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Dehydroeffusol, a phenanthrene isolated from Juncus effusus , is a Chinese medicine. To explore an efficacy of dehydroeffusol administration for prevention and cure of Alzheimer’s disease, here we examined the effect of dehydroeffusol on amyloid β 1-42 (Aβ 1-42 )-mediated hippocampal neurodegeneration . Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aβ 1-42 was injected intracerebroventricularly followed by oral administration for 12 days. Neurodegeneration in the dentate granule cell layer, which was determined 2 weeks after Aβ 1-42 injection, was rescued by dehydroeffusol administration. Aβ staining (uptake) was not reduced in the dentate granule cell layer by pre-administration of dehydroeffusol for 6 days, while increase in intracellular Zn 2+ induced with Aβ 1-42 was reduced, suggesting that pre-administration of dehydroeffusol prior to Aβ 1-42 injection is effective for Aβ 1-42 -mediated neurodegeneration that was linked with intracellular Zn 2+ toxicity. As a matter of fact, pre-administration of dehydroeffusol rescued Aβ 1-42 -mediated neurodegeneration. Interestingly, pre-administration of dehydroeffusol increased synthesis of metallothioneins, intracellular Zn 2+ -binding proteins, in the dentate granule cell layer, which can capture Zn 2+ from Zn-Aβ 1-42 complexes. The present study indicates that pre-administration of dehydroeffusol protects Aβ 1-42 -mediated neurodegeneration in the hippocampus by reducing intracellular Zn 2+ toxicity, which is linked with induced synthesis of metallothioneins. Dehydroeffusol, a novel inducer of metallothioneins, may protect Aβ 1-42 -induced pathogenesis in Alzheimer’s disease.

Dehydroeffusol, a phenanthrene isolated from Juncus effusus, is a Chinese medicine. To explore an efficacy of dehydroeffusol administration for prevention and cure of Alzheimer's disease, here we examined the effect of dehydroeffusol on amyloid β (Aβ )-mediated hippocampal neurodegeneration. Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aβ was injected intracerebroventricularly followed by oral administration for 12 days. Neurodegeneration in the dentate granule cell layer, which was determined 2 weeks after Aβ injection, was rescued by dehydroeffusol administration. Aβ staining (uptake) was not reduced in the dentate granule cell layer by pre-administration of dehydroeffusol for 6 days, while increase in intracellular Zn induced with Aβ was reduced, suggesting that pre-administration of dehydroeffusol prior to Aβ injection is effective for Aβ -mediated neurodegeneration that was linked with intracellular Zn toxicity. As a matter of fact, pre-administration of dehydroeffusol rescued Aβ -mediated neurodegeneration. Interestingly, pre-administration of dehydroeffusol increased synthesis of metallothioneins, intracellular Zn -binding proteins, in the dentate granule cell layer, which can capture Zn from Zn-Aβ complexes. The present study indicates that pre-administration of dehydroeffusol protects Aβ -mediated neurodegeneration in the hippocampus by reducing intracellular Zn toxicity, which is linked with induced synthesis of metallothioneins. Dehydroeffusol, a novel inducer of metallothioneins, may protect Aβ -induced pathogenesis in Alzheimer's disease.

Trypsin is one of the most extensively studied enzymes in biochemistry. However, little information is available on the role of the disulfide bonds to establish the correct conformation and enzyme activity during molecular evolution. To obtain this information, two additional disulfide bonds corresponding to those found in human trypsin were individually or simultaneously introduced into the trypsin-like protease cocoonase (Bombyx mori), which contains three consensus disulfide bonds, and structural effects were analyzed. Enzyme assays of the mutant proteins revealed that, during molecular evolution, the Cys19–Cys154 bond contributed to improving substrate recognition (Km), whereas the Cys134–Cys199 bond contributed to enhancing catalytic turnover (kcat). In addition, the Cys134–Cys199 disulfide bond significantly increased the structural stability, whereas the Cys19–Cys154 disulfide bond promoted a more compact folded ensemble. Interestingly, when both disulfide bridges were introduced together, their effects acted synergistically, yielding the highest catalytic activity toward the substrate BAEE (kcat/Km). Taken together, these findings suggest that trypsin-like proteases evolved through a two-step adaptive process: an initial phase in which the catalytic efficiency (kcat) and structural stability were enhanced, followed by a second phase in which the fold became more compact, thereby improving the overall enzymatic activity.

Objectives Selection criteria for self‐expandable metal stents (SEMSs) with or without cover during palliative treatment of distal malignant biliary obstruction (DMBO) remain unclear. We evaluated factors associated with time to recurrent biliary obstruction (TRBO) in fully covered SEMSs (FCSEMSs) and uncovered SEMSs (UCSEMSs). Methods We retrospectively analyzed consecutive patients with DMBO who received a SEMS. TRBO was determined using the Kaplan–Meier analysis, and complications were compared between the FCSEMS and UCSEMS groups. After TRBO‐associated factors were extracted using multivariate competing‐risks regression (CRR), propensity score‐adjusted CRRs were performed to verify their robustness. Results There were 180 patients (66 FCSEMSs and 114 UCSEMSs) enrolled in this study. There was no significant difference between median TRBO in the FCSEMS and UCSEMS groups (275 vs. 255 days, p = 0.67). Complications were more frequent in the FCSEMS than UCSEMS group (21.2% vs. 8.8%; p = 0.023). Multivariate CRR for TRBO‐associated factors revealed that “pancreatic ductal carcinoma (PDAC) treated with UCSEMS” was the only independent predictor of TRBO (p = 0.03). Similarly, the propensity score‐adjusted CRRs showed no significant difference in TRBO in “FCSEMS” vs “UCSEMS” (p = 0.96); however, there was a significant difference in “PDAC using UCSEMS” vs “other” (p = 0.043). In the palliative care group including any DMBO without chemotherapy, the first quartile of the TRBO of UCSEMS was 100 days. Conclusions UCSEMSs are a possible option for both patients with DMBO arising from PDAC and for patients with any DMBO receiving palliative care who should avoid SEMS‐related complications.

BLM and WRN are RecQ DNA helicases essential for genomic stability. Here we demonstrate that HERC2, a HECT E3 ligase, is critical for their functions to suppress G-quadruplex (G4) DNA. HERC2 interacts with BLM, WRN, and replication protein A (RPA) complexes during S-phase of the cell cycle. Depletion of HERC2 dissociates RPA from BLM and WRN complexes and significantly increases G4 formation. Triple depletion revealed that HERC2 has an epistatic relationship with BLM and WRN in their G4-suppressing function. In vitro, HERC2 releases RPA onto single-stranded DNA (ssDNA), rather than anchoring onto RPA-coated ssDNA. CRISPR/Cas9-mediated deletion of the catalytic ubiquitin-binding site of HERC2 causes RPA accumulation in the helicase complexes and increases G4, indicating an essential role for E3 activity in G4 suppression. Both HERC2 depletion and E3 inactivation sensitize cells to the G4-interacting compounds, telomestatin and pyridostatin. Overall, HERC2 is a master regulator of G4 suppression and affects the sensitivity of cells to G4 stabilizers.