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Iron Prevents Hypoxia-Associated Inflammation Through the Regulation of Nuclear Factor-κB in the Intestinal Epithelium.
Simmen, S, Cosin-Roger, J, Melhem, H, Maliachovas, N, Maane, M, Baebler, K, Weder, B, Maeyashiki, C, Spanaus, K, Scharl, M, et al
Cellular and molecular gastroenterology and hepatology. 2019;(2):339-355
Abstract
BACKGROUND & AIMS Hypoxia-associated pathways influence the development of inflammatory bowel disease. Adaptive responses to hypoxia are mediated through hypoxia-inducible factors, which are regulated by iron-dependent hydroxylases. Signals reflecting oxygen tension and iron levels in enterocytes regulate iron metabolism. Conversely, iron availability modulates responses to hypoxia. In the present study we sought to elucidate how iron influences the responses to hypoxia in the intestinal epithelium. METHODS Human subjects were exposed to hypoxia, and colonic biopsy specimens and serum samples were collected. HT-29, Caco-2, and T84 cells were subjected to normoxia or hypoxia in the presence of iron or the iron chelator deferoxamine. Changes in inflammatory gene expression and signaling were assessed by quantitative polymerase chain reaction and Western blot. Chromatin immunoprecipitation was performed using antibodies against nuclear factor (NF)-κB and primers for the promoter of tumor necrosis factor (TNF) and interleukin (IL)1β. RESULTS Human subjects presented reduced levels of ferritin in the intestinal epithelium after hypoxia. Hypoxia reduced iron deprivation-associated TNF and IL1β expression in HT-29 cells through the induction of autophagy. Contrarily, hypoxia triggered TNF and IL1β expression, and NF-κB activation in Caco-2 and T84 cells. Iron blocked autophagy in Caco-2 cells, while reducing hypoxia-associated TNF and IL1β expression through the inhibition of NF-κB binding to the promoter of TNF and IL1β. CONCLUSIONS Hypoxia promotes iron mobilization from the intestinal epithelium. Hypoxia-associated autophagy reduces inflammatory processes in HT-29 cells. In Caco-2 cells, iron uptake is essential to counteract hypoxia-induced inflammation. Iron mobilization into enterocytes may be a vital protective mechanism in the hypoxic inflamed mucosa.
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Acetyl-L-carnitine (ALCAR) for the prevention of chemotherapy-induced peripheral neuropathy in patients with relapsed or refractory multiple myeloma treated with bortezomib, doxorubicin and low-dose dexamethasone: a study from the Wisconsin Oncology Network.
Callander, N, Markovina, S, Eickhoff, J, Hutson, P, Campbell, T, Hematti, P, Go, R, Hegeman, R, Longo, W, Williams, E, et al
Cancer chemotherapy and pharmacology. 2014;(4):875-82
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Abstract
PURPOSE Retreatment with bortezomib (B) is often considered for patients with relapsed multiple myeloma (MM), but this strategy is hindered by uncertainty of response and emergence of B-induced peripheral neuropathy (PN). We incorporated acetyl-L-carnitine (ALCAR) to prevent PN and allow for adequate dosing. We also investigated the correlation between B-inducible NF-κB activation and response to therapy. METHODS Nineteen patients with relapsed/refractory MM received up to 8 cycles of intravenous bortezomib, doxorubicin and oral low-dose dexamethasone (BDD) to evaluate response and toxicity. Thirteen additional patients received prophylactic ALCAR (BDD-A). Patients receiving BDD-A were evaluated by FACT-GOG-TX, FACIT-Fatigue, Neuropathic Pain index (NPI) and Grooved Pegboard (GP) testing. Primary MM cells from 11 patients were tested for B-inducible NF-κB activation. RESULTS Seventy-six percent of subjects were refractory to previous treatment, 39% refractory to bortezomib. Median cycles received were 5. CR + PR for the entire group were 53% and did not differ between groups. Incidence of ≥3 PN was 32% in the BDD group versus 15 % in the BDD-A group (p = ns). Patient-reported fatigue and PN measured by FACT-GOG-TX increased throughout the treatment period in the BDD-A group, although time to complete GP testing declined. In a sub-study examining constitutive bortezomib-inducible NF-κB activity in primary subject-specific MM cells, the presence of NF-κB activation correlated with lower likelihood of response. CONCLUSIONS Addition of ALCAR to BDD did not alter the incidence or severity of PN in relapsed MM patients receiving a B-based regimen. Bortezomib-inducible NF-κB activation in patient-derived primary MM cells may be associated with poorer response.
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Effect of low-fat diets on plasma levels of NF-κB-regulated inflammatory cytokines and angiogenic factors in men with prostate cancer.
Heymach, JV, Shackleford, TJ, Tran, HT, Yoo, SY, Do, KA, Wergin, M, Saintigny, P, Vollmer, RT, Polascik, TJ, Snyder, DC, et al
Cancer prevention research (Philadelphia, Pa.). 2011;(10):1590-8
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Abstract
Diet, nutritional status, and certain dietary supplements are postulated to influence the development and progression of prostate cancer. Angiogenesis and inflammation are central to tumor growth and progression, but the effect of diet on these processes remains uncertain. We explored changes in 50 plasma cytokines and angiogenic factors (CAF) in 145 men with prostate cancer enrolled in a preoperative, randomized controlled phase II trial with four arms: control (usual diet), low-fat (LF) diet, flaxseed-supplemented (FS) diet, and FS+LS diet. The mean duration of dietary intervention was 30 to 31 days. Among the individual arms, the largest number of significant changes (baseline vs. preoperative follow-up) was observed in the LF arm, with 19 CAFs decreasing and one increasing (P < 0.05). Compared with the control arm, 6 CAFs-including proangiogenic factors (stromal-cell derived-1α) and myeloid factors (granulocyte-colony-stimulating factor, macrophage colony-stimulating factor)-all decreased in the LF arm compared with controls; three and four CAFs changed in the FS and FS+LF arms, respectively. Weight loss occurred in the LF arms and significantly correlated with VEGF decreases (P < 0.001). The CAFs that changed in the LF arm are all known to be regulated by NF-κB, and a pathway analysis identified NF-κB as the most likely regulatory network associated with these changes in the LF arm but not in the FS-containing arms. These results suggest that a LF diet without flaxseed may reduce levels of specific inflammatory CAFs and suggests that the NF-κB pathway may be a mediator of these changes.