SummaryAAA domain-containing 3A (ATAD3A) is a member of the AAA-ATPase family. Three forms of ATAD3 have been identified: ATAD3A, ATAD3B and ATAD3C. In this study, we examined the type and expression of ATAD3 in lung adenocarcinoma (LADC). Expression of ATAD3A was detected by reverse transcription-polymerase chain reaction, immunoblotting, immunohistochemistry and confocal immunofluorescent microscopy. Our results show that ATAD3A is the major form expressed in LADC. Silencing of ATAD3A expression increased mitochondrial fragmentation and cisplatin sensitivity. Serum deprivation increased ATAD3A expression and drug resistance. These results suggest that ATAD3A could be an anti-apoptotic marker in LADC.

We previously demonstrated that metabolic switch and mitochondrial activation are required for osteogenic differentiation of human mesenchymal stem cells (hMSCs). However, stem cells in niches or transplanted into injured tissues constantly encounter hypoxic stress that hinders aerobic metabolism. Therefore, we investigated the effects of oxygen tension (1% vs. 21%) on metabolism and osteogenic differentiation of hMSCs. We found that hypoxia impaired osteogenic differentiation as indicated by attenuation of alkaline phosphatase activity and expression of osteogenic markers core binding factor a-1 and osteopontin. In addition, differentiationinduced mitochondrial activation was compromised as shown by the decrease in the expression of respiratory enzymes and oxygen consumption rate. On the contrary, anaerobic metabolism was augmented as revealed by the upregulation of glycolytic enzymes and increase of lactate production, rendering the cells to rely more on anaerobic glycolysis for energy supply. Moreover, administration of 2-deoxyglucose (a glycolytic inhibitor) but not antimycin A (a respiratory inhibitor) significantly decreased intracellular ATP levels of hMSCs differentiating under hypoxia. Treatment with cobalt chloride, a hypoxia-inducible factor-1a (HIF-1a) stabilizer, recapitulated the inhibitory effects of hypoxia, suggesting that HIF-1a is involved in the compromise of hMSCs differentiation. These results suggest that hypoxia inhibits metabolic switch and mitochondrial function and therefore suppresses osteogenic differentiation of hMSCs. Stem Cells

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The mechanistic role of colonic low folate metabolic stress (LFMS) in colorectal cancer (CRC) malignancy development remains unknown. Folate analysis on the 99 paired human CRC tissues localized LFMS to the deep invasive T3/T4 staged tumours with hypo-methylated sonic hedgehog (Shh) promoter region and amplified expressions of Shh ligand and Gli1 effector, which coincided with deregulated expressions of the epithelial-mesenchymal transition (EMT) mediators. Colonic folate levels of CRC were inversely correlated with pluripotent expressions of the SOX2, NANOG and OCT4 markers (p < 0.05). Exposure of human colon adenocarcinoma cells to LFMS microenvironment significantly hypomethylated Shh promoter region, activated Shh signaling, induced transcript and protein expressions of the pluripotent markers, promoted trans-differentiation as EMT by deregulation of Snail mediator and epithelial marker E-cadherin, increased MMP2/MMP9 enzymatic digestion on matrix protein for invasion, and promoted self-renewal capability of anchorage-independent tumor-spheroid formation. LFMS-induced cancer stem cell (CSC) signature and CRC invasion is synergized with inhibition of DNA methylation by 5-Aza-2-deoxycytidine (5AZA) in rewiring EMT genotypes, which can be blockade by the Shh inhibitor (cyclopamine). The in vivo and in vitro data corroboratively identify CSC-like molecular targets specific to the LFMS-predisposed invasive CRC through reprogramming DNA methylation-activated Shh signaling. The study highlights CSC targets specific to LFMS-predisposed invasive CRC in optimizing folate co-chemotherapy to minimize tumour metastasis potential of CRC patients.

Purpose Prior research on supply chain management has advanced substantially our understanding of how suppliers’ knowledge affects manufacturers’ green innovation. However, overlooking the suppliers’ diverse green knowledge in supplier networks, namely, green knowledge diversity, has limited our understanding of both supply chain management and green innovation development. To address this important issue, this study aims to rely on social network theory as the overarching framework and knowledge-based view as the underlying theoretical foundation to examine how green knowledge diversity contributes to manufacturers’ green innovation performance, while considering three types of supplier network properties (network strength, network heterogeneity and network density). Design/methodology/approach This study collects both survey and secondary proxy data from 209 manufacturing firms over three time periods (mid-2018, mid-2019 and mid-2020). PROCESS macro is applied to test the research hypotheses. Findings The results provide compelling evidence that green knowledge management processes partially mediate the effect of green knowledge diversity on manufacturers’ green innovation performance. The effect of green knowledge diversity is strengthened by supplier network strength and supplier network heterogeneity, but hindered by supplier network density. Practical implications This study provides a practical guide to help manufacturers enhance green innovation performance by properly managing and leveraging their suppliers’ diverse green knowledge domains in supplier networks. Originality/value This study contributes to the supply chain management and green innovation literature by offering novel theoretical and empirical insights into how manufacturers can use their supplier networks to strengthen green innovation.