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Abstract Background Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated. Methods In the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs. Results Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs. Conclusion In conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.

Hardware security primitives, also known as physical unclonable functions(PUFs), perform innovative roles to extract the randomness unique to specific hardware. This paper proposes a novel hardware security primitive using a commercial off-the-shelf flash memory chip that is an intrinsic part of most commercial Internet of Things (IoT) devices. First, we define a hardware security source model to describe a hardware-based fixed random bit generator for use in security applications, such as cryptographic key generation. Then, we propose a hardware security primitive with flash memory by exploiting the variability of tunneling electrons in the floating gate. In accordance with the requirements for robustness against the environment, timing variations, and random errors, we developed an adaptive extraction algorithm for the flash PUF. Experimental results show that the proposed flash PUF successfully generates a fixed random response, where the uniqueness is 49.1%, steadiness is 3.8%, uniformity is 50.2%, and min-entropy per bit is 0.87. Thus, our approach can be applied to security applications with reliability and satisfy high-entropy requirements, such as cryptographic key generation for IoT devices.

The benefit of a smart manufacturing Industrial Internet of Things (IIoT) platform is that it can provide real-time monitoring, accurate analysis, and reporting for equipment by collecting data throughout the whole manufacturing facility. However, the increased internet connectivity of manufacturing machines or devices leads to various security vulnerabilities. In order to securely operate smart manufacturing IIoT systems in unmanned environments, it is necessary to establish a cryptographic key for protecting exchanged data between IIoT devices and stored data in the devices by using cryptographic algorithms. Especially, since the IIoT system is in an unmanned environment, the following two challenges must be solved: 1) The IIoT device must recover its own secret key without user interaction. 2) The IIoT device must prevent secret key recovery when anomaly situations such as unauthorized physical access occur. In this paper, we present a novel method to protect an IIoT device’s secret key in unmanned smart manufacturing environments, called Two-Factor Device DNA-based Fuzzy Vault scheme. To satisfy the two challenges, our proposed method generates a specific two-factor device DNA through the combination of the IIoT device’s intrinsic factor and its surrounding environments and then creates a vault set to conceal the secret key based on the two-factor device DNA. We also implement a prototype for ensuring the feasibility of our method by utilizing an EPUF and IEEE 802.15.4g receiver in a Raspberry Pi and a laptop, respectively, and then measure their performance. We then conduct experiments in an unmanned environment at the Smart Manufacturing Learning Center at Hanyang University by considering various normal and abnormal situations. Our experiment results show that the proposed method quickly extracts the secret key stored in the device in normal cases, but fails at key extraction in abnormal cases.

Transforming growth factor-β (TGF-β) is an important inducer of the epithelial-to-mesenchymal transition (EMT) in various cancers. Our previous study demonstrated that prohaptoglobin (proHp) stimulates Smad1/5 activation via ALK1, a TGF-β type I receptor, in endothelial cells, suggesting that proHp plays a role in TGF-β signaling. However, the function of proHp in cellular events downstream of Smads remains unclear. The current study investigated the effects of proHp on TGF-β-mediated Smad-dependent EMT induction and cell invasion in vitro using proHp-overexpressing SK-Hep1 liver cancer cells. The results of Western blotting, quantitative real-time RT-PCR, and immunocytochemistry indicated that proHp downregulated expression of mesenchymal marker and EMT regulator such as N-cadherin, vimentin, and twist, and upregulated expression of the epithelial marker E-cadherin. Compared with control cells, proHp-overexpressing cells exhibited high levels of ALK1/2/3 receptors and markedly increased Smad1/5 phosphorylation. Interestingly, proHp attenuated TGF-β-induced expression of mesenchymal markers and Smad2/3 phosphorylation. It also significantly suppressed cell invasion and migration. Knockdown of Smad1/5 abolished the inhibitory effects of proHp on TGF-β-stimulated Smad2/3 phosphorylation and mesenchymal marker expression. These findings indicate that proHp suppresses the TGF-β-induced EMT and cell invasion in vitro by enhancing Smad1/5 activation via ALK1/2/3 receptors and thus suppressing the Smad2/3 signaling pathway in SK-Hep1 cells. This study suggests that proHp may prevent a de-differentiation of hepatic cells and induce a cell differentiation by regulating the Smad signaling pathway.

A potential role of haptoglobin in arterial restructuring has been suggested, and our previous study demonstrated that prohaptoglobin, the precursor of haptoglobin, stimulates endothelial angiogenesis. However, the mechanisms underlying the angiogenic effects of prohaptoglobin are still unclear. Here, we investigated angiogenic signaling induced by prohaptoglobin using human umbilical vein endothelial cells. Prohaptoglobin upregulated the expression of placental growth factor (PlGF), vascular endothelial growth factor (VEGF)-A, and VEGF receptor 1 and 2, and also induced cell migration and tube network formation. PlGF knockdown attenuated these angiogenic effects of prohaptoglobin. Furthermore, a transcription factor profiling assay indicated that Smad is involved in PlGF expression in response to prohaptoglobin. Transforming growth factor-β1 (TGF-β1) expression and Smad1/5 phosphorylation were also induced by prohaptoglobin treatment. Blockade of TGF-β1 signaling using the TGF-β receptor kinase inhibitor LY2109761 or Smad1/5 siRNA reduced the prohaptoglobin-induced PlGF expression and in vitro tube formation. Knockdown of the TGF-β receptor ALK1, but not ALK5, with a specific siRNA blocked the Smad1/5 phosphorylation and PlGF expression induced by prohaptoglobin. These findings suggest that the angiogenic effects of prohaptoglobin are dependent on PlGF and mediated via a TGF-β1-ALK1-Smad1/5-PlGF/VEGFR1-VEGF-A/VEGFR2 signaling pathway.

Therapeutic applications of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have attracted considerable attention because of their immunomodulatory properties against immune-mediated, inflammatory diseases. Here, we demonstrated enhanced immunomodulatory properties of EVs secreted from endoplasmic reticulum (ER) stress inducer thapsigargin (TSG)-primed human Wharton’s jelly-derived MSCs (WJ-MSCs). EVs from TSG-primed WJ-MSCs (TSG-EV) showed increased yield and expression of immunomodulatory factors, such as transforming growth factor-β1 (TGFβ), cyclooxygenase-2 (COX2), and especially indoleamine 2,3-dioxygenase (IDO), compared to control EVs. TSG-EV showed a significantly enhanced immunosuppressive effect on human peripheral blood-derived T cell proliferation and Th1 and Th17 differentiation, whereas Treg and M2-type macrophage were enriched compared to a control EV-treated group. Furthermore, TSG-EV substantially mitigated mouse experimental colitis by reducing the inflammatory response and maintaining intestinal barrier integrity. A significant increase of Tregs and M2-type macrophages in colitic colons of a TSG-EV-treated mouse suggests an anti-inflammatory effect of TSG-EV in colitis model, possibly mediated by Treg and macrophage polarization. These data indicate that TSG treatment promoted immunomodulatory properties of EVs from WJ-MSCs, and TSG-EV may provide a new therapeutic approach for treatment of colitis.

Keeping IoT devices secure has been a major challenge recently. One of the possible solutions to secure IoT devices is to use a physically unclonable function (PUF). A PUF is a security primitive that can generate device-specific cryptographic information by extracting the features of hardware uncertainty. Because PUF instances are very difficult to replicate even by the manufacturer, the generated bit sequence can be used as cryptographic keys or as a unique identifier for the device. Regarding the implementation of PUF, the majority of PUFs introduced over the past decade are in the form of active components and have been implemented as separate chips or embedded as a part of a chip, making it difficult to use them in low-cost IoT devices due to cost and design flexibility. One approach to easily adopt PUFs in resource-constrained IoT devices is to use passive components such as resistors and capacitors (RC) that can be configured at low cost. The main feature of this RC-based PUF is that it extracts the small difference caused by charging and discharging of RC circuits and uses it as a response. In this paper, we extend the previous research and show the possibility to secure IoT devices by using the RC-based PUF.

Signal transducer and activator of transcription 3 (STAT3) andtelomerase are considered attractive targets for anticancertherapy. The in vitro anticancer activity of the gold(I) compoundauranofin was investigated using MDA-MB 231 human breastcancer cells, in which STAT3 is constitutively active. In cellculture, auranofin inhibited growth in a dose-dependent manner,and N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygenspecies (ROS), markedly blocked the effect of auranofin.Incorporation of 5-bromo-2’-deoxyuridine into DNA andanchorage-independent cell growth on soft agar were decreasedby auranofin treatment. STAT3 phosphorylation and telomeraseactivity were also attenuated in cells exposed to auranofin, butNAC pretreatment restored STAT3 phosphorylation andtelomerase activity in these cells. These findings indicate thatauranofin exerts in vitro antitumor effects in MDA-MB 231 cellsand its activity involves inhibition of STAT3 and telomerase.Thus, auranofin shows potential as a novel anticancer drug thattargets STAT3 and telomerase. [BMB Reports 2013; 46(1): 59-64]

Auranofin (2,3,4,6-tetra-O-acetyl-1-thio-β-d-glucopyranosato-S-[triethylphosphine] gold) is a gold(I)-containing antirheumatic drug that possesses anti-inflammatory properties. The pharmacological activity of this drug is associated with its ability to induce heme oxygenase-1 (HO-1). However, the mechanism underlying auranofin-mediated HO-1 induction remains unclear. We investigated the action of auranofin on activation of nuclear factor erythroid 2–related factor 2 (Nrf2), an activator of HO-1. Auranofin elevated cellular levels of Nrf2 by increasing protein stability but not transcriptional activation. Coimmunoprecipitation and Western blot analysis indicated that auranofin inhibited Nrf2 degradation by inducing the dissociation of the Nrf2 / Kelch-like ECH-associated protein 1 (Keap1) complex, which resulted in nuclear accumulation of Nrf2. In addition, auranofin treatment activated cellular Rac1 and induced inducible nitric oxide synthase (iNOS) expression. An inhibitor of Rac1 (NSC23766) blocked the iNOS induction as well as Nrf2 activation and HO-1 expression. NG-nitro-l-arginine methyl ester and aminoguanidine, inhibitors of iNOS, diminished the auranofin-induced Nrf2 activation and HO-1 expression. Phosphorylation of mitogen-activated protein kinases (MAPKs) was increased by auranofin treatment, and inhibitors of MAPKs partially diminished the Nrf2 activation. A chromatin immunoprecipitation assay showed that the Nrf2 activated by auranofin was involved in transactivation of the HO-1 gene. These findings indicate that auranofin leads to HO-1 upregulation by activating Keap1/Nrf2 signaling via Rac1/iNOS induction and MAPK activation. Keywords:: auranofin, nuclear factor erythroid 2–related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap1), heme oxygenase-1 (HO-1), Rac1