To date, mechanisms of tumour cell survival under energy stress are not well understood. Cumulative evidence is beginning to reveal that specific mitochondrial morphologies are often associated with energetic states and survival of cells. However, the functional roles of mitochondria in the metabolic adaptation of tumour cells to energy stress remain to be elucidated. In this study, we first investigated the changes in mitochondrial morphology induced by nutrition deprivation in tumour cells, and the underlying molecular mechanism. We then systematically explored glucose metabolism reprogramming by energy stress-induced alteration of mitochondrial morphology and its effect on tumour cell survival. Our results showed that starvation treatment resulted in a dramatic mitochondrial elongation, which was mainly mediated by DRP1 phosphorylation through protein kinase A activation and subsequent suppression of mitochondrial translocation of DRP1. We further observed that tumour cells under an energy stress condition exhibited a clear shift from glycolysis towards oxidative phosphorylation, which was reversed by the recovery of mitochondrial fission induced by forced expression of mutant DRP1. Mechanistically, energy stress-induced mitochondrial elongation facilitated cristae formation and assembly of respiratory complexes to enhance oxidative phosphorylation, which in turn exhibited a feedback inhibitory effect on glycolysis through NAD-dependent SIRT1 activation. In addition, our data indicated that DRP1-mediated mitochondrial elongation under energy stress was essential for tumour cell survival both in vitro and in vivo and predicted poor prognosis of hepatocellular carcinoma patients. Overall, our study demonstrates that remodelling of mitochondrial morphology plays a critical role in tumour cell adaptation to energy stress by reprogramming glucose metabolism.

The probability of suffering the mood disorder depression is up to 30% in women and 15% in men during their life span. Pharmacological options for depression are limited: conventional antidepressants have low efficacy and a delayed onset of action (several weeks). Here we investigate the antidepressant actions of inhibitors of monoacylglycerol lipase (MAGL), the major degradative enzyme of the endocannabinoid 2-arachidonoylglycerol. A low-dose of MAGL inhibitors produces antidepressant effects on acute stress-exposed mice, through glutamatergic synaptic long-term depression (LTD), without significant effects on chronic corticosterone-exposed mice. In contrast, a high-dose of MAGL inhibitors produces pro- or antidepressant effects on acute stress- or chronic corticosterone-exposed mice, respectively, through GABAergic synaptic disinhibition. In the hippocampus, in vivo inhibition of MAGL induces a CB1 cannabinoid receptor (CB1R)-dependent suppression of inhibitory GABAergic synapses and an in vivo LTD of excitatory glutamatergic synapses. LTD induction requires CB1R in astroglial cells (but not in GABAergic or glutamatergic neurons) and postsynaptic glutamate receptors. The conventional antidepressant fluoxetine produces rapid or delayed antidepressant effects in acute stress- or chronic corticosterone-exposed mice, respectively. We propose that depression-like behavior of animals in response to acute stress is the normal behavioral response, and thus, MAGL inhibitors, which produce antidepressant effects in chronic corticosterone-exposed animals through GABAergic synaptic disinhibition, represent a new class of rapidly-acting and long-lasting antidepressants.

We examined whether human fetal mesenchymal stem cells (FMSCs) derived from fetal bone marrow were able to differentiate into functional hepatocyte-like cells in vitro. The surface phenotype of FMSCs was characterized by flow cytometry. To induce hepatic differentiation of FMSCs, we added hepatocyte growth factor, basic fibroblast growth factor and oncostatin M into the cell culture medium. After 21 days of hepatocyte induction, FMSCs expressed the hepatocyte-specific markers, alpha-fetoprotein and cytokeratin 18, as demonstrated by immunofluorescence staining. Differentiated FMSCs also demonstrated in vitro functions characteristic of liver cells, including albumin production, urea secretion and glycogen storage. In conclusion, fetal bone marrow-derived FMSCs are able to differentiate into functional hepatocytelike cells and may serve as a source of cells for liver disease therapy.

This study evaluated the use of a new collagen-reactive monomer (CRM), isocyanate-terminated urethane methacrylate precursor, which has covalent affinity to dental collagen, in the formation of dentin-resin bonds and compared it with 2 other dental adhesives. Dentin specimens were bonded with either the CRM-based adhesive (CBA), One-Step (OS; Bisco, Inc.), or a negative adhesive (NA) control and subjected to 24-h storage in water, thermocycling to simulate 1-y clinical function, or a matrix metalloproteinase–mediated aging process. We tested the microtensile bond strength (µTBS), characterized the bonding interface with an atomic force microscope, conducted micro-Raman analysis, and performed leakage tests and in situ zymography. CBA and OS exhibited comparable bonding strength after 24 h ( P > 0.05); however, there was a sharp decrease in µTBS after aging for all except CBA ( P < 0.001). Raman spectra results indicated increased collagen crosslinking and chemical reaction between the adhesive and collagen in the CBA group. CBA achieved high-quality hybridization with collagen, improving mechanical properties and integrity, and decreased the enzyme-mediated degradation of the bonding interface by inhibiting collagenolytic activity. With the promising bonding durability of coapplied CBA, CRM may be the first dental adhesive to provide strong and long-lasting resin-dental collagen bonding without the additional conditioning step. The use of CBA results in high-quality hybrid layers that protect the resin-dentin interface from harmful biological and chemical activities commonly occurring in the oral environment.

The safety and performance of angioplasty using a normal-sized Gateway(™) balloon and Wingspan(™) stent for intracranial atherosclerotic stenosis were assessed. Seventy-two patients with intracranial stenosis (≥ 50%) were treated using an undersized (group U) or normal-sized (group N) Gateway(™) balloon and a Wingspan(™) stent. All patients were successfully stented. Stenosis improved from 74.2% before treatment to 23.8% immediately after treatment in group U and from 70.9% to 20.1% in group N. The two groups had similar rates of major periprocedural neurological complications (9.0% overall), none of which led to death. Residual stenosis at follow-up was 40.8% and 32.5% in groups U and N, respectively. In-stent re-stenosis (ISR) was significantly less frequent in group N (22.0%) than in group U (33.3%). It is concluded that use of a normal-sized Gateway(™) balloon and Wingspan(™) stent appears to be safe, to have a high rate of technical success, good immediate post-operative results and a low ISR rate.