Long-term use of fluoxetine accelerates bone loss through the disruption of sphingolipids metabolism in bone marrow adipose tissue.

Fluoxetine is a commonly prescribed antidepressant, and the mechanisms of increased bone fragility with its long-term use remain largely unknown. Here, we show that long-term administration of fluoxetine induces the disruption of sphingolipids metabolism in bone marrow adipose tissue (BMAT)through the inhibition of acid sphingomyelinase (ASM). Similarly, a significant reduction of the bone volume was observed in mice with ASM knockout (Smpd1-/-). In detail, inhibition of ASM by fluoxetine reduces the sphingosine-1-phosphate (S1P) level in bone marrow adipocytes, leading to the increase of receptor activator of nuclear factor-kappa-Β ligand (RANKL) secretion, a key regulator for the activation of osteoclastogenesis and bone loss, through the upregulation of cyclooxygenase-2 and its enzymatic product prostaglandin E2 (COX-2/PGE2). In contrast, overexpression of ASM by cisplatin normalizes fluoxetine-induced RANKL overproduction. Furthermore, we conducted a clinical trial with L-serine, a precursor of sphingolipids biosynthesis. The results show that oral supplementation of L-serine (250 mg//kg/d) prevents the acceleration of bone loss caused by long-term fluoxetine (12 months) in postmenopausal women with major depressive disorder (mean total hip bone mineral density reduction: -2.0% vs -1.1%, P = 0.006). Our study provides new insights and potential treatment strategy on the bone loss caused by long-term use of fluoxetine.

Withanolides from the stems and leaves of Physalis pubescens and their cytotoxic activity.

A phytochemical study of Physalis pubescens L. afforded twelve compounds, including six new withanolides (1, 4, and 6i-9), four new withanolide glucosides (2, 3, 5, and 6), and two known withanolides (10 and 11). Their structures were established via extensive spectroscopic analysis. The absolute configuration of 3 was assigned using X-ray crystallography, and the absolute configurations of the 1,2-diol moiety in 1 were determined using the in situ dimolybdenum electronic circular dichroism method. Compounds 7, 9, and 10 exhibited significant cytotoxicity against human prostate cancer cells (C4-2B and 22Rvl), human renal carcinoma cells (786-O, A-498, Caki-2, and ACHN), human melanoma cells (A375 and A375-S2), and human normal hepatic cell line (L02) with IC50 values in the range of 0.17-5.30µM.

Two novel creatinine adducts of andrographolide in human urine.

Andrographolide is a major labdane diterpenoid of the traditional Chinese and Ayurvedic medicine. Andrographis paniculate (Burm) Nees, is used in clinical situations in China mainly to treat fever, cold, and inflammation. In our previous study, fifteen metabolites of andrographolide were identified in human urine. However, there are still two other unknown metabolites. The aim of this study was to elucidate the structures of these two metabolites. 3. The two metabolites which are probably epimers were identified as creatinine adducts, and their structures were determined to be 14-deoxy-12-(creatinine-5-yl)-andrographolide-19-O-ß-D-glucuronide A (Metabolite 1) and 14-deoxy-12-(creatinine-5-yl)-andrographolide-19-O-ß-D-glucuronide B (Metabolite 2) by means of spectroscopic evidences. 4. It is for the first time that the formation of creatinine adducts as a novel metabolic pathway is reported. The mechanism was presumed that ß-carbon (C-12) of α, ß-unsaturated carbonyl was attacked by a 5-anion intermediate of creatinine formed through elimination of a proton, followed by the double bond migration from 12(13) to 13(14) and elimination of the hydroxyl group at C-14.