BackgroundRecently, trimethylamine-N-oxide (TMAO) plasma levels have been proved to be associated with atherosclerosis development. Among the targets aimed to ameliorating atherosclerotic lesions, inducing bile acid synthesis to eliminate excess cholesterol in body is an effective way. Individual bile acid as endogenous ligands for the nuclear receptor has differential effects on regulating bile acid metabolism. It is unclear whether bile acid profiles are mechanistically linked to TMAO-induced development of atherosclerosis.MethodsMale apoE−/− mice were fed with control diet containing 0.3% TMAO for 8 weeks. Aortic lesion development and serum lipid profiles were determined. Bile acid profiles in bile, liver and serum were measured by liquid chromatographic separation and mass spectrometric detection (LC-MS). Real-time PCRs were performed to analyze mRNA expression of genes related to hepatic bile acid metabolism.ResultsThe total plaque areas in the aortas strongly increased 2-fold (P < 0.001) in TMAO administration mice. The levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) in TMAO group were also significantly increased by 25.5% (P = 0.044), 31.2% (P = 0.006), 28.3% (P = 0.032), respectively. TMAO notably changed bile acid profiles, especially in serum, the most prominent inductions were tauromuricholic acid (TMCA), deoxycholic acid (DCA) and cholic acid (CA). Mechanically, TMAO inhibited hepatic bile acid synthesis by specifically repressing the classical bile acid synthesis pathway, which might be mediated by activation of small heterodimer partner (SHP) and farnesoid X receptor (FXR).ConclusionsThese findings suggested that TMAO accelerated aortic lesion formation in apoE−/− mice by altering bile acid profiles, further activating nuclear receptor FXR and SHP to inhibit bile acid synthesis by reducing Cyp7a1 expression.

Nonalcoholic fatty liver disease (NAFLD) has become one predictive factor of death from various illnesses. The present study was to comparatively investigate the effects of eicosapentaenoic acid-enriched and docosahexaenoic acid-enriched phospholipids forage (EPA-PL and DHA-PL) and liposomes (lipo-EPA and lipo-DHA) on NAFLD and demonstrate the possible protective mechanisms involved. The additive doses of EPA-PL and DHA-PL in all treatment groups were 1% of total diets, respectively. The results showed that Lipo-EPA could significantly improve hepatic function by down-regulating orotic acid-induced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels by 55.6% and 34.2%, respectively (p < 0.01). Moreover, lipo-EPA exhibited excellent inhibition on the mRNA expression of SREBP-1c and FAS at the values of 0.454 ± 0.09 (p < 0.01) and 0.523 ± 0.08 (p < 0.01), respectively, thus ameliorating OA-induced NAFLD. Meanwhile, lipo-EPA could significantly suppress the SREBP-2 and HMGR levels (31.4% and 66.7%, p < 0.05, respectively). In addition, EPA-PL and lipo-DHA could also significantly suppress hepatic lipid accumulation mainly by enhancement of hepatic lipolysis and cholesterol efflux. Furthermore, DHA-PL played a certain role in inhibiting hepatic lipogenesis and accelerating cholesterol efflux. The results obtained in this work might contribute to the understanding of the biological activities of EPA/DHA-PL and liposomes and further investigation on its potential application values for food supplements.

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Introduction Bone pain is a debilitating adverse reaction associated with G-CSF (including Peg) in Breast Cancer (BC) pts receiving chemotherapy (Chemo). G-CSF shortens the time to, duration of, and depth of the neutrophil (ANC) nadir, associated with an acceleration of hematopoietic stem cell differentiation into mature neutrophils (Crawford NEJM 1991). We hypothesized that this acceleration is accompanied by an expansion of bone intramedullary contents (including hematopoietic precursors) and can lead to an increase in intra-cavitary pressure and stimulation of intra-osseous Aδ mechano-nociceptors, which are transmitted as pain sensations through Piezo2 signaling to the brain (Nencini and Ivanusic, 2017; Oostinga Bone 2020). Plinabulin (Plin) is a novel, non-G-CSF, small molecule agent with anticancer activity, that also prevents chemotherapy-induced neutropenia (CIN). Plin has a fast onset mechanism of action (MoA) for CIN-prevention acting in the first week of the cycle, whereas Peg has a slow MoA, acting in the second week of the cycle. Combining Plin+Peg resulted in superior CIN prevention, significantly higher ANC nadir and significantly less bone pain (Blayney ASCO 2020; St Gallen 2019). Method Data from the randomized, double-blinded trial PROTECTIVE-2 (NCT0329457) evaluating CIN outcomes with the Plin+Peg combination (n=111) vs Peg alone (n=110) in BC pts receiving TAC were analyzed for timing of bone pain occurrence relative to ANC Nadir, and whether maximum bone pain score was correlated (inversely) with ANC nadir. Patient reported outcome (PRO) bone pain scores were from validated Numerical Rate Scale (NRS)-based questionnaires. Bone AEs were obtained from case report forms. ANC Nadir was evaluated from central laboratory (COVANCE) assessments of almost daily ANC assessments. Results ANC declined rapidly between Day 3 and Day 7 (the time point of ANC nadir in both groups) and significantly steeper with Peg vs Peg+Plin (P&lt;0.013). ANC nadir reached lower levels with Peg vs Plin+Peg: 0.32 vs 0.54 x10E9/L (p=0.0002). Peak bone pain score (NRS method) occurred around Day 5 and was significantly (P&lt;0.05) higher for Peg vs Plin+ Peg Bone pain score (NRS) plotted against the absolute neutrophil count at time of nadir, demonstrated and inverse and statistically significant correlation (p=0.019). The Peg alone group had significantly higher bone pain AE frequency over 4 cycles vs Plin+Peg (30% vs 18%; p=0.03). Conclusion The collective data supports the concept that bone pain in pts receiving myelosuppressive chemotherapy and Peg is a direct consequence of accelerated drop in ANC and to deeper levels by Peg, triggering an accelerated intramedullary compensatory hematopoietic response and associate pressure build up that sensed as bone pain. The addition of Plin to Peg slowed down the Peg-induced speed and deepening of ANC decline, and consequently ameliorates this intramedullary response mechanism and bone pain generation. Citation Format: Douglas W. Blayney, Stephan Ogenstad, Mengru Chang, Yvette Lelorier, Lan Huang, Ramon Mohanlal. Mechanistic evidence associated with the benefit of plinabulin significantly reducing Bone pain in breast cancer patients (pts) treated with TAC (docetaxel, doxorubicin, cyclophosphamide) and pegfilgrastim (Peg) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-01.