Intermittent hypoxia induces tumor immune escape in murine S180 solid tumors via the upregulation of TGF-ß1 in mice.

PURPOSE: Studies have shown that intermittent hypoxia (IH) alters host immune functions and promotes tumor growth. However, the relevant mechanisms of these effects have not been completely elucidated. We hypothesized that IH promotes the growth of tumors by changing cytokine levels in the tumor microenvironment and inducing immune escape. METHODS: Sarcoma-180 (S180) solid tumor cells were injected into the right flank of Kunming mice. The mice were then randomly divided into the IH and room air (RA) groups. The mice were euthanized 2 weeks after IH exposure, and the weight of tumor tissues was measured. Next, IL-6, IL-17, IL-10, and TNF-α levels in tumor tissues were measured via enzyme linked immunosorbent assay (ELISA), and hypoxia inducible factor-1α (HIF-1α) and transforming growth factor ß1 (TGF-ß1) expressions were examined through Western blot analysis. RESULTS: Two weeks of IH exposure significantly accelerated the growth of S180 solid tumors. Western blot analysis results showed that the expression levels of HIF-1α and TGF-ß1 in S180 tumors in the IH group were significantly upregulated compared with those in the RA group. ELISA results showed that compared with the RA group, the IH group had significantly increased TNF-α and IL-10 (P < 0.05) and significantly decreased IL-17 (P < 0.05). CONCLUSION: IH might promote the growth of S180 solid tumors by inhibiting the antitumor immune response and inducing tumor immune escape via the upregulation of TGF-ß1.

Niclosamide attenuates inflammatory cytokines via the autophagy pathway leading to improved outcomes in renal ischemia/reperfusion injury.

Renal ischemia/reperfusion (I/R) injury is a debilitating condition that leads to loss renal function and damage to kidney tissue in the majority of patients with acute kidney disease. Previous studies have indicated that autophagy serves a protective function in renal I/R injury. In the present study, the effect of the anthelmintic niclosamide in the regulation of inflammatory responses in kidney I/R was investigated. A total of 40 Sprague-Dawley rats were randomly divided into the following 5 groups (n=8 in each group): Sham group; renal I/R injury; renal I/R injury plus 3­methyladenine (3­MA) treatment (15 mg/kg); renal I/R injury plus niclosamide (25 mg/kg); and renal I/R injury plus rapamycin (10 mg/kg). The expression levels of autophagy­associated proteins in kidney samples obtained from rats with I/R injury were examined using reverse transcription­quantitative polymerase chain reaction and western blotting techniques. In addition, histopathological alterations, the expression of cytokines and renal function were evaluated. Treatment with niclosamide was associated with induction of autophagy and an overall improvement in renal function. There was an increased expression of autophagosome­associated proteins, suggesting a strong correlation between autophagy and improvement of renal function. The increased levels of anti­inflammatory cytokines and decreased levels of pro­inflammatory cytokines provided additional evidence that niclosamide may be effective for the treatment of renal I/R injury. Clinical studies are required to further validate the results of the present study.

[Effects of 1, 25(OH)(2);D(3); on parathyroid hormone induced transdifferentiation and TGF-ß(1); expression in cultured human renal tubular epithelial cells].

AIM: To explore the effects of 1, 25(OH)(2);D(3); on parathyroid hormone (PTH) induced transdifferentiation and TGF-ß(1); expression in cultured human renal tubular epithelial cells. METHODS: HK-2 cells were cultured in DMEM/F12 medium supplemented with 50 mL/L FBS. Cells were divided into three groups. (1) CONTROL GROUP: without PTH or 1, 25(OH)(2);D(3);; (2) PTH group: 10(-10); mol/L PTH; (3) PTH and 1, 25(OH)(2);D(3); group: 10(-10); mol/L PTH and different concentrations of 1, 25(OH)(2);D(3); (10(-10);, 10(-9);, 10(-8); and 10(-7); mol/L). The gene expressions of α-SMA and TGF-ß(1); were detected by semi-quantitative RT-PCR. The protein expressions of α-SMA and TGF-ß(1); were detected by Western blot. Immunocytochemisty (ICC) was used to measure the expression of α-SMA in HK-2. ELISA was used to assay the level of TGF-ß(1); in the supernatant. RESULTS: The gene expressions of α-SMA and TGF-ß(1); in PTH group were significantly higher than those in control group (P<0.05). In contrast, they were significantly lower in PTH and 1, 25(OH)(2);D(3); group than those in PTH group (P<0.05). Western blot results showed α-SMA could not be detected in normal HK-2 cells, which could be detected in PTH group. TGF-ß(1); protein expression in PTH group was higher than that in control group. In PTH and 1, 25(OH)(2);D(3); group, α-SMA and TGF-ß(1); protein expressions were significantly lower than those in PTH group (P<0.05). ICC results showed that α-SMA was hardly expressed in cells of control group. However, positive expression of α-SMA could be seen in many cells in PTH group. In PTH and 1, 25(OH)(2);D(3); group, the cells of α-SMA positive expressed were significantly less than those in PTH group (P<0.05). ELISA results showed that the level of TGF-ß(1); in the supernatant of PTH group was higher than that in control group, which was also higher than that in PTH and 1, 25(OH)(2);D(3); group (P<0.05). CONCLUSION: 1, 25(OH)(2);D(3); can attenuate PTH-induced transdifferentiation and TGF-ß(1); expression in cultured human renal tubular epithelial cells.