato and nephro toxicity. Data in hand suggest promising potential of developed NPs in ameliorating the pharmacokinetic and therapeutic profile of combinatorial regimen of DTX and GEM. Statement of Significance The present report is the original state of art technology to selectively target dual drug (DTX and GEM) loaded BSA NPs via exploring tumor targeting potential of AA, having high affinity towards VEGF receptors (angiogenesis marker) overexpressed in tumor. The AA and GEM bio-conjugated BSA was synthesized and further used to develop DTX loaded nanoparticles (AA-GEM-BSA NPs). The optimized NPs were further evaluated via extensive in vitro and in vivo studies, demonstrating ameliorated cellular uptake, pharmacokinetic and toxicity profile of drugs. Conclusively, DTX loaded AA-GEM-BSA NPs, holds promising potential in increasing the therapeutic efficiency of drugs and overcoming solvent and drug mediated side effects and can be explored further as a scalable platform technology for difficult to deliver drugs. [ABSTRACT FROM AUTHOR]

Cashew nut shell liquid (CNSL) contains phenolic lipids with aliphatic chains that are of commercial interest. In this work, a chromatographic method was developed to monitor and quantify anacardic acids (AnAc) in CNSL. Samples containing AnAc were analyzed on a high-performance liquid chromatograph coupled to a diode array detector, equipped with a reversed phase C18 (150 x 4.6mm x 5 µm) column using acetonitrile and water as the mobile phase both acidified with acetic acid to pH 3.0 in an isocratic mode (80:20:1). The chromatographic method showed adequate selectivity, as it could clearly separate the different AnAc. To validate this method, AnAc triene was used as an external standard at seven different concentrations varying from 50 to 1,000 µgmL-1. The Student's t-test and F-test were applied to ensure high confidence for the obtained data from the analytical calibration curve. The results were satisfactory with respect to intra-day (relative standard deviation (RSD) = 0.60%) and inter-day (RSD = 0.67%) precision, linearity (y = 2,670.8x - 26,949, r² > 0.9998), system suitability for retention time (RSD = 1.02%), area under the curve (RSD = 0.24%), selectivity and limits of detection (19.8 µg mg-1) and quantification (60.2 µg mg-1). The developed chromatographic method was applied for the analysis of different CNSL samples, and it was deemed suitable for the quantification of AnAc. [ABSTRACT FROM AUTHOR]

To establish a sensitive bioassay for Nostocean hormogonium induction, we compared the effectiveness of the morpho-differentiation induction on two gelled plates, agar and gellan gum, for anacardic acid C15:1-Δ8 decyl ester (1) (100 nmol/disc). On BG-110 (nitrogen-free) medium-based 0.6 and 0.8% agar plates, Nostoc sp. strain Yaku-1 isolated from a coralloid root of Cycas revoluta in Yakushima Island showed clear morpho-differentiation from filamentous aggregates into hormogonia, and the induced hormogonia dispersed within 24 h; however, similar hormogonium formation was not observed at agar concentrations of 1.0% or higher. Conversely, hormogonium induction was considerably more pronounced on gellan gum plates than those on agar plates through concentrations ranging from 0.6 to 1.6% even after 12 h of incubation, particularly active on the 0.8-1.0% gellan gum plates. Thus, gellan gum plates can achieve clear results within 12 h and are thus highly useful for primary screening for hormogonium-inducing factors (HIFs). [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the effect of feeding laying hens diets containing cashew nut shell liquid ( CNSL) as a source of anacardic acid on the blood biochemical parameters as well as the enzymatic activity and lipid peroxidation of liver and tissues of the reproductive system (ovary, magnum, and uterus). A total of 216 Hisex White commercial laying hens were distributed randomly into six treatments, with six replicates of six birds. Treatments consisted of a diet without growth promoter ( GP); a diet with GP; and diets without GP, with addition of increasing levels of CNSL (0.25, 0.50, 0.75 and 1.0%). Addition of CNSL to the diet did not affect the blood biochemical parameters (uric acid, creatinine, alanine aminotransferase, aspartate aminotransferase, total cholesterol, high density lipoproteins, low-density lipoproteins and triglycerides), the enzymatic activity (superoxide dismutase and nonprotein sulphydryl groups) in the organs (liver, ovary, magnum and uterus) or the peroxidation of lipids from the blood serum, liver, magnum and uterus (p > 0.05). However, the addition of 0.75% and 1.00% CNSL provided a lower thiobarbituric acid reactive substances content in the birds' ovary (p < 0.001) compared to birds of other treatments, whereas the treatment without the GP provided a higher value. Addition of up to 1% of the CNSL as a source of anacardic acid in the laying hens' diets does not influence blood biochemical parameters or the endogenous enzymatic activity in the liver, ovary, magnum and uterus, but affects the lipid peroxidation in the ovary, although the problem is reduced from the inclusion of 0.75% CNSL. [ABSTRACT FROM AUTHOR]

Cashew nuts are important both nutritionally and industrially, but can also cause food allergies in some individuals. The present study aimed to assess the effect(s) of industrial processing on anacardic acids and allergens present in cashew nuts. Sample analyses were performed using liquid chromatography coupled with mass spectrometry, SDS-PAGE and immunoassay. The anacardic acid concentration ranged from 6.2 to 82.6 mg/g during processing, and this variation was attributed to cashew nut shell liquid incorporation during storage and humidification. Dehydrated and selected samples did not significantly differ in anacardic acid content, having values similar to the raw sample. SDS-PAGE and immunoassay analysis with rabbit polyclonal sera and human IgE indicated only minor differences in protein solubility and antibody binding following processing steps. The findings indicate that appreciable amounts of anacardic acid remain in processed nuts, and that changes to cashew allergens during industrial processing may only mildly affect antibody recognition. [ABSTRACT FROM AUTHOR]

Hypertension represents one of the most common maladies of western civilizations caused by bad dietary practices and lack of exercise. Angiotensin-I-converting enzyme inhibitors (ACEi) have been shown to be very efficient in the prevention of hypertension. ACEi are also implicated (by their ability to reduce the product of ACE activity namely angiotensin-II levels, which has oncogenic and increased cell proliferation effects) to be efficient anticancer agents. Therefore, we evaluated the potential antihypertension capacities of anacardic acids purified from Cashew (Anacardium occidentale Linn.) nut shell liquid by inhibition of ACE using analytical reverse-phase high performance liquid chromatography. The ability to inhibit ACE showed the following relation: anacardic-3 (IC50 = 12 µM) > anacardic acid-4 (IC50 = 20 µM) > anacardic acid-2 (IC50 = 33 µM) > anacardic acid-1 (IC50 = 39 µM) as compared to the positive control captopril (IC50 = 6.85 nM). Salicylic acid lacking a phytyl side chain was negative. The capacity of purified anacardic acids to inhibit ACE thereby represents the most potent naturally available plant chemicals described so far, as a potential means of reducing hypertension. The inhibition of angiotensin II production indicated that anacardic acids could also have utility in cancer prevention and recurrence, and reduction of cardiotoxicity during chemotherapy. [ABSTRACT FROM AUTHOR]

This is the first prospective study of the effects of human gutmicrobiota andmetabolites on immune checkpoint inhibitor (ICT) response in metastatic melanoma patients. Whereas many melanoma patients exhibit profound response to ICT, there are fewer options for patients failing ICT--particularly with BRAF-wild-type disease. In preclinical studies, specific gutmicrobiota promotes regression ofmelanoma inmice.Wetherefore conducted a study of the effects of pretreatment gutmicrobiota and metabolites on ICT Response EvaluationCriteria in Solid Tumors response in 39 metastatic melanoma patients treated with ipilimumab, nivolumab, ipilimumab plus nivolumab (IN), or pembrolizumab (P). IN yielded 67% responses and 8% stable disease; P achieved 23% responses and 23% stable disease. ICT responders for all types of therapies were enriched for Bacteroides caccae. Among IN responders, the gut microbiome was enriched for Faecalibacterium prausnitzii, Bacteroides thetaiotamicron, and Holdemania filiformis. Among P responders, the microbiome was enriched for Dorea formicogenerans. Unbiased shotgun metabolomics revealed high levels of anacardic acid in ICT responders.Based on these pilot studies, both additional confirmatory clinical studies and preclinical testing of these bacterial species and metabolites are warranted to confirm their ICT enhancing activity. [ABSTRACT FROM AUTHOR]