Lipid-Lowering Meroterpenoids Penihemeroterpenoids A-F from Penicillium herquei GZU-31-6 via Targeting the AMPK/ACC/SREBP-1c Signaling Pathway.

Penihemeroterpenoids A-C, the first meroterpenoids with an unprecedented 6/5/6/5/5/6/5 heptacyclic ring system, together with precursors penihemeroterpenoids D-F, were co-isolated from the fungus Penicillium herquei GZU-31-6. Among them, penihemeroterpenoids C-F exhibited lipid-lowering effects comparable to those of the positive control simvastatin by the activation of the AMPK/ACC/SREBP-1c signaling pathway, downregulated the mRNA levels of lipid synthesis genes FAS and PNPLA3, and increased the level of mRNA expression of the lipid export gene MTTP.

Acetyl-CoA carboxylase inhibitor increases LDL-apoB production rate in NASH with cirrhosis: prevention by fenofibrate.

Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4-45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.

Fenofibrate Mitigates Hypertriglyceridemia in Nonalcoholic Steatohepatitis Patients Treated With Cilofexor/Firsocostat.

BACKGROUND & AIMS: Patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH) are at high risk of morbidity and mortality. We previously found that a combination of the farnesoid X receptor agonist cilofexor (CILO) and the acetyl-CoA carboxylase inhibitor firsocostat (FIR) improved liver histology and biomarkers in NASH with advanced fibrosis but was associated with hypertriglyceridemia. We evaluated the safety and efficacy of icosapent ethyl (Vascepa) and fenofibrate to mitigate triglyceride elevations in patients with NASH treated with CILO and FIR. METHODS: Patients with NASH with elevated triglycerides (≥150 and <500 mg/dL) were randomized to Vascepa 2 g twice daily (n = 33) or fenofibrate 145 mg daily (n = 33) for 2 weeks, followed by the addition of CILO 30 mg and FIR 20 mg daily for 6 weeks. Safety, lipids, and liver biochemistry were monitored. RESULTS: All treatments were well-tolerated; most treatment-emergent adverse events were Grade 1 to 2 severity, and there were no discontinuations due to adverse events. At baseline, median (interquartile range [IQR]) triglycerides were similar in the Vascepa and fenofibrate groups (median, 177 [IQR, 154-205] vs 190 [IQR, 144-258] mg/dL, respectively). Median changes from baseline in triglycerides for Vascepa vs fenofibrate after 2 weeks of pretreatment were -12 mg/dL (IQR, -33 to 7 mg/dL; P = .09) vs -32 mg/dL (IQR, -76 to 6 mg/dL; P = .012) and at 6 weeks were +41 mg/dL (IQR, 16-103 mg/dL; P < .001) vs -2 mg/dL (IQR, -42 to 54 mg/dL; P = .92). In patients with baseline triglycerides <250 mg/dL, fenofibrate was more effective vs Vascepa in mitigating triglyceride increases after 6 weeks of combination treatment (+6 vs +39 mg/dL); similar trends were observed in patients with baseline triglycerides ≥250 mg/d (-61 vs +99 mg/dL). CONCLUSIONS: In patients with NASH with hypertriglyceridemia treated with CILO and FIR, fenofibrate was safe and effectively mitigated increases in triglycerides associated with acetyl-CoA carboxylase inhibition. CLINICALTRIALS: gov, Number: NCT02781584.

Total Synthesis of the Acetyl CoA Carboxylase Inhibitor Soraphen A: Asymmetric Tsuji Reduction Enables Successive Olefin Metathesis.

The total synthesis of soraphen A, a myxobacterial metabolite and inhibitor of acetyl CoA carboxylase, was completed in 11 steps (longest linear sequence), less than half the steps previously required. Seven metal-catalyzed processes were deployed to unlock step-economy (comprising five asymmetric processes and four C-C bond formations). The present route does not utilize chiral auxiliaries, and four of five C-C bond formations exploit non-premetalated partners. To maximize convergency, an asymmetric Tsuji reduction was developed using a Pd-AntPhos catalyst that allows a metathesis-inactive allylic carbonate to serve as a masked terminal olefin, thereby enabling successive olefin metathesis events.

Targeting ACC for NASH resolution.

A recent paper published in Nature Medicine by Calle et al. reported anti-nonalcoholic steatohepatitis (NASH) efficiencies by acetyl-CoA carboxylase (ACC) 1/2 inhibitors alone or by co-administration with a ACC1/2 inhibitor and a diacylglycerol acyltransferase 2 (DGAT2) inhibitor. Whereas the monotherapy achieved remarkable reductions in liver steatosis but induced hyperlipidemia, DGAT2 inhibitor co-administration mitigated the increase in serum triglycerides (TGs).

Acetyl-CoA Carboxylase Inhibitor CP640.186 Increases Tubulin Acetylation and Impairs Thrombin-Induced Platelet Aggregation.

Acetyl-CoA carboxylase (ACC) is the first enzyme regulating de novo lipid synthesis via the carboxylation of acetyl-CoA into malonyl-CoA. The inhibition of its activity decreases lipogenesis and, in parallel, increases the acetyl-CoA content, which serves as a substrate for protein acetylation. Several findings support a role for acetylation signaling in coordinating signaling systems that drive platelet cytoskeletal changes and aggregation. Therefore, we investigated the impact of ACC inhibition on tubulin acetylation and platelet functions. Human platelets were incubated 2 h with CP640.186, a pharmacological ACC inhibitor, prior to thrombin stimulation. We have herein demonstrated that CP640.186 treatment does not affect overall platelet lipid content, yet it is associated with increased tubulin acetylation levels, both at the basal state and after thrombin stimulation. This resulted in impaired platelet aggregation. Similar results were obtained using human platelets that were pretreated with tubacin, an inhibitor of tubulin deacetylase HDAC6. In addition, both ACC and HDAC6 inhibitions block key platelet cytoskeleton signaling events, including Rac1 GTPase activation and the phosphorylation of its downstream effector, p21-activated kinase 2 (PAK2). However, neither CP640.186 nor tubacin affects thrombin-induced actin cytoskeleton remodeling, while ACC inhibition results in decreased thrombin-induced reactive oxygen species (ROS) production and extracellular signal-regulated kinase (ERK) phosphorylation. We conclude that when using washed human platelets, ACC inhibition limits tubulin deacetylation upon thrombin stimulation, which in turn impairs platelet aggregation. The mechanism involves a downregulation of the Rac1/PAK2 pathway, being independent of actin cytoskeleton.

Impact of a Novel W2027L Mutation and Non-Target Site Resistance on Acetyl-CoA Carboxylase-Inhibiting Herbicides in a French Lolium multiflorum Population.

Herbicides that inhibit acetyl-CoA carboxylase (ACCase) are among the few remaining options for the post-emergence control of Lolium species in small grain cereal crops. Here, we determined the mechanism of resistance to ACCase herbicides in a Lolium multiflorum population (HGR) from France. A combined biological and molecular approach detected a novel W2027L ACCase mutation that affects aryloxyphenoxypropionate (FOP) but not cyclohexanedione (DIM) or phenylpyraxoline (DEN) subclasses of ACCase herbicides. Both the wild-type tryptophan and mutant leucine 2027-ACCase alleles could be positively detected in a single DNA-based-derived polymorphic amplified cleaved sequence (dPACS) assay that contained the targeted PCR product and a cocktail of two discriminating restriction enzymes. Additionally, we identified three well-characterised I1781L, I2041T, and D2078G ACCase target site resistance mutations as well as non-target site resistance in HGR. The non-target site component endowed high levels of resistance to FOP herbicides whilst partially impacting on the efficacy of pinoxaden and cycloxydim. This study adequately assessed the contribution of the W2027L mutation and non-target site mechanism in conferring resistance to ACCase herbicides in HGR. It also highlights the versatility and robustness of the dPACS method to simultaneously identify different resistance-causing alleles at a single ACCase codon.

ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.

Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD. The first study ( NCT03248882 ) examined the effects of monotherapy with a novel ACC1/2 inhibitor, PF-05221304 (2, 10, 25 and 50 mg once daily (QD)), versus placebo at 16 weeks of treatment; the second study ( NCT03776175 ) investigated the effects of PF-05221304 (15 mg twice daily (BID)) co-administered with a DGAT2 inhibitor, PF-06865571 (300 mg BID), versus placebo after 6 weeks of treatment. The primary endpoint in both studies was percent change from baseline in liver fat assessed by magnetic resonance imaging-proton density fat fraction. Dose-dependent reductions in liver fat reached 50-65% with PF-05221304 monotherapy doses ≥10 mg QD; least squares mean (LSM) 80% confidence interval (CI) was -7.2 (-13.9, 0.0), -17.1 (-22.7, -11.1), -49.9 (-53.3, -46.2), -55.9 (-59.0, -52.4) and -64.8 (-67.5, -62.0) with 16 weeks placebo and PF-05221304 2, 10, 25 and 50 mg QD, respectively. The overall incidence of adverse events (AEs) did not increase with increasing PF-05221304 dose, except for a dose-dependent elevation in serum triglycerides (a known consequence of hepatic acetyl-coenzyme A carboxylase (ACC) inhibition) in 23/305 (8%) patients, leading to withdrawal in 13/305 (4%), and a dose-dependent elevation in other serum lipids. Co-administration of PF-05221304 and PF-06865571 lowered liver fat compared to placebo (placebo-adjusted LSM (90% CI) -44.6% (-54.8, -32.2)). Placebo-adjusted LSM (90% CI) reduction in liver fat was -44.5% (-55.0, -31.7) and -35.4% (-47.4, -20.7) after 6 weeks with PF-05221304 or PF-06865571 alone. AEs were reported for 10/28 (36%) patients after co-administered PF-05221304 and PF-06865571, with no discontinuations due to AEs, and the ACC inhibitor-mediated effect on serum triglycerides was mitigated, suggesting that PF-05221304 and PF-06865571 co-administration has the potential to address some of the limitations of ACC inhibition alone.

Resistance to post-emergent herbicides is becoming common for grass weeds on New Zealand wheat and barley farms.

To estimate the prevalence of herbicide-resistant weeds, 87 wheat and barley farms were randomly surveyed in the Canterbury region of New Zealand. Over 600 weed seed samples from up to 10 mother plants per taxon depending on abundance, were collected immediately prior to harvest (two fields per farm). Some samples provided by agronomists were tested on an ad-hoc basis. Over 40,000 seedlings were grown to the 2-4 leaf stage in glasshouse conditions and sprayed with high priority herbicides for grasses from the three modes-of-action acetyl-CoA carboxylase (ACCase)-inhibitors haloxyfop, fenoxaprop, clodinafop, pinoxaden, clethodim, acetolactate synthase (ALS)-inhibitors iodosulfuron, pyroxsulam, nicosulfuron, and the 5-enolpyruvyl shikimate 3-phosphate synthase (EPSPS)-inhibitor glyphosate. The highest manufacturer recommended label rates were applied for the products registered for use in New Zealand, often higher than the discriminatory rates used in studies elsewhere. Published studies of resistance were rare in New Zealand but we found weeds survived herbicide applications on 42 of the 87 (48%) randomly surveyed farms, while susceptible reference populations died. Resistance was found for ALS-inhibitors on 35 farms (40%) and to ACCase-inhibitors on 20 (23%) farms. The number of farms with resistant weeds (denominator is 87 farms) are reported for ACCase-inhibitors, ALS-inhibitors, and glyphosate respectively as: Avena fatua (9%, 1%, 0% of farms), Bromus catharticus (0%, 2%, 0%), Lolium spp. (17%, 28%, 0%), Phalaris minor (1%, 6%, 0%), and Vulpia bromoides (0%, not tested, 0%). Not all farms had the weeds present, five had no obvious weeds prior to harvest. This survey revealed New Zealand's first documented cases of resistance in P. minor (fenoxaprop, clodinafop, iodosulfuron) and B. catharticus (pyroxsulam). Twelve of the 87 randomly sampled farms (14%) had ALS-inhibitor chlorsulfuron-resistant sow thistles, mostly Sonchus asper but also S. oleraceus. Resistance was confirmed in industry-supplied samples of the grasses Digitaria sanguinalis (nicosulfuron, two maize farms), P. minor (iodosulfuron, one farm), and Lolium spp. (cases included glyphosate, haloxyfop, pinoxaden, iodosulfuron, and pyroxsulam, 9 farms). Industry also supplied Stellaria media samples that were resistant to chlorsulfuron and flumetsulam (ALS-inhibitors) sourced from clover and ryegrass fields from the North and South Island.

Selective Acetyl-CoA Carboxylase 1 Inhibitor Improves Hepatic Steatosis and Hepatic Fibrosis in a Preclinical Nonalcoholic Steatohepatitis Model.

Acetyl-CoA carboxylase (ACC) 1 and ACC2 are essential rate-limiting enzymes that synthesize malonyl-CoA (M-CoA) from acetyl-CoA. ACC1 is predominantly expressed in lipogenic tissues and regulates the de novo lipogenesis flux. It is upregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), which ultimately leads to the formation of fatty liver. Therefore, selective ACC1 inhibitors may prevent the pathophysiology of NAFLD and nonalcoholic steatohepatitis (NASH) by reducing hepatic fat, inflammation, and fibrosis. Many studies have suggested ACC1/2 dual inhibitors for treating NAFLD/NASH; however, reports on selective ACC1 inhibitors are lacking. In this study, we investigated the effects of compound-1, a selective ACC1 inhibitor for treating NAFLD/NASH, using preclinical in vitro and in vivo models. Compound-1 reduced M-CoA content and inhibited the incorporation of [14C] acetate into fatty acids in HepG2 cells. Additionally, it reduced hepatic M-CoA content and inhibited de novo lipogenesis in C57BL/6J mice after a single dose. Furthermore, compound-1 treatment of 8 weeks in Western diet-fed melanocortin 4 receptor knockout mice-NAFLD/NASH mouse model-improved liver hypertrophy and reduced hepatic triglyceride content. The reduction of hepatic M-CoA by the selective ACC1 inhibitor was highly correlated with the reduction in hepatic steatosis and fibrosis. These findings support further investigations of the use of this ACC1 inhibitor as a new treatment of NFLD/NASH. SIGNIFICANCE STATEMENT: This is the first study to demonstrate that a novel selective inhibitor of acetyl-CoA carboxylase (ACC) 1 has anti-nonalcoholic fatty liver disease (NAFLD) and anti-nonalcoholic steatohepatitis (NASH) effects in preclinical models. Treatment with this compound significantly improved hepatic steatosis and fibrosis in a mouse model. These findings support the use of this ACC1 inhibitor as a new treatment for NAFLD/NASH.

Acetyl-CoA carboxylase 2 inhibition reduces skeletal muscle bioactive lipid content and attenuates progression of type 2 diabetes in Zucker diabetic fatty rats.

Intramyocellular lipid (IMCL) accumulation in skeletal muscle is closely associated with development of insulin resistance. In particular, diacylglycerol and ceramide are currently considered as causal bioactive lipids for impaired insulin action. Recently, inhibition of acetyl-CoA carboxylase 2 (ACC2), which negatively modulates mitochondrial fatty acid oxidation, has been shown to reduce total IMCL content and improve whole-body insulin resistance. This study aimed to investigate whether ACC2 inhibition-induced compositional changes in bioactive lipids, especially diacylglycerol and ceramide, within skeletal muscle contribute to the improved insulin resistance. In skeletal muscle of normal rats, treatment of the ACC2 inhibitor compound 2e significantly decreased both diacylglycerol and ceramide levels while having no significant impact on other lipid metabolite levels. In skeletal muscle of Zucker diabetic fatty (ZDF) rats, which exhibited greater lipid accumulation than that of normal rats, compound 2e significantly decreased diacylglycerol and ceramide levels corresponding to reduced long chain acyl-CoA pools. Additionally, in the lipid metabolomics study, ZDF rats treated with compound 2e also showed improved diabetes-related metabolic disturbance, as reflected by delayed hyperinsulinemia as well as upregulated gene expression associated with diabetic conditions in skeletal muscle. These metabolic improvements were strongly correlated with the bioactive lipid reductions. Furthermore, long-term treatment of compound 2e markedly improved whole-body insulin resistance, attenuated hyperglycemia and delayed insulin secretion defect even at severe diabetic conditions. These findings suggest that ACC2 inhibition decreases diacylglycerol and ceramide accumulation within skeletal muscle by enhancing acyl-CoA breakdown, leading to attenuation of lipid-induced insulin resistance and subsequent diabetes progression.

WNT6/ACC2-induced storage of triacylglycerols in macrophages is exploited by Mycobacterium tuberculosis.

In view of emerging drug-resistant tuberculosis (TB), host-directed adjunct therapies are urgently needed to improve treatment outcomes with currently available anti-TB therapies. One approach is to interfere with the formation of lipid-laden "foamy" macrophages in the host, as they provide a nutrient-rich host cell environment for Mycobacterium tuberculosis (Mtb). Here, we provide evidence that Wnt family member 6 (WNT6), a ligand of the evolutionarily conserved Wingless/Integrase 1 (WNT) signaling pathway, promotes foam cell formation by regulating key lipid metabolic genes including acetyl-CoA carboxylase 2 (ACC2) during pulmonary TB. Using genetic and pharmacological approaches, we demonstrated that lack of functional WNT6 or ACC2 significantly reduced intracellular triacylglycerol (TAG) levels and Mtb survival in macrophages. Moreover, treatment of Mtb-infected mice with a combination of a pharmacological ACC2 inhibitor and the anti-TB drug isoniazid (INH) reduced lung TAG and cytokine levels, as well as lung weights, compared with treatment with INH alone. This combination also reduced Mtb bacterial numbers and the size of mononuclear cell infiltrates in livers of infected mice. In summary, our findings demonstrate that Mtb exploits WNT6/ACC2-induced storage of TAGs in macrophages to facilitate its intracellular survival, a finding that opens new perspectives for host-directed adjunctive treatment of pulmonary TB.

Synthesis and biological evaluation of 4-phenoxy-phenyl isoxazoles as novel acetyl-CoA carboxylase inhibitors.

Acetyl-CoA carboxylase (ACC) is a crucial enzyme in fatty acid metabolism, which plays a major role in the occurrence and development of certain tumours. Herein, one potential ACC inhibitor (6a) was identified through high-throughput virtual screening (HTVS), and a series of 4-phenoxy-phenyl isoxazoles were synthesised for structure-activity relationship (SAR) studies. Among these compounds, 6g exhibited the most potent ACC inhibitory activity (IC50=99.8 nM), which was comparable to that of CP-640186. Moreover, the antiproliferation assay revealed that compound 6l exhibited the strongest cytotoxicity, with IC50 values of 0.22 µM (A549), 0.26 µM (HepG2), and 0.21 µM (MDA-MB-231), respectively. The preliminary mechanistic studies on 6g and 6l suggested that the compounds decreased the malonyl-CoA levels, arrested the cell cycle at the G0/G1 phase, and induced apoptosis in MDA-MB-231 cells. Overall, these results indicated that the 4-phenoxy-phenyl isoxazoles are potential for further study in cancer therapeutics as ACC inhibitors.

Faster lipid ß-oxidation rate by acetyl-CoA carboxylase 2 inhibition alleviates high-glucose-induced insulin resistance via SIRT1/PGC-1α in human podocytes.

Diabetic nephropathy (DN) is becoming a research hotspot in recent years because the prevalence is high and the prognosis is poor. Lipid accumulation in podocytes induced by hyperglycemia has been shown to be a driving mechanism underlying the development of DN. However, the mechanism of lipotoxicity remains unclear. Increasing evidence shows that acetyl-CoA carboxylase 2 (ACC2) plays a crucial role in the metabolism of fatty acid, but its effect in podocyte injury of DN is still unclear. In this study, we investigated whether ACC2 could be a therapeutic target of lipid deposition induced by hyperglycemia in the human podocytes. Our results showed that high glucose (HG) triggered significant lipid deposition with a reduced ß-oxidation rate. It also contributed to the downregulation of phosphorylated ACC2 (p-ACC2), which is an inactive form of ACC2. Knockdown of ACC2 by sh-RNA reduced lipid deposition induced by HG. Additionally, ACC2-shRNA restored the expression of glucose transporter 4 (GLUT4) on the cell surface, which was downregulated in HG and normalized in the insulin signaling pathway. We verified that ACC2-shRNA alleviated cell injury, apoptosis, and restored the cytoskeleton disturbed by HG. Mechanistically, SIRT1/PGC-1α is close related to the insulin metabolism pathway. ACC2-shRNA could restore the expression of SIRT1/PGC-1α, which was downregulated in HG. Rescue experiment revealed that inhibition of SIRT1 by EX-527 counteracted the effect of ACC2-shRNA. Taken together, our data suggest that podocyte injury mediated by HG-induced insulin resistance and lipotoxicity could be alleviated by ACC2 inhibition via SIRT1/PGC-1α.

Computational exploration and anti-mycobacterial activity of potential inhibitors of Mycobacterium tuberculosis acetyl coenzyme A carboxylase as anti-tubercular agents.

Acetyl Coenzyme A Carboxylase (AccD6) is a homodimeric protein which is involved in the carboxylation of acetyl coenzyme A to produce malonyl coenzyme A, which plays an important role in the biosynthesis of fatty acid chain. However, studies suggest that AccD6 in combination with AccA3 produces malonyl co-A. Certain herbicides are known to inhibit plant ACC. Among these herbicides, haloxyfop was found to inhibit AccD6 at IC50 of 21.1 ± 1 µM. In this study, we have performed molecular docking of the Maybridge database consisting of ~55,000 compounds in the active site of the protein with haloxyfop as a reference molecule, followed by molecular dynamics study and biological activity determination of prioritized compounds. Out of the nine compounds selected for biological evaluation, three compounds - CD07230, HTS08529 and KM08871 - were found to exhibit anti-mycobacterial activity.

Design and synthesis of a monocyclic derivative as a selective ACC1 inhibitor by chemical modification of biphenyl ACC1/2 dual inhibitors.

A structure-activity relationship (SAR) study towards novel ACC1-selective inhibitors was carried out by modifying the molecular length of the linker in biaryl derivative 1 g, an ACC1/2 dual inhibitor. Ultimately, this leads us to discover novel phenoxybenzyloxy derivative 1i as a potent ACC1-selective inhibitor. Further chemical modification of this scaffold to improve cellular potency as well as physicochemical and pharmacokinetic (PK) properties produced N-2-(pyridin-2-ylethyl)acetamide derivative 1n, which showed highly potent ACC1-selective inhibition as well as sufficient PK profile for further in vivo evaluations. Oral administration of 1n significantly reduced the concentration of malonyl-CoA in HCT-116 xenograft tumors at doses of 100 mg/kg. Accordingly, our novel series of potent ACC1-selective inhibitors represents a set of useful orally-available research tools, as well as potential therapeutic agents for cancer and fatty acid-related diseases.

Multiple Herbicide Resistance Evolution: The Case of Eleusine indica in Brazil.

The occurrence of multiple herbicide resistant weeds has increased considerably in glyphosate-resistant soybean fields in Brazil; however, the mechanisms governing this resistance have not been studied. In its study, the target-site and nontarget-site mechanisms were characterized in an Eleusine indica population (R-15) with multiple resistance to the acetyl-CoA carboxylase (ACCase) inhibitors, glyphosate, imazamox, and paraquat. Absorption and translocation rates of 14C-diclofop-methyl14C-imazamox and 14C-glyphosate of the R-15 population were similar to those of a susceptible (S-15) population; however, the R-15 population translocated ∼38% less 14C-paraquat to the rest of plant and roots than the S-15 population. Furthermore, the R-15 plants metabolized (by P450 cytochrome) 55% and 88% more diclofop-methyl (conjugate) and imazamox (imazamox-OH and conjugate), respectively, than the S-15 plants. In addition, the Pro-106-Ser mutation was found in the EPSPS gene of this population. This report describes the first characterization of the resistance mechanisms in a multiple herbicide resistant weed from Brazil.

The L-α-Lysophosphatidylinositol/G Protein-Coupled Receptor 55 System Induces the Development of Nonalcoholic Steatosis and Steatohepatitis.

BACKGROUND AND AIMS: G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. APPROACH AND RESULTS: We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing ß-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. CONCLUSIONS: The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC.

Synthesis and in vitro evaluation of novel spiroketopyrazoles as acetyl-CoA carboxylase inhibitors and potential antitumor agents.

Acetyl-CoA carboxylase (ACC) is a rate-limiting enzyme in de novo fatty acid synthesis, which plays a critical role in the growth and survival of cancer cells. In this study, a series of spiroketopyrazole derivatives bearing quinoline moieties were synthesized, and in vitro anticancer activities of these compounds as ACC inhibitors were evaluated. The biological evaluation showed that compound 7j exhibited the strongest enzyme inhibitory activity (IC50 = 1.29 nM), while compound 7m displayed the most potent anti-proliferative activity against A549, HepG2, and MDA-MB-231 cells with corresponding IC50 values of 0.55, 0.38, and 1.65 µM, respectively. The preliminary pharmacological studies confirmed that compound 7m reduced the intracellular malonyl-CoA and TG levels in a dose-dependent manner. Moreover, it could down-regulate cyclin D1 and CDK4 to disturb the cell cycle and up-regulate Bax, caspase-3, and PARP along with the suppression of Bcl-2 to induce apoptosis. Notably, the combination of 7m with doxorubicin synergistically decreased the HepG2 cell viability. These results indicated that compound 7m as a single agent, or in combination with other antitumor drugs, might be a promising therapeutic agent for the treatment of hepatocellular carcinoma.

A brief overview on recent advances in spiro[chromane-2,4'-piperidine]-4(3H)-one-functionalized compounds in medicinal chemistry research.

The spiro[chromane-2,4'-piperidine]-4(3H)-one is an important pharmacophore. It is a structural component in many drugs, drug candidates (or lead compounds) and various biochemical reagents. This review demonstrated an impressive progress in syntheses of spiro[chromane-2,4'-piperidine]-4(3H)-one-derived compoundsin the recent years and focuses on features of their biological relevance's. The prospects for the development of new biologically active substances containing a spiro[chromane-2,4'-piperidine]-4(3H)-one pharmacophore are analyzed and briefly discussed in terms of its structure, reaction, mechanism, scope and potential utility.