Network Pharmacology, Molecular Docking Analysis and Experiment Validations on Molecular Targets and Mechanisms of the Dispel-Scar Ointment in Scar Treatment

Article

Author: Li, Hui ; Yin, Libo ; Le, Sihua ; Li, Zhaoyi ; Cao, Yi

Background:Dispel-Scar Ointment is used in Traditional Chinese Medicine to treat scarred tissue and increasing evidence has shown that DSO is a potent therapeutic; however, its exact mechanism remains unexplored.Aim of the Study:This study explored the molecular mechanisms of action of DSO in scarring using network pharmacology, molecular docking, and experimental validation.Materials and Methods:Public databases were applied to predict the bioactive ingredients and putative targets of DSO against scars. A compounds-targets network was constructed using the Cytoscape software. Molecular docking was performed to verify the correlation between the major positive ingredients and hub targets, visualised using PyMol 2.3. Enrichment analysis was implemented using ClueGo and FunRich to specify the biological capabilities and related pathways of hub targets. SwissADME software was used to predict the ADME capabilities of the protein-related active compounds between DSO and scar in order to analyse the absorption and permeation across cell membranes of DSO. We assessed the skin sensitizer potential of the bioactive compounds of DSO using Pred-Skin computational tool. Experimental validations were conducted to elucidate the influence of DSO on keloid fibroblast cells using the CCK-8, woundscratch, cell reactive oxygen species, and western blot assays.Results:Network pharmacological analysis of DSO for scar treatment identified 146 ingredients and 1078 gene targets. Major targets included prostaglandin-endoperoxide synthase 2 matrix metallopeptidases and nitric oxide synthase 2. Molecular docking showed MMP2-flavoxanthin, MMP9-luteolin and MMP-9-kaempferol bound best to DSO. ClueGo analysis revealed 29 pathways (p<0.05) and FunRich 345 pathways (p<0.05), mainly toll-like receptor, TGF-β, interleukin- 4/13, glypican, and tumour necrosis factor-related apoptosis-inducing ligand pathways. The results valued by the SwissADME and PreADMET tools illustrated that 12 compounds in DSO were almost permeable through the skin. Pred-Skin computational tool represented that these 12 bioactive compounds reflected skin sensitizer potential. Experimental analysis revealed that DSO could restrain the proliferation and migration of scar fibroblasts and facilitate their apoptosis in a concentration-dependent manner. DSO also decreased TGF-β1, -βR2, pSMAD2, pSMAD3, SMAD4, CoL1a1, and MMP2 expression.Conclusion:Network pharmacology, molecular docking, and experimental validation showed DSO's feasibility in scar therapy. It may restrain scars through the TGF-β1/SMADs/MMPs signalling pathway, providing a basis for DSO's scar treatment application.

01 Nov 2021·LeukemiaQ1 · MEDICINE

CAR T cells targeting CD13 controllably induce eradication of acute myeloid leukemia with a single domain antibody switch

Q1 · MEDICINE

Article

Author: June, Carl H ; Ling, Sunbin ; Ma, Jian ; Hua, Xianxin ; Xing, Bowen ; Cao, Yan ; Wu, Yuan ; Katona, Bryson W ; Zhang, Xuyao ; Feng, Zijie ; Wang, Lei ; He, Xin

Acute myeloid leukemia (AML) has a poor prognosis after development of resistance to chemotherapy , chimeric antigen receptor (CAR) T immunotherapy has been successful in treating B cell-lineage mali gnancies by targeting CD19 , however, CAR T immunotherapy for AML is hindered by the challenge of toxic side effect including those that are on-target/off-tumor.The conventional CD13 CAR redir- ected by Nb157 eliminated AML in vitro and in vivo, but also damaged the normal hematopoietic stem cell (HSC) in a humanized immunol. system (HIS) mouse model.Herein we used sCAR T cells targeting CD13 to induce complete remission in AML, following the adminis- tration of the Nb157-switch targeting CD13, in both an AML cell line and patient-derived AML in vitro and in vivo.It is worth noting that CD13 is also expressed in some normal tissues besides hematopoietic cells, such as liver or kidney, and potential off-tumor toxicity for these tissues remains further evaluated. Toge- ther, these results demonstrate that the use of Nb switch in combination with sCAR can eradicate AML, while partially preserving HSC.

07 Jun 2021·Molecular Pharmaceutics

Preparation, Characterization, and Selection of Optimal Forms of (S)-Carvedilol Salts for the Development of Extended-Release Formulation

Article

Author: Zhao, Jie ; Cai, Zheng ; Lin, Zimin ; Zhang, Qi ; Xue, Hongjiao ; Huang, Baolin

(S)-carvedilol (S-CAR) is the dominant pharmacodynamic conformation of carvedilol, but its further development for extended-release formulation is restricted by its poor solubility. This study aimed to prepare and screen S-CAR salts that could be used to improve solubility and allow extended release. Five salts of S-CAR with well-known acid counterions (i.e., phosphate, hydrochloride, sulfate, fumarate, and tartrate) were produced using similar processes. However, these salts were obtained with water contents of 1.60-12.28%, and their physicochemical properties differed. The melting points of phosphate, hydrochloride, and tartrate were 1.1-1.5 times higher than that of the free base. The solubility of S-CAR salts was promoted to approximately 3-32 times higher than that of the free base at pH 5.0-8.0. Typical pH-dependent solubilities were evidently observed in S-CAR salts, but considerable differences in solubility properties among these salts were observed. S-CAR phosphate and hydrochloride possessed high melting points, considerable solubility, and excellent chemical and crystallographic stabilities. Accordingly, S-CAR phosphate and hydrochloride were chosen for further pharmacokinetic experiments and pharmaceutical study. S-CAR phosphate and hydrochloride extended-release capsules were prepared using HPMC K15 as the matrix and presented extended release in in vitro and in vivo evaluations. Results implied that water molecules in the hydrated salt were a potential threat to the achievement of crystal stability and thermostability. S-CAR phosphate and hydrochloride are suitable for further development of the extended-release formulation.

100 Deals associated with Scar(Caregen)

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Indication	Highest Phase	Country/Location	Organization	Date
Cicatrix	Preclinical	South Korea	Caregen Co., Ltd.	08 Sep 2024

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