Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism

A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

The Dynamic Gait Index in Evaluating Patients with Normal Pressure Hydrocephalus for Cerebrospinal Fluid Diversion

BACKGROUND: Diagnosing normal pressure hydrocephalus (NPH) remains challenging. Most clinical tests currently used to evaluate suspected NPH patients for shunt surgery are invasive, require inpatient admission, and are not without complications. An objective, noninvasive, and low-cost alternative would be ideal. METHODS: A retrospective review was performed of prospectively collected dynamic gait index (DGI) scores, obtained at baseline and on every day of a 3- to 5-day lumbar cerebrospinal fluid (CSF) drainage trial on patients with suspected NPH at our institution. RESULTS: Between 2003 and 2014, 170 patients were suspected to have primary NPH (166, 97.6%) or secondary NPH (4, 2.4%). Using responsiveness to lumbar CSF drainage and subsequent shunting as the reference standard, we found that a baseline DGI ≥ 7 was found to have significant ability in selecting patients for permanent CSF diverting shunt surgery: sensitivity of 84.2% (95% confidence interval [95% CI]: 75.6%-90.2%), specificity of 80.6% (95% CI 70.0%-88.0%), and diagnostic odds ratio of 22.1 (95% CI 9.9-49.3). CONCLUSIONS: A baseline DGI ≥ 7 appears to provide an objective, low-cost, noninvasive measure to select patients with suspected NPH for a positive response to CSF diversion with high sensitivity, specificity and diagnostic odds ratio

Curve Laterality for Lateral Lumbar Interbody Fusion in Adult Scoliosis Surgery: The Concave Versus Convex Controversy

BACKGROUND: Minimally invasive lateral lumbar interbody fusion (LLIF) is an effective adjunct in adult degenerative scoliosis (ADS) surgery. LLIF approaches performed from the concavity or convexity have inherent approach-related risks and benefits. OBJECTIVE: To analyze LLIF approach-related complications and radiographic and clinical outcomes in patients with ADS. METHODS: A multicenter retrospective review of a minimally invasive adult spinal deformity database was queried with a minimum of 2-yr follow-up. Patients were divided into 2 groups as determined by the side of the curve from which the LLIF was performed: concave or convex. RESULTS: No differences between groups were noted in demographic, and preoperative or postoperative radiographic parameters (all P >.05). There were 8 total complications in the convex group (34.8%) and 21 complications in the concave group (52.5%; P =.17). A subgroup analysis was performed in 49 patients in whom L4-5 was in the primary curve and not in the fractional curve. In this subset of patients, there were 6 complications in the convex group (31.6%) compared to 19 in the concave group (63.3%; P < .05) and both groups experienced significant improvements in coronal Cobb angle, Oswestry Disability Index, and Visual Analog Scale score with no difference between groups. CONCLUSION: Patients undergoing LLIF for ADS had no statistically significant clinical or operative complication rates regardless of a concave or convex approach to the curve. Clinical outcomes and coronal plane deformity improved regardless of approach side. However, in cases wherein L4-5 is in the primary curve, approaching the fractional curve at L4-5 from the concavity may be associated with a higher complication rate compared to a convex approach

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism

Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism