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Obesity-associated complications are causing increasing morbidity and mortality worldwide. Expansion of adipose tissue in obesity leads to a state of low-grade chronic inflammation and dysregulated metabolism, resulting in insulin resistance and metabolic syndrome. Adipose tissue macrophages (ATMs) accumulate in obesity and are a source of proinflammatory cytokines that further aggravate adipocyte dysfunction. Macrophages are rich sources of cyclooxygenase (COX), the rate limiting enzyme for prostaglandin E2 (PGE2) production. When mice were fed a high-fat diet (HFD), ATMs increased expression of COX-2. Selective myeloid cell COX-2 deletion resulted in increased monocyte recruitment and proliferation of ATMs, leading to increased proinflammatory ATMs with decreased phagocytic ability. There were increased weight gain and adiposity, decreased peripheral insulin sensitivity and glucose utilization, increased adipose tissue inflammation and fibrosis, and abnormal adipose tissue angiogenesis. HFD pair-feeding led to similar increases in body weight, but mice with selective myeloid cell COX-2 still exhibited decreased peripheral insulin sensitivity and glucose utilization. Selective myeloid deletion of the macrophage PGE2 receptor subtype, EP4, produced a similar phenotype, and a selective EP4 agonist ameliorated the metabolic abnormalities seen with ATM COX-2 deletion. Therefore, these studies demonstrated that an ATM COX-2/PGE2/ EP4 axis plays an important role in inhibiting adipose tissue dysfunction., Introduction There are currently about 2 billion people globally who are obese or overweight, leading to health complications, type 2 diabetes, cardiovascular disease, and liver disease. The expansion of adipose [...]

Loxoprofen sodium is a chiral drug with two chiral centers. In our previous work, we found that the elimination of its four isomers showed stereospecificity in rats, while how the stereospecific behavior occurred in vivo was unclear. To clarify this issue, each single isomer of loxoprofen sodium was prepared by a chiral semi‐preparative high‐performance liquid chromatography (HPLC) and then administered to rats. By analysis of each isomer in rat plasma utilizing an analytical chiral HPLC, it was discovered that the chiral inversion occurred only to its (2R)‐isomers, one from (1′S,2R)‐ to (1′S,2S)‐isomer and the other from (1′R,2R)‐ to (1′R,2S)‐isomer. The reduction of α‐substituted cyclopentanone occurred only to its (1′R)‐isomers, with (1′R,2R)‐isomer reduced to (2′S,1′R,2R)‐trans‐alcohol and (1′R,2S)‐ to (2′S,1′R,2S)‐trans‐alcohol. Interestingly, both the inversion and the reduction reaction occurred to its (1′R,2R)‐isomer due to the special stereo‐structure with both (2R)‐ and (1′R)‐configuration, and conversely, neither of them occurred to its (1′S,2S)‐isomer, which caused the significantly different elimination rate in vivo. These new findings were meaningful for evaluation of the safety and efficacy of chiral drugs. [ABSTRACT FROM AUTHOR]

Podocyte injury is important in development of diabetic nephropathy (DN). Although several studies have reported single-cell-based RNA sequencing (RNA-seq) of podocytes in type 1 DN (T1DN), the podocyte translating mRNA profile in type 2 DN (T2DN) has not previously been compared with that of T1DN. We analyzed the podocyte translatome in T2DN in podocin-Cre; Rosa26fsTRAP; eNOS-/-; db/db mice and compared it with that of streptozotocin-induced T1DN in podocin-Cre; Rosa26fsTRAP; eNOS-/- mice using translating ribosome affinity purification (TRAP) and RNA-seq. More than 125 genes were highly enriched in the podocyte ribosome. More podocyte TRAP genes were differentially expressed in T2DN than in T1DN. TGF-β signaling pathway genes were upregulated, while MAPK pathway genes were downregulated only in T2DN, while ATP binding and cAMP-mediated signaling genes were downregulated only in T1DN. Genes regulating actin filament organization and apoptosis increased, while genes regulating VEGFR signaling and glomerular basement membrane components decreased in both type 1 and type 2 diabetic podocytes. A number of diabetes-induced genes not previously linked to podocyte injury were confirmed in both mouse and human DN. On the basis of differences and similarities in the podocyte translatome in T2DN and T1DN, investigators can identify factors underlying the pathophysiology of DN and novel therapeutic targets to treat diabetes-induced podocyte injury. [ABSTRACT FROM AUTHOR]

Renal epidermal growth factor receptor (EGFR) signaling is activated in models of diabetic nephropathy (DN), and inhibition of the EGFR signaling pathway protects against the development of DN. We have now determined that in cultured podocytes, high glucose led to increases in activation of EGFR signaling but decreases in autophagy activity as indicated by decreased beclin-1 and inhibition of LC3B autophagosome formation as well as increased rubicon (an autophagy inhibitor) and SQSTM1 (autophagy substrate). Either genetic (small interfering [si]EGFR) or pharmacologic (AG1478) inhibition of EGFR signaling attenuated the decreased autophagy activity. In addition, rubicon siRNA knockdown prevented high glucose-induced inhibition of autophagy in podocytes. We further examined whether selective EGFR deletion in podocytes affected the progression of DN in type 2 diabetes. Selective podocyte EGFR deletion had no effect on body weight or fasting blood sugars in either db/db mice or nos3-/-; db/db mice, a model of accelerated type 2 DN. However selective podocyte EGFR deletion led to relative podocyte preservation and marked reduction in albuminuria and glomerulosclerosis, renal proinflammatory cytokine/chemokine expression, and decreased profibrotic and fibrotic components in nos3-/-; db/db mice. Podocyte EGFR deletion led to decreased podocyte expression of rubicon, in association with increased podocyte autophagy activity. Therefore, activation of EGFR signaling in podocytes contributes to progression of DN at least in part by increasing rubicon expression, leading to subsequent autophagy inhibition and podocyte injury. [ABSTRACT FROM AUTHOR]

Loxoprofen sodium (LOX) is a propionic acid derivative non-steroidal anti-inflammatory drug (NSAID), existing in the form of four stereoisomers. The main metabolites of LOX in vivo were trans - and cis -alcohol, each consisting of four stereoisomers. The objectives of the present study were to examine the selective pharmacokinetic behavior of LOX stereoisomers and stereoselective formation of its alcohol metabolites in rats based on a chiral liquid chromatographytandem mass spectrometry (LC-MS/MS) method by using an FLM Chiral NQ-RH column, which was reported for the first time. The significant difference in pharmacokinetic parameters of four stereoisomers indicated that stereoselective behavior has occurred in rats after oral administration of LOX. (1′ S ,2 S)-LOX showed the highest concentration among the four stereoisomers in both plasma and urine samples. Trans - and cis -alcohol metabolites of LOX were also detected in plasma and urine, and trans -alcohol was found to be primary and the stereoisomeric fractions (SF s) of its four stereoisomers at different times were calculated. Examination of the stereoisomeric composition indicated a stereo preference for (2 S)-configuration with respect to trans -alcohol formation. The overall results of the present study revealed the enantioselective pharmacokinetic properties of LOX stereoisomers in rats, which provided a means to advance understanding of the complex pharmacokinetic of LOX. [ABSTRACT FROM AUTHOR]