Pyruvate Kinase M2 Accelerates Cutaneous Wound Healing via Glycolysis and Wnt/ß-Catenin Signaling.

Cutaneous wound healing is a complex and dynamic process with high energy demand. The activation of glycolysis is essential for restoring the structure and function of injured tissues in wounds. Pyruvate kinase M2 (PKM2) is an enzyme that plays a crucial role in the last step of glycolysis. PKM2-mediated glycolysis is known to play an important role in diseases related to regeneration and inflammation. However, the role of PKM2 in wound healing has not been fully elucidated. In this study, we found that PKM2 expression and pyruvate kinase (PK) activity were increased with the activation of Wnt/ß-catenin signaling during wound healing in mice. TEPP-46, an allosteric activator of PKM2, enhanced HaCaT human keratinocyte migration and cutaneous wound healing with an increment of PK activity. Moreover, we confirmed the effect of co-treatment with TEPP-46 and KY19382, a Wnt/ß-catenin signaling activator through the interference with the CXXC-type zinc finger protein 5 (CXXC5) Dishevelled interaction, on wound healing. The combination treatment significantly accelerated wound healing, which was confirmed by the expression level of PCNA, keratin 14, and α-SMA. Furthermore, co-treatment induced angiogenesis in the wound beds. Overall, activation of both glycolysis and Wnt/ß-catenin signaling has the potential to be used as a therapeutic approach for wound healing.

KY19382 Accelerates Cutaneous Wound Healing via Activation of the Wnt/ß-Catenin Signaling Pathway.

The Wnt/ß-catenin signaling pathway plays important roles in the multi-phases of wound healing: homeostasis, inflammation, proliferative, and remodeling phases. However, there are no clinically available therapeutic agents targeting the Wnt/ß-catenin pathway. In this study, we tested the effect of 5, 6-dichloroindirubin-3'-methoxime (KY19382), a small molecule that activates the Wnt/ß-catenin pathway via interference with the function of the negative feedback regulator CXXC5, on cutaneous wound healing. KY19382 significantly enhanced cell migration of human keratinocytes and dermal fibroblasts with increased levels of ß-catenin, phalloidin, Keratin 14, proliferating cell nuclear antigen (PCNA), Collagen I, and alpha-smooth muscle actin (α-SMA) by activating the Wnt/ß-catenin signaling pathway without causing significant cytotoxicity. In addition, levels of Collagen I, Keratin 14, PCNA, and stem cell markers were significantly increased by KY19382 in a cutaneous murine wound healing model. Moreover, KY19382 treatment accelerated re-epithelialization and neo-epidermis formation with collagen deposition and stem cell activation at an early stage of cutaneous wound healing. Overall, KY19382 accelerates wound healing via activating the Wnt/ß-catenin pathway, and may have the potential to be used for the development of a new wound healing agent.

CXXC5 Mediates DHT-Induced Androgenetic Alopecia via PGD2.

The number of people suffering from hair loss is increasing, and hair loss occurs not only in older men but also in women and young people. Prostaglandin D2 (PGD2) is a well-known alopecia inducer. However, the mechanism by which PGD2 induces alopecia is poorly understood. In this study, we characterized CXXC5, a negative regulator of the Wnt/ß-catenin pathway, as a mediator for hair loss by PGD2. The hair loss by PGD2 was restored by Cxxc5 knock-out or treatment of protein transduction domain-Dishevelled binding motif (PTD-DBM), a peptide activating the Wnt/ß-catenin pathway via interference with the Dishevelled (Dvl) binding function of CXXC5. In addition, suppression of neogenic hair growth by PGD2 was also overcome by PTD-DBM treatment or Cxxc5 knock-out as shown by the wound-induced hair neogenesis (WIHN) model. Moreover, we found that CXXC5 also mediates DHT-induced hair loss via PGD2. DHT-induced hair loss was alleviated by inhibition of both GSK-3ß and CXXC5 functions. Overall, CXXC5 mediates the hair loss by the DHT-PGD2 axis through suppression of Wnt/ß-catenin signaling.

Pyruvate Kinase M2 Promotes Hair Regeneration by Connecting Metabolic and Wnt/ß-Catenin Signaling.

Hair follicle stem cells (HFSCs) utilize glycolytic metabolism during their activation and anagen induction. However, the role of pyruvate kinase M2 (PKM2), which catalyzes the final step of glycolysis, in hair regeneration has not been elucidated. In this study, we investigated the expression pattern and activity of PKM2 during the depilation-induced anagen progression in mice. We found that TEPP-46, a selective activator of PKM2, enhanced hair re-growth and proliferation of HFSCs. PKM2 expression was increased via up-regulation of Wnt/ß-catenin signaling, which is involved in hair regeneration. Moreover, a combined treatment with KY19382, a small molecule that activates Wnt/ß-catenin signaling, and TEPP-46 significantly enhanced hair re-growth and wound-induced hair follicle neogenesis (WIHN). These results indicate that simultaneous activation of the PKM2 and Wnt/ß-catenin signaling could be a potential strategy for treating alopecia patients.

Design of a Capacitorless DRAM Based on a Polycrystalline-Silicon Dual-Gate MOSFET with a Fin-Shaped Structure.

In this study, a capacitorless one-transistor dynamic random-access memory (1T-DRAM) cell based on a polycrystalline silicon dual-gate metal-oxide-semiconductor field-effect transistor with a fin-shaped structure was optimized and analyzed using technology computer-aided design simulation. The proposed 1T-DRAM demonstrated improved memory characteristics owing to the adoption of the fin-shaped structure on the side of gate 2. This was because the holes generated during the program operation were collected on the side of gate 2, allowing an expansion of the area where the holes were stored using the fin-shaped structure. Therefore, compared with other previously reported 1T-DRAM structures, the fin-shaped structure has a relatively high retention time due to the increased hole storage area. The proposed 1T-DRAM cell exhibited a sensing margin of 2.51 µA/µm and retention time of 598 ms at T = 358 K. The proposed 1T-DRAM has high retention time and chip density, so there is a possibility that it will replace DRAM installed in various applications such as PCs, mobile phones, and servers in the future.

Wnt/ß-catenin signaling activator restores hair regeneration suppressed by diabetes mellitus.

Diabetes mellitus is one of the most prevalent diseases in modern society. Many complicationssuch as hepatic cirrhosis, neuropathy, cardiac infarction, and so on are associated with diabetes. Although a relationship between diabetes and hair loss has been recently reported, the treatment of diabetic hair loss by Wnt/ß-catenin activators has not been achieved yet. In this study, we found that the depilation-induced anagen phase was delayed in both db/db mice and high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic mice. In diabetic mice, both hair regrowth and wound-induced hair follicle neogenesis (WIHN) were reduced because of suppression of Wnt/ß-catenin signaling and decreased proliferation of hair follicle cells. We identified that KY19382, a small molecule that activates Wnt/ß-catenin signaling, restored the capabilities of regrowth and WIHN in diabetic mice. The Wnt/ß-catenin signaling activator also increased the length of the human hair follicle which was decreased under high glucose culture conditions. Overall, the diabetic condition reduced both hair regrowth and regeneration with suppression of the Wnt/ß-catenin signaling pathway. Consequently, the usage of Wnt/ß-catenin signaling activators could be a potential strategy to treat diabetes-induced alopecia patients. [BMB Reports 2022; 55(11): 559-564].

3-D stacked polycrystalline-silicon-MOSFET-based capacitorless DRAM with superior immunity to grain-boundary's influence.

In this paper, a capacitorless one-transistor dynamic random access memory (1 T-DRAM) based on a polycrystalline silicon (poly-Si) metal-oxide-semiconductor field-effect transistor with the asymmetric dual-gate (ADG) structure is designed and analyzed through a technology computer-aided design (TCAD) simulation. A poly-Si thin film was used within the device due to its low fabrication cost and feasibility in high-density three-dimensional (3-D) memory arrays. We studied the transfer characteristics and memory performances of the single-layer ADG 1 T-DRAMs and the 3-D stacked ADG 1 T-DRAMs and analyze the reliability depending on the location and the number of grain-boundaries (GBs). The relative standard deviation (RSD) of the threshold voltages (Vth) is depending on the location and the number of GBs. The RSDs of the single-layer ADG 1 T-DRAM and the 3-D stacked ADG 1 T-DRAM are 1.58% and 0.68%, respectively. The RSDs of retention time representing the memory performances are 54.7% and 41%, respectively. As a result of the 3-D stacked structure, the averaging effect occurs, which greatly aids in improving the reliability of the memory performances as well as the transfer characteristics of 1 T-DRAMs depending on the influence of GBs. The proposed 3-D stacked ADG 1 T-DRAM helps implement a high-reliability single-cell memory device.

Analysis for DC and RF Characteristics Recessed-Gate GaN MOSFET Using Stacked TiO2/Si3N4 Dual-Layer Insulator.

The self-heating effects (SHEs) on the electrical characteristics of the GaN MOSFETs with a stacked TiO2/Si3N4 dual-layer insulator are investigated by using rigorous TCAD simulations. To accurately analyze them, the GaN MOSFETs with Si3N4 single-layer insulator are conducted to the simulation works together. The stacked TiO2/Si3N4 GaN MOSFET has a maximum on-state current of 743.8 mA/mm, which is the improved value due to the larger oxide capacitance of TiO2/Si3N4 than that of a Si3N4 single-layer insulator. However, the electrical field and current density increased by the stacked TiO2/Si3N4 layers make the device's temperature higher. That results in the degradation of the device's performance. We simulated and analyzed the operation mechanisms of the GaN MOSFETs modulated by the SHEs in view of high-power and high-frequency characteristics. The maximum temperature inside the device was increased to 409.89 K by the SHEs. In this case, the stacked TiO2/Si3N4-based GaN MOSFETs had 25%-lower values for both the maximum on-state current and the maximum transconductance compared with the device where SHEs did not occur; Ron increased from 1.41 mΩ·cm2 to 2.56 mΩ·cm2, and the cut-off frequency was reduced by 26% from 5.45 GHz. Although the performance of the stacked TiO2/Si3N4-based GaN MOSFET is degraded by SHEs, it shows superior electrical performance than GaN MOSFETs with Si3N4 single-layer insulator.