No abstract

Pepper, a daily-used seasoning for promoting appetite, is widely used in folk medicine for treating gastrointestinal diseases. Piperine is the major alkaloid in pepper and possesses a wide range of pharmacological activities. However, the mechanism for linking metabolic and medicinal activities of piperine remains unknown. Here we report that piperine robustly boosts mTORC1 activity by recruiting more system L1 amino acid transporter (SLC7A5/SLC3A2) to the cell membrane, thus promoting amino acid metabolism. Piperine-induced increase of mTORC1 activity in resident peritoneal macrophages (pMΦs) is correlated with enhanced production of IL-6 and TNF-α upon LPS stimulation. Such an enhancement of cytokine production could be abrogated by inhibitors of the mTOR signaling pathway, indicating mTOR's action in this process. Moreover, piperine treatment protected resident pMΦs from bacterium-induced apoptosis and disappearance, and increased their bacterial phagocytic ability. Consequently, piperine administration conferred mice resistance against bacterial infection and even sepsis. Our data highlight that piperine has the capacity to metabolically reprogram peritoneal resident macrophages to fortify their innate functions against bacterial infection.

Background. The role of flow cytometry in predicting prognosis for cervical carcinoma remains unclear. Methods. Flow cytometric analysis was performed on tissues, fixed in formaldehyde solution and embedded in paraffin, from 411 patients with Stage IB or II cervical carcinoma who had been treated with radical abdominal hysterectomy and bilateral pelvic lymphadenectomy. Results. DNA aneuploid‐multiploid tumors were found in 37.5%, tetraploid in 4.6%, and diploid‐peridiploid in 57.9%. Five‐year recurrence‐free survival rates of the three groups were 74.3%, 77.8%, and 76.4%, respectively (P > 0.05). DNA aneuploidy and DNA index (DI) of greater than 1.3 were highly correlated to parametria extension. In univariate analysis, pelvic lymph node metastases, stage, parametrial extension, depth of cervical stromal invasion, tumor size, and DI (1.3, 1.4, 1.5 as breakpoint) were significant prognostic factors. DNA ploidy, S‐phase fraction, and S‐G2M fraction were not significant. In multivariate analysis, DI of greater than 1.3, pelvic node metastases, clinical Stage II, and depth of stromal invasion greater than two‐thirds of full cervical thickness were independent and significant variables. The prognostic index (PI), defined by the model, was able to categorize the patients into three distinct risk groups. The 5‐year recurrence free survival rates of the low‐, intermediate‐, and high‐risk groups were 89.5%, 73.0%, and 58.9%, respectively (P = 0.0001). Conclusions. The prognostic value of the DI as a single variable is promising and warrants additional investigation to establish its appropriate use.

CPT-11 (Irinotecan) is a first-line chemotherapeutic agent in clinic, but it may induce side effects including diarrhea and enteritis in patients. The underlying mechanism of CPT-11's intestinal toxicity is unclear. Peritoneal resident macrophages have been reported to be important for the maintenance of intestinal homeostasis. In this study, we evaluated the cytotoxic effects of CPT-11 on mouse peritoneal resident macrophages. CPT-11 was administered intraperitoneally to mice and their peritoneal exudate cells were isolated for evaluation. CPT-11 treatment strikingly decreased the ratio of F4/80(hi)MHCII(low) large peritoneal macrophages (LPMs), which are regarded as prenatally-originated peritoneal resident macrophages. Consistent with this, the transcription factor GATA6 specifically expressed in LPMs was barely detectable in the macrophages from CPT-11-treated mice, indicative of elimination of LPMs. Such elimination of LPMs was at least partly due to CPT-induced apoptosis in macrophages, because inhibition of apoptosis by caspase-3 inhibitor z-DEVD-fmk significantly diminished the loss of GATA6(+) LPMs. As GATA6 is a transcription factor that controls expression of multiple genes regulating peritoneal B-1 cell development and translocation, elimination of GATA6(+) LPMs led to a great reduction in B-1 cells in the peritoneal cavity after CPT-11 treatment. These results indicated that CPT-11-induced apoptosis contributed to the elimination of peritoneal resident macrophages, which might in turn impair the function of peritoneal B-1 cells in maintaining intestinal homeostasis. Our findings may at least partly explain why CPT-11 treatment in cancer patients induces diarrhea and enteritis, which may provide a novel avenue to prevent such side effects.