Combinations of an acetyl CoA carboxylase inhibitor with hepatic lipid modulating agents do not augment antifibrotic efficacy in preclinical models of NASH and fibrosis.

Dysregulated hepatocyte lipid metabolism is a hallmark of hepatic lipotoxicity and contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl CoA carboxylase (ACC) inhibitors decrease hepatocyte lipotoxicity by inhibiting de novo lipogenesis and concomitantly increasing fatty acid oxidation (FAO), and firsocostat, a liver-targeted inhibitor of ACC1/2, is under evaluation clinically in patients with NASH. ACC inhibition is associated with improvements in indices of NASH and reduced liver triglyceride (TG) content, but also increased circulating TG in subjects with NASH and preclinical rodent models. Here we evaluated whether enhancing hepatocyte FAO by combining ACC inhibitors with peroxisomal proliferator-activated receptor (PPAR) or thyroid hormone receptor beta (THRß) agonists could drive greater liver TG reduction and NASH/antifibrotic efficacy, while ameliorating ACC inhibitor-induced hypertriglyceridemia. In high-fat diet-fed dyslipidemic rats, the addition of PPAR agonists fenofibrate (Feno), elafibranor (Ela), lanifibranor (Lani), seladelpar (Sela) or saroglitazar (Saro), or the THRb agonist resmetirom (Res), to an analogue of firsocostat (ACCi) prevented ACCi-induced hypertriglyceridemia. However, only PPARα agonists (Feno and Ela) and Res provided additional liver TG reduction. In the choline-deficient high-fat diet rat model of advanced liver fibrosis, neither PPARα (Feno) nor THRß (Res) agonism augmented the antifibrotic efficacy of ACCi. Conclusion: These data suggest that combination therapies targeting hepatocyte lipid metabolism may have beneficial effects on liver TG reduction; however, they may not be sufficient to drive fibrosis regression.

Dislocations in molecular crystals.

Dislocations in molecular crystals remain terra incognita. Owing to the complexity of molecular structure, dislocations in molecular crystals can be difficult to understand using only the foundational concepts devised over decades for hard materials. Herein, we review the generation, structure, and physicochemical consequences of dislocations in molecular crystals. Unlike metals, ceramics, and semiconductors, molecular crystals are often characterized by flexible building units of low symmetry, thereby limiting analysis, complicating modeling, and prompting new approaches to elucidate their role in crystallography from growth to mechanics. Such considerations affect applications ranging from plastic electronics and mechanical actuators to the tableting of pharmaceuticals.

Structure, Energetics, and Dynamics of Screw Dislocations in Even n-Alkane Crystals.

Spiral hillocks on n-alkane crystal surfaces were observed immediately after Frank recognized the importance of screw dislocations for crystal growth, yet their structures and energies in molecular crystals remain ill-defined. To illustrate the structural chemistry of screw dislocations that are responsible for plasticity in organic crystals and upon which the organic electronics and pharmaceutical industries depend, molecular dynamics was used to examine heterochiral dislocation pairs with Burgers vectors along [001] in n-hexane, n-octane, and n-decane crystals. The cores were anisotropic and elongated in the (110) slip plane, with significant local changes in molecular position, orientation, conformation, and energy. This detailed atomic level picture produced a distribution of strain consistent with linear elastic theory, giving confidence in the simulations. Dislocations with doubled Burgers vectors split into pairs with elementary displacements. These results suggest a pathway to understanding the mechanical properties and failure associated with elastic and plastic deformation in soft crystals.

Serum vitamin D metabolites in colorectal cancer patients receiving cholecalciferol supplementation: correlation with polymorphisms in the vitamin D genes.

Cholecalciferol (D(3)) supplementation results in variable increases in serum 25(OH)D(3) levels, however, the influence of genetic polymorphisms on these variable responses is unclear. We measured serum 25(OH)D(3), 24,25(OH)(2)D(3), 1,25(OH)2D(3) and VDBP levels in 50 colorectal cancer (CRC) patients before and during 2,000 IU daily oral D(3) supplementation for six months and in 263 archived CRC serum samples. Serum PTH levels and PBMC 24-OHase activity were also measured during D(3) supplementation. TagSNPs in CYP2R1, CYP27A1, CYP27B1, CYP24A1, VDR, and GC genes were genotyped in all patients, and the association between these SNPs and serum vitamin D(3) metabolites levels before and after D(3) supplementation was analyzed. The mean baseline serum 25(OH)D(3) level was less than 32 ng/mL in 65 % of the 313 CRC patients. In the 50 patients receiving D(3) supplementation, serum levels of 25(OH)D(3) increased (p = 0.008), PTH decreased (p = 0.036) and 24,25(OH)(2)D(3), 1,25(OH)(2)D(3), VDBP levels and PBMC 24-OHase activity were unchanged. GC SNP rs222016 was associated with high 25(OH)D(3) and 1,25(OH)(2)D(3) levels at baseline while rs4588 and rs2282679 were associated with lower 25(OH)D(3) and 1,25(OH)(2)D(3) levels both before and after D(3) supplementation. CYP2R1 rs12794714 and rs10500804 SNPs were significantly associated with low 25(OH)D(3) levels after supplementation but not with baseline 25(OH)D(3). Our results show that D(3) supplementation increased 25(OH)D(3) levels in all patients. GC rs4588 and rs2283679 SNPs were associated with increased risk of vitamin D(3) insufficiency and suboptimal increase in 25(OH)D(3) levels after D(3) supplementation. Individuals with these genotypes may require higher D(3) supplementation doses to achieve vitamin D(3) sufficiency.

Measurement of heterogeneous reaction rates: three strategies for controlling mass transport and their application to indium-mediated allylations.

We describe three new strategies for determining heterogeneous reaction rates using photomicroscopy to measure the rate of retreat of metal surfaces: (i) spheres in a stirred solution, (ii) microscopic powder in an unstirred solution, and (iii) spheres on a rotating shaft. The strategies are applied to indium-mediated allylation (IMA), which is a powerful tool for synthetic chemists because of its stereoselectivity, broad applicability, and high yields. The rate-limiting step of IMA, reaction of allyl halides at indium metal surfaces, is shown to be fast, with a minimum value of the heterogeneous rate constant of 1 × 10(-2) cm/s, an order of magnitude faster than the previously determined minimum value. The strategies described here can be applied to any reaction in which the surface is retreating or advancing, thereby broadening the applicability of photomicroscopy to measuring heterogeneous reaction kinetics.

Measurement of heterogeneous reaction rates during indium-mediated allylation.

Indium-mediated allylation provides remarkable stereo- and regioselectivity, and it proceeds easily and in high yield in aqueous solutions. In spite of its widespread use, there have been few fundamental studies of this reaction. We have developed a photomicrographic technique for measuring rates of reaction of allyl halides at indium surfaces, and we describe the mathematical model for discriminating between diffusion and kinetic control. The measurements demonstrate that this reaction is diffusion controlled, and the minimum value of the heterogeneous rate constant is 1 x 10(-3) cm s(-1). These results broaden the applicability of photomicroscopy for measuring heterogeneous rates of reactions that result in consumption of solid metals.