Uncovering the multifaceted properties of 6-pentyl-alpha-pyrone for control of plant pathogens.

Some volatile organic compounds (VOCs) produced by microorganisms have the ability to inhibit the growth and development of plant pathogens, induce the activation of plant defenses, and promote plant growth. Among them, 6-pentyl-alpha-pyrone (6-PP), a ketone produced by Trichoderma fungi, has emerged as a focal point of interest. 6-PP has been isolated and characterized from thirteen Trichoderma species and is the main VOC produced, often accounting for >50% of the total VOCs emitted. This review examines abiotic and biotic interactions regulating the production of 6-PP by Trichoderma, and the known effects of 6-PP on plant pathogens through direct and indirect mechanisms including induced systemic resistance. While there are many reports of 6-PP activity against plant pathogens, the vast majority have been from laboratory studies involving only 6-PP and the pathogen, rather than glasshouse or field studies including a host plant in the system. Biopesticides based on 6-PP may well provide an eco-friendly, sustainable management tool for future agricultural production. However, before this can happen, challenges including demonstrating disease control efficacy in the field, developing efficient delivery systems, and determining cost-effective application rates must be overcome before 6-PP's potential for pathogen control can be turned into reality.

Development of a Pyrone-Fused Tricyclic Scaffold-based Ratiometric Fluorescent Probe for Al3+ Detection.

Aluminum (Al3+) is environmentally abundant and can harm living organisms in various ways, such as by inhibiting root growth, damaging faunal nervous systems, and promoting tumor cell proliferation. However, the dynamics of Al3+ in living organisms are largely unknown; thus, detecting Al3+ in the environment and organisms is crucial. Fluorescent probes are useful tools for the selective detection of metal ions. In particular, ratiometric fluorescent probes exhibit a detection response at two different maximum fluorescence emission wavelengths; which is advantageous for avoiding the influence of background fluorescence. A novel pyrone-fused tricyclic scaffold-based ratiometric fluorescent probe for detecting Al3+, ethyl 11-imino-1-oxo-3-phenyl-1H,11H-pyrano[4,3-b] quinolizine-5-carboxylate (PQ), was developed in this study. The PQ fluorescence blue shifted from 505 to 457 nm upon the addition of Al3+. The blue shift was accompanied by a change in the fluorescence color of the PQ solution from green to blue. Fluorescence titration experiments demonstrated that the fluorescence intensity ratio at the two peaks of interest (457/505 nm) increased in a concentration-dependent manner upon the addition of Al3+. Moreover, this study demonstrated that a PQ-soaked paper displays a visible color change under ultraviolet light upon exposure to Al3+. The above results suggest that PQ is an effective ratiometric probe for the detection of Al3+ in the environment. Future studies will be conducted to introduce various substituents and develop fluorescent probes by leveraging the fluorescence property of a pyrone-fused tricyclic scaffolds.

Structure-Functional Activity of Pyrone Derivatives for Inhibition of Barnacle Settlement and Biofilm Formation.

Naturally occurring 6-pentyl-2H-pyran-2-one and its synthetic analogues greatly inhibit the settlement of Amphibalanus amphitrite cyprids and the growth and biofilm formation of marine bacteria. To optimize the antifouling activities of pyrone derivatives, this study designed pyrone analogues by modifying functional groups, such as the benzyl group, cyclopentane, and halides, substituted on both sides of a pyrone. The antifouling effects of the synthesized pyrone derivatives were subsequently evaluated against five marine biofilm-forming bacteria, Loktanella hongkongensis, Staphylococcus cohnii, S. saprophyticus, Photobacterium angustum, and Alteromonas macleodii, along with barnacle cyprids of Amphibalanus amphitrite. Substituting nonpolar parts-such as the aliphatic, cyclopentyl, or phenyl moieties on C-5 or the furan moieties on C-3-not only increased antibacterial activity and inhibited biofilm formation but also inhibited barnacle cyprid settlement when compared to 6-pentyl-2H-pyran-2-one.

Synthesis and Performance of Deep-Red Phosphorescent Iridium Complexes with Pyrone as an Auxiliary Ligand.

Two bis-cyclometalated heteroleptic iridium complexes incorporating 1-phenylisoquinoline (piq) as the main cyclometalating ligand and 3-hydroxy-2-methyl-4-pyrone (ma) or 2-ethyl-3-hydroxy-4H-pyran-4-one (ema) as the auxiliary ligand, namely Ir(piq)2(ma) (Ir-1) and Ir(piq)2(ema) (Ir-2), were developed and applied as deep-red phosphors in organic light-emitting diodes (OLEDs). The two auxiliary ligands had similar influences on the photophysical, electrochemical, and electroluminescent properties of the iridium complexes. Ir(piq)2(ma) (Ir-1) showed better luminescence performance in a simple phosphorescent OLED compared to the traditional red iridium complex Ir(piq)2(acac) and exhibited a current efficiency of 9.39 cd A-1 (EQE of 12.09%). In contrast, Ir(piq)2(ema) exhibited an efficiency of 8.6 cd A-1 (EQE of 10.19%).

Andrastin-type meroterpenoids, α-pyrone polyketides, and sesquicarane derivatives from Penicillium sp., a fungus isolated from Pinus koraiensis seed.

The genus Penicillium has provided us with the household antibiotic penicillin and the well-known lipid-lowering agent mevastatin. The strain Penicillium sp. SZ-1 was found to grow vigorously in an intact Pinus koraiensis seed, it is inferred that the strain may develop unique mechanisms associated with the biosynthesis of rare metabolites. Further fermentation of the strain on solid rice medium yielded thirteen undescribed compounds, including three andrastin-type meroterpenoids (1-3), two α-pyrone polyketides (4 and 5), and eight sesquicarane derivatives (6-13), along with seven known compounds (14-20). Their structures were determined by detailed analysis of the spectroscopic and spectrometric data (NMR and HRESIMS), in addition to comparisons of the experimental and calculated ECD data for absolute configurational assignments. The hemiacetal moiety in compounds 1 and 2 and the 3α-hydroxy group in compound 3 were rarely found in the andrastin-type meroterpenoid family. The sesquicaranes belong to a small group of sesquiterpenoid that are rarely reported. Bioassay study showed that compound 1 exhibited inhibitory effects against Staphylococcus aureus ATCC 29213 and Escherichia coli ATCC 25922 with MIC values of 64 and 32 µg/mL, respectively. In addition, compounds 1 and 3 displayed weak DPPH radical scavenging activities. The andrastins and sesquicaranes in this study enriched the structural diversity of these classes of terpenoids. Of note, this study is the first report on the metabolites of a fungus isolated from P. koraiensis seed.

New Meroterpenoids and α-Pyrone Derivatives Isolated from the Mangrove Endophytic Fungal Strain Aspergillus sp. GXNU-Y85.

Two new meroterpenoids, aspergienynes O and P (1 and 2), one new natural compound, aspergienyne Q (3), and a new α-pyrone derivative named 3-(4-methoxy-2-oxo-2H-pyran-6-yl)butanoic acid (4) were isolated from the mangrove endophytic fungal strain Aspergillus sp. GXNU-Y85, along with five known compounds (5-9). The absolute configurations of those new isolates were confirmed through extensive analysis using spectroscopic data (HRESIMS, NMR, and ECD). The pharmacological study of the anti-proliferation activity indicated that isolates 5 and 9 displayed moderate inhibitory effects against HeLa and A549 cells, with the IC50 values ranging from 16.6 to 45.4 µM.

Isolation and Structure Determination of New Pyrones from Dictyostelium spp. Cellular Slime Molds Coincubated with Pseudomonas spp.

Cellular slime molds are excellent model organisms in the field of cell and developmental biology because of their simple developmental patterns. During our studies on the identification of bioactive molecules from secondary metabolites of cellular slime molds toward the development of novel pharmaceuticals, we revealed the structural diversity of secondary metabolites. Cellular slime molds grow by feeding on bacteria, such as Klebsiella aerogenes and Escherichia coli, without using medium components. Although changing the feeding bacteria is expected to affect dramatically the secondary metabolite production, the effect of the feeding bacteria on the production of secondary metabolites is not known. Herein, we report the isolation and structure elucidation of clavapyrone (1) from Dictyostelium clavatum, intermedipyrone (2) from D. magnum, and magnumiol (3) from D. intermedium. These compounds are not obtained from usual cultural conditions with Klebsiella aerogenes but obtained from coincubated conditions with Pseudomonas spp. The results demonstrate the diversity of the secondary metabolites of cellular slime molds and suggest that widening the range of feeding bacteria for cellular slime molds would increase their application potential in drug discovery.

α-Pyrone mediates quorum sensing through the conservon system in Nocardiopsis sp.

Actinobacteria produce a plethora of bioactive secondary metabolites that are often regulated by quorum-sensing signaling molecules via specific binding to their cognate TetR-type receptors. Here, we identified monocyclic α-pyrone as a new class of actinobacterial signaling molecules influencing quorum sensing process in Nocardiopsis sp. LDBS0036, primarily evidenced by a significant reduction in the production of phenazines in the pyrone-null mutant compared to the wild-type strain. Exogenous addition of the α-pyrone can partially restore the expression of some pathways to the wild strain level. Moreover, a unique multicomponent system referred to as a conservon, which is widespread in actinobacteria and generally contains four or five functionally conserved proteins, may play an important role in detecting and transmitting α-pyrone signals in LDBS0036. We found the biosynthetic gene clusters of α-pyrone and their associated conservon genes are highly conserved in Nocardiopsis, indicating the widespread prevalence and significant function of this regulate mechanism within Nocardiopsis genus. Furthermore, homologous α-pyrones from different actinobacterial species were also found to mediate interspecies communication. Our results thus provide insights into a novel quorum-sensing signaling system and imply that various modes of bacterial communication remain undiscovered.

Coumarin-Synthetic Methodologies, Pharmacology, and Application as Natural Fluorophore.

Coumarins are secondary metabolites made up of benzene and α-pyrone rings fused together that can potentially treat various ailments, including cancer, metabolic, and degenerative disorders. Coumarins are a diverse category of both naturally occurring as well as synthesized compounds with numerous biological and therapeutic properties. Coumarins as fluorophores play a key role in fluorescent labeling of biomolecules, metal ion detection, microenvironment polarity detection, and pH detection. This review provides a detailed insight into the characteristics of coumarins as well as their biosynthesis in plants and metabolic pathways. Various synthetic strategies for coumarin core involving both conventional and green methods have been discussed comparing advantages and disadvantages of each method. Conventional methods discussed are Pechmann, Knoevenagel, Perkin, Wittig, Kostanecki, Buchwald-Hartwig, and metal-induced coupling reactions such as Heck and Suzuki, as well as green approaches involving microwave or ultrasound energy. Various pharmacological applications of coumarin derivatives are discussed in detail. The structural features and conditions responsible for influencing the fluorescence of coumarin core are also elaborated.

Bioactive α-Pyrone Analogs from the Endophytic Fungus Diaporthe sp. CB10100: α-Glucosidase Inhibitory Activity, Molecular Docking, and Molecular Dynamics Studies.

Two α-pyrone analogs were isolated from the endophytic fungus Diaporthe sp. CB10100, which is derived from the medicinal plant Sinomenium acutum. These analogs included a new compound, diaporpyrone F (3), and a known compound, diaporpyrone D (4). The structure of 3 was identified by a comprehensive examination of HRESIMS, 1D and 2D NMR spectroscopic data. Bioinformatics analysis revealed that biosynthetic gene clusters for α-pyrone analogs are common in fungi of Diaporthe species. The in vitro α-glucosidase inhibitory activity and antibacterial assay of 4 revealed that it has a 46.40% inhibitory effect on α-glucosidase at 800 µM, while no antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), Mycolicibacterium (Mycobacterium) smegmatis or Klebsiella pneumoniae at 64 µg/mL. Molecular docking and molecular dynamics simulations of 4 with α-glucosidase further suggested that the compounds are potential α-glucosidase inhibitors. Therefore, α-pyrone analogs can be used as lead compounds for α-glucosidase inhibitors in more in-depth studies.

Enzymatic one-step synthesis of natural 2-pyrones and new-to-nature derivatives from coenzyme A esters.

The 2-pyrone moiety is present in a wide range of structurally diverse natural products with various biological activities. The plant biosynthetic routes towards these compounds mainly depend on the activity of either type III polyketide synthase-like 2-pyrone synthases or hydroxylating 2-oxoglutarate dependent dioxygenases. In the present study, the substrate specificity of these enzymes is investigated by a systematic screening using both natural and artificial substrates with the aims of efficiently forming (new) products and understanding the underlying catalytic mechanisms. In this framework, we focused on the in vitro functional characterization of a 2-pyrone synthase Gh2PS2 from Gerbera x hybrida and two dioxygenases AtF6'H1 and AtF6'H2 from Arabidopsis thaliana using a set of twenty aromatic and aliphatic CoA esters as substrates. UHPLC-ESI-HRMSn based analyses of reaction intermediates and products revealed a broad substrate specificity of the enzymes, enabling the facile "green" synthesis of this important class of natural products and derivatives in a one-step/one-pot reaction in aqueous environment without the need for halogenated or metal reagents and protective groups. Using protein modeling and substrate docking we identified amino acid residues that seem to be important for the observed product scope.

Critical sample collection delayed? Urine organic acid analysis can still save the day! A new case of HMG-CoA synthase deficiency.

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase (mHS) deficiency is an autosomal recessive disorder of ketone body synthesis caused by biallelic pathogenic variants in HMGCS2. Clinical symptoms are precipitated by prolonged fasting and/or intercurrent illness with onset before the first year of life. Clinically, patients may present with hypo-/ non-ketotic hypoglycemia, metabolic acidosis, hyperammonemia, lethargy, hepatomegaly, and encephalopathy. During periods of decompensation, elevations of 4-hydroxy-6-methyl-2-pyrone (4-HMP), several hydroxylated hexanoic and hexenoic acid species, and medium-chain dicarboxylic acids in the absence of significant ketonuria may be observed in the urine organic acid profile. Abnormalities may also be observed in plasma which includes elevated acetylcarnitine (C2) and 3-hydroxybutyryl/3-hydroxyisobutyryl (C4-OH) carnitine. We report a patient who presented to the ED at 13 months of age with an undetectable point-of-care blood glucose level. Continuous infusion of dextrose-containing intravenous (IV) fluids were required to correct the hypoglycemia and routine chemistries were notable for an anion gap metabolic acidosis, transaminasemia, and elevated creatine kinase and lactate dehydrogenase. Urine and blood ketones were undetectable. Qualitative assessment of urine organic acids collected ∼46 and âˆ¼ 99 h post-admission were significant for mild elevations of 4-HMP and hydroxy-hexanoic and hydroxy-hexenoic acid species with a notable absence of ketones. Previously, biochemical abnormalities in urine have been shown to normalize in as few as 27 h after treatment giving providers a narrow window with which to obtain a critical sample. Direct communication of laboratory findings to the ordering provider guided the molecular testing and assisted in results interpretation to confirm the molecular diagnosis. Our case emphasizes the importance of collecting samples for biochemical analysis even if the critical period has been missed and acute metabolic decompensation seems to be resolved, as residual abnormalities observed in our patient greatly narrowed the differential diagnosis.

Novel triterpenoid pyrones, phthalimides and phthalates are selectively cytotoxic in CCRF-CEM cancer cells - Synthesis, potency, and mitochondrial mechanism of action.

A series of triterpenoid pyrones was synthesized and subsequently modified to introduce phthalimide or phthalate moieties into the triterpenoid skeleton. These compounds underwent in vitro cytotoxicity screening, revealing that a subset of six compounds exhibited potent activity, with IC50 values in the low micromolar range. Further biological evaluations, including Annexin V and propidium iodide staining experiment revealed, that all compounds induce selective apoptosis in cancer cells. Measurements of mitochondrial potential, cell cycle analysis, and the expression of pro- and anti-apoptotic proteins confirmed, that apoptosis was mediated via the mitochondrial pathway. These findings were further supported by cell cycle modulation and DNA/RNA synthesis studies, which indicated a significant increase in cell accumulation in the G0/G1 phase and a marked reduction in S-phase cells, alongside a substantial inhibition of DNA synthesis. The activation of caspase-3 and the cleavage of PARP, coupled with a decrease in the expression of Bcl-2 and Bcl-XL proteins, underscored the induction of apoptosis through the mitochondrial pathway. Given their high activity and pronounced effect on mitochondria function, trifluoromethyl pyrones 1f and 2f, and dihydrophthalimide 2h have been selected for further development.

Chemical constituents of Penicillium ferraniaense GE-7 and their cytotoxicities.

Phytochemical investigation on the plant endophytic fungus Penicillium ferraniaense GE-7 led to the isolation of 18 compounds including one new α-pyrone derivative, peniferranige A (1). The structure including the absolute configuration of compound 1 was elucidated by NMR, HRMS, and ECD data. Demethoxyfumitremorgin C (16) and meleagrin (17) possessed moderate activities against the human lung cancer cell line H1975 with IC50 values of 28.52 ± 1.07 and 13.94 ± 1.92 µM, respectively.

Development of a water-soluble fluorescent Al3+ probe based on phenylsulfonyl-2-pyrone in biological systems.

BACKGROUND: Al exists naturally in the environment and is an important component in acidic soils, which harm almost all plants. Furthermore, Al is widely used in food additives, cosmetics, and medicines, resulting in living organisms ingesting traces of Al orally or dermally every day. Accordingly, Al accumulates in the body, which can cause negative bioeffects and diseases, and this concern is gaining increasing attention. Therefore, to detect and track Al in the environment and in living organisms, the development of novel Al-selective probes that are water-soluble and exhibit fluorescence at long wavelengths is necessary. RESULTS: In this study, an Al3+-selective fluorescent probe PSP based on a novel pyrone molecule was synthesized and characterized to detect and track Al in biological systems. PSP exhibited fluorescence enhancement at 580 nm in the presence of Al3+ in aqueous media. Binding analysis using Job's plot and structural analysis using 1H NMR showed that PSP formed a 1:1 complex with Al3+ at the two carbonyl groups of the dimethyl malonate of the pyrone ring. Upon testing in biological systems, PSP showed good cell membrane permeability, detected intracellular Al3+ in human breast cancer cells (MDA-MB-231), and successfully imaged accumulated Al3+ in Microcystis aeruginosa and the larvae of Rheocricotopus species. SIGNIFICANCE: The novel Al3+-selective fluorescent probe PSP is highly effective and is expected to aid in elucidating the role of Al3+ in the environment and living organisms.

New Hydroxyphenylacetic Acids and α-Pyrone Derivative from the Deep-Sea Cold Seep Sediment-Derived Fungus Penicillium corylophilum CS-682.

Two pairs of new enantiomeric hydroxyphenylacetic acid derivatives, (±)-corylophenols A and B ((±)-1 and (±)-2), a new α-pyrone analogue, corylopyrone A (3), and six andrastin-type meroterpenoids (4-9) were isolated and identified from the deep-sea cold-seep sediment-derived fungus Penicillium corylophilum CS-682. Their structures and stereo configurations were determined by detailed spectroscopic analysis of NMR and MS data, chiral HPLC analysis, J-based configuration analysis, and quantum chemical calculations of ECD, specific rotation, and NMR (with DP4+ probability analysis). Compound 3 showed inhibitory activity against some strains of pathogenic bacteria.

An unusual 2-O-glyceryl-glycosyl-γ-pyrone from Erigeron annuus (L.) with potential antifungal activity: in-vitro and in-silico study.

Phytochemical characterisation of the polar fraction of Erigeron annuus extract led to the isolation of glycerylerigeroside (1), a unique γ-pyrone derivative. Structure of 1 was decided by intensive study of NMR and mass spectra as 3-O-[4'-((1,3-dihydroxypropan-2-yl)oxy)-ß-D-glucopyranoside)]-4H-pyran-4-one, with uncommon glyceroxy side chain attached to 4' position of pyromeconic acid ß-D-glucopyranoside. Antimicrobial potential of 1 was tested against Staphylococcus aureus, Salmonella enterica, and Candida albicans. Compound 1 strongly inhibited growth of Candida albicans (MIC = 17.24 µM/disc), compared to fluconazole (MIC = 16.33 µM/disc). Meanwhile, it moderately inhibited the growth of Staphylococcus aureus (MIC = 71.84 µM/disc) and Salmonella enterica (MIC = 71.84 µM/disc), as compared with thiophenicol (MIC = 14.05 µM/disc) and (MIC = 14.05 µM/disc), respectively. The binding mode of 1 with the active site of sterol 14α-demethylase (CYP51) from Candida albicans (PDB ID: 5TZ1), in combination with fluconazole, was predicted by molecular docking study and supported the antifungal activity.

Hyperhenrones: Prenylated α-pyrones with anti-inflammatory activity from Hypericum henryi.

Fourteen previously undescribed α-pyrone derivatives (1-14) together with four known analogs (15-18) were isolated from a traditional Chinese medicinal plant Hypericum henryi. Compounds (+)/(-)-1, 2, and 3 share a rare 6/6/4/6/6 polycyclic skeleton. Compound 14 was the first example of a 7,7-dimethyl-pyran-4-one moiety. Their structures were elucidated using comprehensive spectroscopic analyses and electronic circular dichroism calculations. The anti-inflammatory activities of 1-18 were screened in lipopolysaccharide-induced RAW264.7 cells. Among them, compounds 14, (+)-18, and (-)-18 exhibited inhibitory effects against nitric oxide production in LPS-induced RAW264.7 cells. Additionally, compound 14 suppressed the expression of cyclooxygenase-2 and inducible nitric oxide synthase in LPS-induced RAW264.7 cells. Furthermore, preliminary mechanism studies indicated that compound 14 suppressed the phosphorylation and degradation of the inhibitor of NF-κB, and this led to the inhibition of NF-κB activation.

Psiguanol, a novel α-pyrone derivative from Psidium guajava leaves and vasorelaxant activity in rat aorta cells through intracellular cGMP-dependent opening of calcium-activated potassium channels.

The phytochemical investigation of Psidium guajava leaves led to the isolation of total nineteen compounds which belongs to meroterpenoids, flavonoid, phenolics, and triterpenoids. The compounds were isolated using extensive chromatography techniques and identified as psiguanol (4), as new compound along with guajadial (1), psidial A (2), ß-caryophyllene (3), quercetin (5), avicularin (6), guaijaverin (7), hyperin (8), rutin (9), ursolic acid (10), corosolic acid (11), asiatic acid (12), ß-sitosterol (13), ß-sitosterol-D-glucoside (14), ellagic acid (15), 3,3',4'-trimethylellagic acid 4-O-glucoside (16), protocatechuic acid (17), gallic acid (18), and tricosanoic acid (19) as known molecules. The compound 16 was isolated for the first time from this plant. The isolated compounds were evaluated for vasorelaxation activity in rat aorta cells and it was observed that compound 4 exhibited the most potent vasorelaxation response in the ex-vivo model in isolated rat aorta cells. Mechanistically, the vasorelaxation activity of 4 was mediated through cGMP-dependent BKCa channel opening.

6-Pentyl-α-Pyrone from Trichoderma gamsii Exert Antioxidant and Anti-Inflammatory Properties in Lipopolysaccharide-Stimulated Mouse Macrophages.

Filamentous fungi produce several beneficial secondary metabolites, including bioactive compounds, food additives, and biofuels. Trichoderma, which is a teleomorphic Hypocrea that falls under the taxonomic groups Ascomycota and Dikarya, is an extensively studied fungal genus. In an ongoing study that seeks to discover bioactive natural products, we investigated potential bioactive metabolites from the methanolic extract of cultured Trichoderma gamsii. Using liquid chromatography-mass spectrometry (LC-MS), one major compound was isolated and structurally identified as 6-pentyl-α-pyrone (6PP) based on nuclear magnetic resonance data and LC-MS analysis. To determine its antioxidant and anti-inflammatory activity, as well as the underlying mechanisms, we treated lipopolysaccharide (LPS)-stimulated Raw264.7 mouse macrophages with 6PP. We found that 6PP suppresses LPS-induced increase in the levels of nitric oxide, a mediator of oxidative stress and inflammation, and restores LPS-mediated depletion of total glutathione by stabilizing nuclear factor erythroid 2-related factor 2 (Nrf2), an antioxidative factor, and elevating heme oxygenase-1 levels. Furthermore, 6PP inhibited LPS-induced production of proinflammatory cytokines, which are, at least in part, regulated by heme oxygenase-1 (HO-1). 6PP suppressed proinflammatory responses by inhibiting the nuclear localization of nuclear factor kappa B (NF-κB), as well as by dephosphorylating the mitogen-activated protein kinases (MAPKs). These results indicate that 6PP can protect macrophages against oxidative stress and LPS-induced excessive inflammatory responses by activating the Nrf2/HO-1 pathway while inhibiting the proinflammatory, NF-κB, and MAPK pathways.