Hyperlipidemia and statins affect neurological outcome in lumbar spine injury.

The disabling pathophysiologic effects of lipid and neuroprotective effects of statins have recently been demonstrated for acute spinal cord injuries in animal models. This large scale population-based study aimed to investigate the effect hyperlipidemia and the use of statins in patients with lumbar spine injury. The National Health Insurance Research Database of Taiwan was used to identify patients with lumbar spine injury. A total of 2844 patients were grouped into three: no hyperlipidemia, hyperlipidemia using low-dose of statins (≤90 of the defined daily dosage (DDD)), and severe hyperlipidemia using high-dose of statins (>90 DDD). A Cox multiple regression model was used to compare the incidence rates of disability among the three groups. The results showed that patients with hyperlipidemia appeared a higher risk of permanent disability (adjusted HR = 1.38, p = 0.28). In subgroup analysis, patients with severe hyperlipidemia had a higher risk of disability (adjusted HR = 3.1, p < 0.004), whereas hyperlipidemia using low-dose statins had a similar risk of permanently disability (adjusted HR = 0.83, p = 0.661). Hyperlipidemia adversely affected the neurological outcomes of lumbar spinal injury. Statins may have the potential to reverse this higher risk of disability. However, this beneficiary effect of statins only existed in patients using a lower dose (≤90 DDD).

Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia.

From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism.

Involvement of p42/p44 MAPK, JNK, and NF-kappaB in IL-1beta-induced ICAM-1 expression in human pulmonary epithelial cells.

Interleukin-1beta (IL-1beta) has been shown to induce the expression of intercellular adhesion molecule-1 (ICAM-1) on airway epithelial cells and contributes to inflammatory responses. However, the mechanisms regulating ICAM-1 expression by IL-1beta in human A549 cells was not completely understood. Here, the roles of mitogen-activated protein kinases (MAPKs) and NF-kappaB pathways for IL-1beta-induced ICAM-1 expression were investigated in A549 cells. IL-1beta induced expression of ICAM-1 protein and mRNA in a time- and concentration-dependent manner. The IL-1beta induction of ICAM-1 mRNA and protein were partially inhibited by U0126 and PD98059 (specific inhibitors of MEK1/2) and SP600125 [a specific inhibitor of c-Jun-N-terminal kinase (JNK)]. U0126 was more potent than other inhibitors to attenuate IL-1beta-induced ICAM-1 expression. Consistently, IL-1beta stimulated phosphorylation of p42/p44 MAPK and JNK which was attenuated by pretreatment with U0126 or SP600125, respectively. Moreover, transfection with dominant negative mutants of MEK1/2 (MEK K97R) or ERK2 (ERK2 K52R) also attenuated IL-1beta-induced ICAM-1 expression. The combination of PD98059 and SP600125 displayed an additive effect on IL-1beta-induced ICAM-1 gene expression. IL-1beta-induced ICAM-1 expression was almost completely blocked by a specific NF-kappaB inhibitor helenalin. Consistently, IL-1beta stimulated translocation of NF-kappaB into the nucleus and degradation of IkappaB-alpha which was blocked by helenalin, U0126, or SP600125. Taken together, these results suggest that activation of p42/p44 MAPK and JNK cascades, at least in part, mediated through NF-kappaB pathway is essential for IL-1beta-induced ICAM-1 gene expression in A549 cells. These results provide new insight into the mechanisms of IL-1beta action that cytokines may promote inflammatory responses in the airway disease.