Biology subjects

Okawa, H.

Publications and source records attributed to Okawa, H..

3 recordsLinked to original sources

bioRxiv2023

Factor XI localization in human deep venous thrombus and function of activated factor XI on venous thrombus formation and hemostasis in rabbit

BackgroundNovel anticoagulants targeting coagulation factor XI (FXI)/activated FXI (FXIa) are under development. However, whether FXI is present in human deep vein thrombosis (DVT) and whether FXIa and activated factor X (FXa) play different roles in venous thrombus formation and hemostasis remain unclear. This study aimed to determine the presence of FXI in DVT and the effects of direct oral FXIa and FXa inhibitors on venous thrombus formation and hemostasis in rabbits and mural thrombus formation in flow chamber system. MethodsWe immunohistochemically assessed FXI localization in human aspirated DVT (n=15). Additionally, we compared thrombus formation induced by endothelial denudation and stenosis in jugular vein, and skin bleeding time and volume between rabbits treated with direct FXIa inhibitors (ONO-1600586) and FXa inhibitors (rivaroxaban). Ex vivo rabbit and human blood were perfused on a flow chamber under low shear rates (70/s). ResultFXI was localized in all DVT, predominantly in fibrin-rich areas. The FXI-immunopositive area in the non-organizing area was greater than that in the organizing area. Although FXIa and FXa inhibitors comparably inhibited venous thrombus formation, FXIa inhibitors did not affect bleeding time or volume in rabbits. FXIa or FXa inhibitors mildly or strongly inhibited fibrin formation at low shear rates respectively. Furthermore, the FXIa inhibitor suppressed human FXIa activity, thrombin generation, and fibrin formation during perfusion. ConclusionThe pathological findings of human DVT suggest FXIs role in human DVT. FXIa inhibitors may inhibit less fibrin formation than FXa inhibitors, and may explain the minor role of FXIa in hemostasis. EssentialO_LIPresence of factor XI (FXI) in venous thrombus and less bleeding in its inhibition are unclear. C_LIO_LIWe assessed FXI localization in deep vein thrombosis (DVT) and function of FXIa in rabbit. C_LIO_LIFXI localized in human DVT that provide a rationale for FXI inhibition in human DVT. C_LIO_LIFXIa inhibitor inhibited less fibrin formation than factor Xa inhibitor under low-shear rate. C_LI

pathology↗

bioRxiv2023

Mouse gingival single-cell transcriptomic atlas: An activated fibroblast subpopulation guides oral barrier immunity in periodontitis

Periodontitis, one of the most common non-communicable diseases, is characterized by chronic oral inflammation and uncontrolled tooth supporting alveolar bone resorption. Its underlying mechanism to initiate aberrant oral barrier immunity has yet to be delineated. Here, we report a unique fibroblast subpopulation activated to guide oral inflammation (AG fibroblasts) identified in a single-cell RNA sequencing gingival cell atlas constructed from the mouse periodontitis models. AG fibroblasts localized beneath the gingival epithelium and in the cervical periodontal ligament responded to the ligature placement and to the discrete application of Toll-like receptor stimulants to mouse maxillary tissue. The upregulated chemokines and ligands of AG fibroblasts linked to the putative receptors of neutrophils in the early stages of periodontitis. In the established chronic inflammation, neutrophils together with AG fibroblasts appeared to induce type 3 innate lymphoid cells (ILC3s) that were the primary source of interleukin-17 cytokines. The comparative analysis of Rag2-/- and Rag2{gamma}c-/-mice suggested that ILC3 contributed to the cervical alveolar bone resorption interfacing the gingival inflammation. We propose that AG fibroblasts function as a previously unrecognized surveillant to initiate gingival inflammation leading to periodontitis through the AG fibroblast-neutrophil-ILC3 axis.

pathology↗

bioRxiv2021

Therapeutic downregulation of neuronal PAS domain 2 (Npas2) promotes surgical skin wound healing

Attempts to minimize scarring remain among the most difficult challenges facing surgeons, despite the use of optimal wound closure techniques. Previously, we reported improved healing of dermal excisional wounds in circadian clock neuronal PAS domain 2 (Npas2)-null mice. In this study, we performed high-throughput drug screening to identify a compound that downregulates Npas2 activity. The hit compound (Dwn1) suppressed circadian Npas2 expression, increased murine dermal fibroblast cell migration, and decreased collagen synthesis in vitro. Based on the in vitro results, Dwn1 was topically applied to iatrogenic full-thickness dorsal cutaneous wounds in a murine model. The Dwn1-treated dermal wounds healed faster with favorable mechanical strength and developed less granulation tissue than the controls. The expression of type I collagen, Tgf{beta}1, and -smooth muscle actin was significantly decreased in Dwn1-treated wounds, suggesting that hypertrophic scarring and myofibroblast differentiation are attenuated by Dwn1 treatment. NPAS2 may represent an important target for therapeutic approaches to optimal surgical wound management.

bioengineering↗