Satellite glia as a critical component of diabetic neuropathy: Role of lipocalin‐2 and pyruvate dehydrogenase kinase‐2 axis in the dorsal root ganglion

Background The mechanisms underlying fibromyalgia (FM) pain are not understood. The US Food and Drug Administration has recommended three drugs for treating FM—namely, pregabalin, duloxetine and milnacipran; however, these medications are associated with severe side effects. Objective To create a mouse model of FM pain using dual injections of acidic saline to cause mechanical hyperalgesia and test whether ASIC3, Nav1.7 and Nav1.8 are involved in this process and whether electroacupuncture (EA) can reverse these phenomena. Methods The FM model was established by injecting acidic saline twice into 40 ICR mice. The mice were assigned to subgroups (n=8 each) treated with different EA frequencies (2, 15 and 50 Hz). ASIC3, Nav1.7 and Nav1.8 expression levels were measured by Western blotting and immunohistochemistry. Results Significant mechanical hyperalgesia was induced on day 8 in FM mice, which was reversed by 2, 15 and 50 Hz EA. ASIC3, Nav1.7 and Nav1.8 protein levels increased significantly in both the dorsal root ganglion and in the spinal cord of FM model mice. These changes were further attenuated by 2, 15 and 50 Hz EA. Conclusion Reduced nociceptive ASIC3, Nav1.7 and Nav1.8 proteins are involved in the preventive effects of EA against FM, and this series of molecules may represent targets for FM treatment.

Download Full-text

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

Cancers ◽

10.3390/cancers12071731 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1731 ◽

Cited By ~ 1

Author(s):

Carina Neitzel ◽

Philipp Demuth ◽

Simon Wittmann ◽

Jörg Fahrer

Keyword(s):

Colorectal Cancer ◽

Energy Metabolism ◽

Pyruvate Dehydrogenase ◽

Pyruvate Dehydrogenase Complex ◽

Tca Cycle ◽

Dietary Factors ◽

Pyruvate Dehydrogenase Kinase ◽

Driver Mutations ◽

The Tca Cycle

Colorectal cancer (CRC) is among the most frequent cancer entities worldwide. Multiple factors are causally associated with CRC development, such as genetic and epigenetic alterations, inflammatory bowel disease, lifestyle and dietary factors. During malignant transformation, the cellular energy metabolism is reprogrammed in order to promote cancer cell growth and proliferation. In this review, we first describe the main alterations of the energy metabolism found in CRC, revealing the critical impact of oncogenic signaling and driver mutations in key metabolic enzymes. Then, the central role of mitochondria and the tricarboxylic acid (TCA) cycle in this process is highlighted, also considering the metabolic crosstalk between tumor and stromal cells in the tumor microenvironment. The identified cancer-specific metabolic transformations provided new therapeutic targets for the development of small molecule inhibitors. Promising agents are in clinical trials and are directed against enzymes of the TCA cycle, including isocitrate dehydrogenase, pyruvate dehydrogenase kinase, pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase (KGDH). Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy.

Download Full-text