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Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase α 1 (MATα1) have lower PHB1 expression and we reported c-MYC interacts directly with both proteins. Furthermore, c-MYC and MATα1 expert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MATα1 and c-MYC and PHB1's role in liver tumorigenesis. We found PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down-regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1's expression correlate inversely with growth. PHB1 and MAT1A positively regulate each other's expression, whereas PHB1 negatively regulates the expression of c-MYC, MAFG and c-MAF. Both PHB1 and MATα1 heterodimerize with MAX, bind to the E-box element and repress E-box promoter activity. PHB1 promoter contains a repressive E-box element, is occupied mainly by MAX, MNT and MATα1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c-MYC, c-MAF and MAFG in cancer cells and human HCC/CCA. All 8-month old liver-specific Phb1 knockout mice developed HCC and one developed CCA. 5-month old Phb1 heterozygotes but not Phb1 flox mice developed aberrant bile duct proliferation and one developed CCA 3.5 months after left and median bile duct ligation (LMBDL). Phb1 heterozygotes had a more profound fall in the expression of GSH synthetic enzymes and higher hepatic oxidative stress following LMBDL. Conclusion We have identified PHB1, down-regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E-box. PHB1 positively regulates MAT1A while suppressing c-MYC, MAFG and c-MAF expression. In mice, reduced PHB1 expression predisposes to the development of cholestasis-induced CCA.

Polyamines can alleviate the inhibitory effects of salinity on plant growth by regulating photosynthetic efficiency. However, little information is available to explain the specific mechanisms underlying the contribution of polyamines to salt tolerance of the photosynthetic apparatus. Here, we investigated the role of putrescine (Put) on the photosynthetic apparatus of cucumber seedlings under salt stress. We found that NaCl stress resulted in severe ion toxicity and oxidative stress in cucumber chloroplasts. In addition, salinity caused a significant increase in the saturated fatty acid contents of thylakoid membranes. Put altered unsaturated fatty acid content, thereby alleviating the disintegration of thylakoid grana lamellae and reducing the number of plastoglobuli in thylakoid membranes. BN-PAGE revealed Put up-regulated the expression of ATP synthase, CP47, D1, Qb, and psbA proteins and down-regulated CP24, D2, and LHCII type III in NaCl-stressed thylakoid membranes. qRT-PCR analysis of gene expression was used to compare transcript and protein accumulation among 10 candidate proteins. For five of these proteins, induced transcript accumulation was consistent with the pattern of induced protein accumulation. Our results suggest that Put regulates protein expression at transcriptional and translational levels by increasing endogenous polyamines levels in thylakoid membranes, which may stabilise photosynthetic apparatus under salt stress.

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Neuropathic pain represents a challenge to clinicians, because it is resistant to commonly prescribed analgesics due to its largely unknown mechanisms. Here, we investigated a descending dopaminergic pathway-mediated modulation of trigeminal neuropathic pain. We performed chronic constriction injury of the infraorbital nerve from the maxillary branch of trigeminal nerve to induce trigeminal neuropathic pain in mice. Our retrograde tracing showed that the descending dopaminergic projection from hypothalamic A11 nucleus to spinal trigeminal nucleus caudalis is bilateral. Optogenetic/chemogenetic manipulation of dopamine receptors D1 and D2 in the spinal trigeminal nucleus caudalis produced opposite effects on the nerve injury-induced trigeminal neuropathic pain. Specific excitation of dopaminergic neurons in the A11 nucleus attenuated the trigeminal neuropathic pain via the activation of D2 receptors in the spinal trigeminal nucleus caudalis. Conversely, specific ablation of the A11 dopaminergic neurons exacerbated such pain. Our results suggest that the descending A11-spinal trigeminal nucleus caudalis dopaminergic projection is critical for the modulation of trigeminal neuropathic pain and could be manipulated to treat such pain.

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