BACKGROUNDIt is well known that dehydration can impair bodily functions. To evaluate the impact of hydration status under ambient environmental temperature on the immune system, 25 male collegiate wrestlers were recruited to undergo an experimental dehydration program.

METHODSThirteen subjects had controlled diets with individual energy requirements to prevent body mass loss and restricted water intake to cause 4.52% dehydration; they formed the dehydrated group (DE). These subjects developed a urine specific gravity of about 1.030 in 84 hours. Twelve other subjects had no water restriction and maintained their total body weight comprised the euhydrated group (EU). Peripheral blood monocytes (PBMNC) were isolated after dehydration to perform immune response testing by being incubated with a polysaccharide fraction from fu-ling, Poria cocos (polysaccharide fraction from Poria cocos, PCPS, 1 - 30 £g/L), to prepare a conditioned medium termed conditioned medium of PBMNC stimulated by PCPS (PCPS-MNC-CM). More PCPS (25 µg/L) was needed in the DE group to prepare the PCPS-MNC-CM, which was assayed with a growth inhibitory curve for treated U973 cells.

RESULTSThe treated U937 cells, incubated together with PCPS-MNC-CM from the DE group, exhibited a much lower nitroblue tetrazolium (NBT) positive value of (63.7 ± 4.7)%. The concentration of interferon-gamma (IFN-γ), interleukin (IL)-1β and tumor necrosis factor (TNF)-α in PCPS-MNC-CM from subjects after dehydration was much lower than in the CM from the EU group.

CONCLUSIONThe immune response to PCPS in the DE group was lower than in normally hydrated subjects.

Adolescent ; Adult ; Dehydration ; physiopathology ; Drugs, Chinese Herbal ; chemistry ; Fever ; Humans ; Immunologic Factors ; Interferon-gamma ; metabolism ; Interleukin-1beta ; metabolism ; Leukocytes, Mononuclear ; drug effects ; metabolism ; Male ; Polysaccharides ; chemistry ; immunology ; Tumor Necrosis Factor-alpha ; metabolism ; U937 Cells ; Universities ; Wolfiporia ; Wrestling ; Young Adult

Triple-negative breast cancer (TNBC) remains difficult to treat and urgently needs new therapeutic options. Nintedanib, a multikinase inhibitor, has exhibited efficacy in early clinical trials for HER2-negative breast cancer. In this study, we examined a new molecular mechanism of nintedanib in TNBC. The results demonstrated that nintedanib enhanced TNBC cell apoptosis, which was accompanied by a reduction of p-STAT3 and its downstream proteins. STAT3 overexpression suppressed nintedanib-mediated apoptosis and further increased the activity of purified SHP-1 protein. Moreover, treatment with either a specific inhibitor of SHP-1 or SHP-1-targeted siRNA reduced the apoptotic effects of nintedanib, which validates the role of SHP-1 in nintedanib-mediated apoptosis. Furthermore, nintedanib-induced apoptosis was attenuated in TNBC cells expressing SHP-1 mutants with constantly open conformations, suggesting that the autoinhibitory mechanism of SHP-1 attenuated the effects of nintedanib. Importantly, nintedanib significantly inhibited tumor growth via the SHP-1/p-STAT3 pathway. Clinically, SHP-1 levels were downregulated, whereas p-STAT3 was upregulated in tumor tissues, and SHP-1 transcripts were associated with improved disease-free survival in TNBC patients. Our findings revealed that nintedanib induces TNBC apoptosis by acting as a SHP-1 agonist, suggesting that targeting STAT3 by enhancing SHP-1 expression could be a viable therapeutic strategy against TNBC.
Apoptosis* ; Breast Neoplasms ; Disease-Free Survival ; Humans ; Protein-Tyrosine Kinases* ; RNA, Small Interfering ; Triple Negative Breast Neoplasms* ; Tyrosine*