Hyperthermia promotes degradation of the acute promyelocytic leukemia driver oncoprotein ZBTB16/RARα.

The acute promyelocytic leukemia (APL) driver ZBTB16/RARα is generated by the t(11;17) (q23;q21) chromosomal translocation, which is resistant to combined treatment of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) or conventional chemotherapy, resulting in extremely low survival rates. In the current study, we investigated the effects of hyperthermia on the oncogenic fusion ZBTB16/RARα protein to explore a potential therapeutic approach for this variant APL. We showed that Z/R fusion protein expressed in HeLa cells was resistant to ATO, ATRA, and conventional chemotherapeutic agents. However, mild hyperthermia (42 °C) rapidly destabilized the ZBTB16/RARα fusion protein expressed in HeLa, 293T, and OCI-AML3 cells, followed by robust ubiquitination and proteasomal degradation. In contrast, hyperthermia did not affect the normal (i.e., unfused) ZBTB16 and RARα proteins, suggesting a specific thermal sensitivity of the ZBTB16/RARα fusion protein. Importantly, we found that the destabilization of ZBTB16/RARα was the initial step for oncogenic fusion protein degradation by hyperthermia, which could be blocked by deletion of nuclear receptor corepressor (NCoR) binding sites or knockdown of NCoRs. Furthermore, SIAH2 was identified as the E3 ligase participating in hyperthermia-induced ubiquitination of ZBTB16/RARα. In short, these results demonstrate that hyperthermia could effectively destabilize and subsequently degrade the ZBTB16/RARα fusion protein in an NCoR-dependent manner, suggesting a thermal-based therapeutic strategy that may improve the outcome in refractory ZBTB16/RARα-driven APL patients in the clinic.

Carbon monoxide attenuates lipopolysaccharide-induced lung injury by mitofusin proteins via p38 MAPK pathway.

BACKGROUND: The protective effects of carbon monoxide against the lipopolysaccharide (LPS)-induced lung injury were attributed to maintenance of mitochondrial dynamics, but the mechanisms remain unexplored. MATERIALS AND METHODS: Using a rat model of acute lung injury induced by LPS and the LPS attacking cell model, we investigated the effects of pretreatment of carbon monoxide molecule-2 (CORM-2) on the acute lung injury and expressions of mitofusin proteins that play a critical role in mitochondrial dynamics. RESULTS: We found that preadministration of CORM-2, not the inactive form of CORM-2, significantly reduced the lung injury, levels of inflammatory cytokines, and the degree of oxidative stress caused by LPS. What was more, it increased the expressions of mitofusin proteins. Similar findings were also found in LPS-stimulating cell model. However, when the cells were treated in combination with LPS, CORM-2, and SB203580, it completely abolished the protection of CORM-2, reflected by increased levels of inflammatory cytokines and malonaldehyde, decreased activities of superoxide dismutase, along with the lower expressions of mitofusin proteins and the ratio of p-p38 mitogen activated protein kinase to p38 mitogen activated protein kinase. CONCLUSIONS: Our observations suggest that pretreatment with CORM-2 could attenuate LPS-induced lung injury by inducing the expressions of mitofusin proteins via p38 mitogen activated protein kinase pathway.

Efficacy and tolerability of initial high vs low doses of S-(-)-amlodipine in hypertension.

In an 8-week randomized trial of patients with mild or moderate hypertension, the authors investigated the efficacy and tolerability of initial high (5.0 mg/d) vs low (2.5 mg/d) doses of S-(-)-amlodipine (equivalent to 5 and 10 mg of racemic amlodipine, respectively). In the S-(-)-amlodipine 2.5-mg group (n=263), 24-hour ambulatory systolic/diastolic blood pressure (±standard deviation) decreased from 131.5±15.0/82.1±10.7 mm Hg at baseline to 126.0±13.5/78.5±9.5 mm Hg at 8 weeks of follow-up by a least square mean (±standard error) change of 6.0±0.6/3.8±0.4 mm Hg. In the S-(-)-amlodipine 5-mg group (n=260), the corresponding changes were from 133.6±13.7/83.1±9.9 mm Hg to 125.0±12.0/78.2±8.9 mm Hg by 8.1±0.6/4.7±0.4 mm Hg, respectively. The between-group differences in changes in 24-hour systolic/diastolic blood pressure were 2.1/0.9 (P=.02/.17) mm Hg. Similar trends were observed for daytime and nighttime ambulatory and clinic blood pressure. The incidence rate was similar for all adverse events. An initial high dose of S-(-)-amlodipine improved ambulatory blood pressure control with similar tolerability as an initial low dose in hypertension.