Replacing crude oil as the primary industrial source of carbon‐based chemicals has become crucial for both environmental and resource sustainability reasons. In this scenario, wood arises as an ...excellent candidate, whilst depolymerization approaches have emerged as promising strategies to unlock the lignin potential as a resource in the production of high‐value organic chemicals. However, many drawbacks, such as toxic solvents, expensive catalysts, high energy inputs, and poor product selectivity have represented major challenges to this task. Herein, we present an unprecedented approach using electrocatalysis for the simultaneous depolymerization and dearomatization of lignin in aqueous medium under ambient conditions. By employing water/sodium carbonate as a solvent system, we demonstrated a pathway for selectively depolymerizing lignin under reductive electrochemical conditions using carbon as an electrocatalyst. After reductive electrocatalysis, the presence of aromatic compounds was no longer detected via nuclear magnetic resonance (NMR) spectroscopy. Further characterization by NMR, FTIR spectroscopy, and mass spectrometry revealed the major presences of sodium levulinate, sodium 4‐hydroxyvalerate, sodium formate, and sodium acetate as products. By achieving a complete dearomatization, valuable aliphatic intermediates with enhanced reactivity were selectively obtained, opening new avenues for further synthesis of many different organic chemicals, and contributing to a more sustainable and circular economy.
An unprecedented strategy has been proposed, using electrocatalysis to selectively depolymerize lignin into valuable aliphatic compounds in an aqueous solvent system under ambient conditions. Our innovative approach breaks down lignin‘s aromatic structure, yielding sodium levulinate, sodium 4‐hydroxyvalerate, sodium formate, and sodium acetate as major products, representing an important milestone into lignin valorization and sustainability.
Triclosan (TCS), a high-production-volume chemical used as a bactericide in personal care products, is a priority pollutant of growing concern to human and environmental health. TCS is capable of ...altering the activity of type 1 ryanodine receptor (RyR1), but its potential to influence physiological excitation–contraction coupling (ECC) and muscle function has not been investigated. Here, we report that TCS impairs ECC of both cardiac and skeletal muscle in vitro and in vivo. TCS acutely depresses hemodynamics and grip strength in mice at doses ≥12.5 mg/kg i.p., and a concentration ≥0.52 μM in water compromises swimming performance in larval fathead minnow. In isolated ventricular cardiomyocytes, skeletal myotubes, and adult flexor digitorum brevis fibers TCS depresses electrically evoked ECC within ∼10–20 min. In myotubes, nanomolar to low micromolar TCS initially potentiates electrically evoked Ca ²⁺ transients followed by complete failure of ECC, independent of Ca ²⁺ store depletion or block of RyR1 channels. TCS also completely blocks excitation-coupled Ca ²⁺ entry. Voltage clamp experiments showed that TCS partially inhibits L-type Ca ²⁺ currents of cardiac and skeletal muscle, and ³HPN200 binding to skeletal membranes is noncompetitively inhibited by TCS in the same concentration range that enhances ³Hryanodine binding. TCS potently impairs orthograde and retrograde signaling between L-type Ca ²⁺ and RyR channels in skeletal muscle, and L-type Ca ²⁺ entry in cardiac muscle, revealing a mechanism by which TCS weakens cardiac and skeletal muscle contractility in a manner that may negatively impact muscle health, especially in susceptible populations.
Omega-6 polyunsaturated fatty acid (
-6 PUFA) is the predominant polyunsaturated fatty acid (PUFA), especially in Western diet. A high omega-6/omega-3 ratio in Western diets is implicated in the ...development of cardiovascular diseases and inflammatory processes. Studies in animal models and in humans have demonstrated beneficial effects of omega-3 PUFA (
-3 PUFA) in a variety of diseases, including cardiac arrhythmias and inflammatory diseases, as well as breast and colon cancer. The molecular mechanisms underlying the effects of
-3 PUFA are still not well understood. Possible mechanisms include competition between
-3 and
-6 PUFAs at the cyclooxygenase (COX) and lipoxygenase (LOX) and cytochrome P450 levels, and subsequent formation of oxylipins with specific anti-inflammatory or anti-arrhythmic effects. In this study, we report the impact of routine long-term treatment with prescription-grade
-3 PUFA (either 840 mg or 1680 mg per day) on blood cell membrane fatty acid composition, as well as plasma oxylipin patterns, in a patient population with severe hyperlipidemia and cardiovascular disease who are on standard lipid-lowering and cardioprotective medications. Lipidomics analyses were performed by LC/ESI-MS/MS. Supplementation led to a dose-dependent increase in
-3 PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the blood cell fraction. We also observed a dose-dependent increase in EPA- and DHA-derived epoxy metabolites, whereas the effect of
-3 PUFA supplementation on LOX-dependent EPA- and DHA-derived hydroxy metabolites was less pronounced, with a tendency towards lower metabolites in subjects with higher
-3 PUFA levels. These data thus generally confirm effects of
-3 PUFA supplementation observed previously in healthy individuals. Additionally, they indicate a suppressive effect of high
-3 PUFA supplementation on the formation of LOX metabolites in the context of concomitant aspirin medication.
Hepatocellular carcinoma (HCC) is a leading cause of cancer death. The multikinase inhibitor sorafenib is widely used for systemic therapy in advanced HCC. Sorafenib might affect epoxyeicosanoids, as ...it is also a potent inhibitor of the soluble epoxide hydrolase (sEH), which catalyzes the conversion of epoxides derived from long-chain polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and omega-3 docosahexaenoic acid (DHA), into their corresponding diols. Experimental studies with AA-derived epoxyeicosatrienoic acids (EETs) showed that they can promote tumor growth and metastasis, while DHA-derived 19,20-epoxydocosapentaenoic acid (19,20-EDP) was shown to have anti-tumor activity in mice. In this pilot study, we assessed the effect of sorafenib treatment on the presence of lipid mediators, such as EETs, in blood of the patients with HCC using the lipidomics technology. We found a significant increase in 11,12-EET and 14,15-EET levels in HCC patients treated with sorafenib. Furthermore, while not significant in this small sample set, the data presented indicate that sorafenib can also increase the level of omega-3 DHA-derived 19,20-EDP. While the effect on EETs might hamper the anti-tumor effect of sorafenib, we hypothesize that supplementation of DHA in sorafenib-treated HCC patients could increase the level of 19,20-EDP and thereby enhance its anti-tumor effect.
Macrophage polarization switches during the course of inflammation along with the lipid mediators released. We investigated the lipid mediator formation in human monocyte-derived macrophages during ...in vitro differentiation and pathogen stimulation. For this, peripheral blood monocytes were differentiated into M1 (CSF-2/IFNγ) or M2 (CSF-1/IL-4) macrophages followed by stimulation with the toll-like receptor (TLR) ligands zymosan (TLR-2), Poly(I:C) (TLR-3) or bacterial lipopolysaccharides (TLR-4) mimicking fungal, viral and bacterial infection, respectively. Expression of enzymes involved in lipid mediator formation such as 5- and 15-lipoxygenases (LO), the 5-LO activating protein and cyclooxygenase-2 (COX-2) was monitored on mRNA and protein level and lipid mediator formation was assessed. In addition, cytokine release was measured. In vitro differentiation of human peripheral blood monocytes to M1 and M2 macrophages considerably attenuated 5-LO activity. Furthermore, while TLR-2 and -4 stimulation of M1 macrophages primarily triggered pro-inflammatory cytokines and lipid mediators, persistent stimulation (16 h) of human M2 macrophages induced a coordinated upregulation of 5- and 15-LO-2 expression. This was accompanied by a marked increase in IL-10 and monohydroxylated 15-LO products in the conditioned media of the cells. After additional stimulation with Ca2+ ionophore combined with supplementation of arachidonic, eicosapentaenoic and docosahexaenoic acid these cells also released small amounts of SPM such as lipoxins and resolvins. From this we conclude that activation of TLR-2 or -4 triggers the biosynthesis of pro-inflammatory 5-LO and COX-2 derived lipid mediators in human monocyte-derived M1 macrophages while persistent stimulation of M2 macrophages induces a shift towards pro-resolving 15-LO derived oxylipins.
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•In vitro monocyte to macrophage differentiation inhibits 5-LO activity.•Persistent TLR-2/-4 activation elevates 5-/15-LO-2 expression in M2 macrophages.•15-LO products increase after persistent TLR-2/-4 stimulation in M2 macrophages.•SPM in M2 macrophages after persistent TLR-4 stimulation only after ionophore use
Pain is a major health concern even though numerous analgesic agents are available. Side effects and lack of wide-spectrum efficacy of current drugs justify efforts to better understand pain ...mechanisms. Stabilization of natural epoxy-fatty acids (EFAs) through inhibition of the soluble epoxide hydrolase (sEH) reduces pain. However, in the absence of an underlying painful state, inhibition of sEH is ineffective. Surprisingly, a pain-mediating second messenger, cAMP, interacts with natural EFAs and regulates the analgesic activity of sEH inhibitors. Concurrent inhibition of sEH and phosphodiesterase (PDE) dramatically reduced acute pain in rodents. Our findings demonstrate a mechanism of action of cAMP and EFAs in the pathophysiology of pain. Furthermore, we demonstrate that inhibition of various PDE isozymes, including PDE4, lead to significant increases in EFA levels through a mechanism independent of sEH, suggesting that the efficacy of commercial PDE inhibitors could result in part from increasing EFAs. The cross-talk between the two major pathways—one mediated by cAMP and the other by EFAs—paves the way to new approaches to understand and control pain.
The nerve damage occurring as a consequence of glucose toxicity in diabetes leads to neuropathic pain, among other problems. This pain dramatically reduces the quality of life in afflicted patients. ...The progressive damage to the peripheral nervous system is irreversible although strict control of hyperglycemia may prevent further damage. Current treatments include tricyclic antidepressants, anticonvulsants, and opioids, depending on the severity of the pain state. However, available therapeutics have drawbacks, arguing for the need to better understand the pathophysiology of neuropathic pain and develop novel treatments. Here we demonstrate that stabilization of a class of bioactive lipids, epoxygenated fatty acids (EpFAs), greatly reduces allodynia in rats caused by streptozocin-induced type I diabetes. Inhibitors of the soluble epoxide hydrolase (sEHI) elevated and stabilized the levels of plasma and spinal EpFAs, respectively, and generated dose-dependent antiallodynic effects more potently and efficaciously than gabapentin. In acute experiments, positive modulation of EpFAs did not display differences in insulin sensitivity, glucose tolerance, or insulin secretion, indicating the efficacy of sEHIs are not related to the glycemic status. Quantitative metabolomic analysis of a panel of 26 bioactive lipids demonstrated that sEHI-mediated antiallodynic effects coincided with a selective elevation of the levels of EpFAs in the plasma, and a decrease in degradation products coincided with the dihydroxy fatty acids in the spinal cord. Overall, these results argue that further efforts in understanding the spectrum of effects of EpFAs will yield novel opportunities in treating neuropathic pain.
Objective
This study aimed to assess polyunsaturated fatty acid (PUFA) status and association with systemic inflammation and fish consumption in systemic lupus erythematosus (SLE).
Methods
Parameters ...of PUFA status including the proportion of omega-6 and -3 fatty acids in highly unsaturated fatty acids (omega-6%, omega-3%), essential fatty acids linoleic acid (LA) and alpha-linolenic acid (ALA), the omega-6 PUFA arachidonic acid (ARA) and the sum of key omega-3 PUFA eicosapentaenoic acid+docosahexaenoic acid (omega-3 status) were measured by gas chromatography in 68 SLE patients (88.2% female, aged 45.7±12.5 years). Associations with serum CRP, disease activity, damage and fish consumption were assessed by linear regression modelling adjusted for age, sex and body mass index. Associations are reported in terms of regression coefficients (β).
Results
Omega-6 PUFA were associated with higher CRP: omega-6% (β = 0.052, p = 0.02), the ratio of LA/ALA (β = 0.007, p = 0.02) and ARA (β = 0.308, p = 0.001). Conversely, omega-3% was associated with lower CRP (β = −0.051, p = 0.02). Increased dietary PUFA consumption from fish (g/day) was linked to a higher omega-3 status (β = 2.21, p = 0.02) and lower self-reported damage (Brief Index of Lupus Damage; β = −3.22, p = 0.02).
Conclusions
Omega-3 and omega-6 fatty acid status differentially reflect systemic inflammation in SLE and are linked to fish consumption.
The Alternaria toxins alternariol (AOH; 3,7,9‐trihydroxy‐1‐methyl‐6H‐benzocchromen‐6‐one) and alternariol methyl ether (AME, 3,7‐dihydroxy‐9‐methoxy‐1‐methyl‐6H‐benzocchromen‐6‐one) are common ...contaminants of food and feed, but their oxidative metabolism in mammals is as yet unknown. We have therefore incubated AME and AOH with microsomes from rat, human, and porcine liver and analyzed the microsomal metabolites with HPLC and GC‐MS/MS. Seven oxidative metabolites of AME and five of AOH were detected. Their chemical structures were derived from their mass spectra using deuterated trimethylsilyl (TMS) derivatives, and from the information obtained from enzymatic methylation. Several of the metabolites were identified by comparison with synthetic reference compounds. AME as well as AOH were monohydroxylated at each of the four possible aromatic carbon atoms and also at the methyl group. In addition, AME was demethylated to AOH and dihydroxylated to a small extent. As the four metabolites arising through aromatic hydroxylation of AME and AOH are either catechols or hydroquinones, the oxidative metabolism of these mycotoxins may be of toxicological significance.
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