Pharmacological inhibition of mTORC1 activity protects against inflammation-induced apoptosis of nucleus pulposus cells

Lumbar disc herniation is a common disease characterized by the degeneration of intervertebral discs (IVDs), accompanied by imbalance of metabolic and inflammatory homeostasis. Current studies establish that IVD degeneration is induced by increased apoptosis of nucleus pulposus (NP) cells. However, the underlying mechanisms of NP cell survival/apoptosis are not well elucidated. Here, we reveal a novel mechanism by which mTORC1 signaling controls NP cell survival through regulating metabolic homeostasis. We demonstrated that hyperactivated mTORC1 activity induced by inflammatory cytokines engenders the apoptosis of NP cells, whereas pharmacological inhibition of mTORC1 activity promotes NP cell survival. Using an integrative approach spanning metabolomics and biochemical approaches, we showed that mTORC1 activation enhanced glucose metabolism and lactic acid production, and therefore caused NP cell apoptosis. Our study identified mTORC1 in NP cells as a novel target for IVD degeneration, and provided potential strategies for clinical intervention of lumbar disc herniation.

Detection of genetic variations of regulator of G-protein signaling 2 in hypertensives by sequencing / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the new genetic variations of regulator of G-protein signalling 2 (RGS2) gene in Kazakh hypertensives.</p><p><b>METHODS</b>Totally 94 Kazakh patients with essential hypertension were enrolled and genomic DNA was extracted from their peripheral blood leukocytes. All the exon regions and their flanking sequences of RGS2 were directly sequenced.</p><p><b>RESULTS</b>We identified 13 variants including 5 common- single nucleotide polymorphisms with a minor allele frequency over 5%single nucleotide polymorphisms and 8 novel variations in 94 Kazakh hypertensives. Among these variations, 2 were in the introns and 7 in the promoter region. One subject had a G-to-C substitution at nucleotide 54 in exon 1, which lead to an amino acid substitution from K-to-N at position 18; another individual had an A-to-G substitution at nucleotide 2422 in exon 5, resulting in an amino acid from Y-to-C at position 178. Among eight common single nucleotide polymorphisms, -638A>G, -395G>C, 1891-1892TC I/D, and 2971G>C,and -43A>T and 2297A>G were in tight linkage disequilibrium with an r-square of more than 0.8, respectively.</p><p><b>CONCLUSIONS</b>The variants and their frequencies in RGS2 gene in Kazakh hypertensives may have ethnic differences when compared with other populations. The frequencies of the mutations are low in this population, and whether they influence blood pressure regulation requires further functional experiments.</p>