Down‐regulated TINAGL1 in fibroblasts impairs wound healing in diabetes

Tian, Wenqing; Chen, Siyu; Chuan, Fengning; Zhao, Wenrui; Zhou, Bo

doi:10.1096/fj.202101438rr

Cited by 3 publications

(2 citation statements)

References 30 publications

(59 reference statements)

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“…Considering the short half‐life of the recombinant protein, we adopted the method of high dose and multi‐frequency intradermal injection. This refers to several previous studies on the application of recombinant protein in the treatment of diabetic wounds 14–17 . Diabetic mice were injected with 100 μL PDK4 (1 μg) intradermally on Days 0, 3, 5, 7, and 9.…”

Section: Methodsmentioning

confidence: 99%

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PDK4 facilitates fibroblast functions and diabetic wound healing through regulation of HIF‐1α protein stability and gene expression

Ma,

Mo,

Yang

et al. 2023

The FASEB Journal

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Fibroblast activation disorder is one of the main pathogenic characteristics of diabetic wounds. Orchestrated fibroblast functions and myofibroblast differentiation are crucial for wound contracture and extracellular matrix (ECM) formation. Pyruvate dehydrogenase kinase 4 (PDK4), a key enzyme regulating energy metabolism, has been implicated in modulating fibroblast function, but its specific role in diabetic wounds remains poorly understood. In this study, we investigated the impact of PDK4 on diabetic wounds and its underlying mechanisms. To assess the effect of PDK4 on human dermal fibroblasts (HDFs), we conducted CCK‐8, EdU proliferation assay, wound healing assay, transwell assay, flow cytometry, and western blot analyses. Metabolic shifts were analyzed using the Seahorse XF analyzer, while changes in metabolite expression were measured through LC–MS. Local recombinant PDK4 administration was implemented to evaluate its influence on wound healing in diabetic mice. Finally, we found that sufficient PDK4 expression is essential for a normal wound‐healing process, while PDK4 is low expressed in diabetic wound tissues and fibroblasts. PDK4 promotes proliferation, migration, and myofibroblast differentiation of HDFs and accelerates wound healing in diabetic mice. Mechanistically, PDK4‐induced metabolic reprogramming increases the level of succinate that inhibits PHD2 enzyme activity, thus leading to the stability of the HIF‐1α protein, during which process the elevated HIF‐1α mRNA by PDK4 is also indispensable. In conclusion, PDK4 promotes fibroblast functions through regulation of HIF‐1α protein stability and gene expression. Local recombinant PDK4 administration accelerates wound healing in diabetic mice.

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Section: Methodsmentioning

confidence: 99%

“…This refers to several previous studies on the application of recombinant protein in the treatment of diabetic wounds. [14][15][16][17] Diabetic mice were injected with 100 μL PDK4 (1 μg) intradermally on Days 0, 3, 5, 7, and 9. At the same time, the diabetic mice in the control group were injected with the same amount of PBS.…”

Section: Animal Experimentsmentioning

confidence: 99%

PDK4 facilitates fibroblast functions and diabetic wound healing through regulation of HIF‐1α protein stability and gene expression

Ma,

Mo,

Yang

et al. 2023

The FASEB Journal

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Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin β1

Lee,

Ham,

et al. 2024

J Transl Med

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Background Tumor cells of diffuse-type gastric cancer (DGC) are discohesive and infiltrate into the stroma as single cells or small subgroups, so the stroma significantly impacts DGC progression. Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma. Here, we identified CAF-specific secreted molecules and investigated the mechanism underlying CAF-induced DGC progression. Methods We conducted transcriptome analysis for paired normal fibroblast (NF)-CAF isolated from DGC patient tissues and proteomics for conditioned media (CM) of fibroblasts. The effects of fibroblasts on cancer cells were examined by transwell migration and soft agar assays, western blotting, and in vivo. We confirmed the effect of blocking tubulointerstitial nephritis antigen-like 1 (TINAGL1) in CAFs using siRNA or shRNA. We evaluated the expression of TINAGL1 protein in frozen tissues of DGC and paired normal stomach and mRNA in formalin-fixed, paraffin-embedded (FFPE) tissue using RNA in-situ hybridization (RNA-ISH). Results CAFs more highly expressed TINAGL1 than NFs. The co-culture of CAFs increased migration and tumorigenesis of DGC. Moreover, CAFs enhanced the phosphorylation of focal adhesion kinase (FAK) and mesenchymal marker expression in DGC cells. In an animal study, DGC tumors co-injected with CAFs showed aggressive phenotypes, including lymph node metastasis. However, increased phosphorylation of FAK and migration were reduced by blocking TINAGL1 in CAFs. In the tissues of DGC patients, TINAGL1 was higher in cancer than paired normal tissues and detected with collagen type I alpha 1 chain (COL1A1) in the same spot. Furthermore, high TINAGL1 expression was significantly correlated with poor prognosis in several public databases and our patient cohort diagnosed with DGC. Conclusions These results indicate that TINAGL1 secreted by CAFs induces phosphorylation of FAK in DGC cells and promotes tumor progression. Thus, targeting TINAGL1 in CAFs can be a novel therapeutic strategy for DGC.

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Integrating RNA-sequencing and network analysis to explore the mechanism of topical Pien Tze Huang treatment on diabetic wounds

Cao,

Tian,

Hou

et al. 2024

Front. Pharmacol.

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Introduction: Diabetic ulcers have become one of the major complications of diabetes mellitus (DM) and are a leading cause of death and disabling disease. However, current therapies are not effective enough to meet clinical needs. A traditional Chinese medicine (TCM) formula, Pien Tze Huang (PZH), is known as a medicine that is used to treat diabetic ulcers.Methods: In this study, PZH (0.05 g/cm2 and 0.15 g/cm2) and the positive drug-rhEGF were topically administered in a high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic full-thickness incisional wounds, respectively. Wound healing was assessed by wound closure rate, two-photon microscope (SHG), staining with Hematoxylin and eosin (H&E), and Masson's trichrome (MTC). Then, RNA sequencing (RNA-seq) analysis, Enzyme-linked immunosorbent assay (ELISA), western blotting, and immunofluorescence (IF), network analysis, were performed.Results and discussion: The results showed that PZH significantly accelerated wound healing, as well as enhanced the expression of collagen. RNA-seq analysis showed that PZH has functions on various biological processes, one of the key biological processes is inflammatory response. Tlr9, Klrk1, Nod2, Tlr2, and Ifng were identified as vital targets and the NF-κB signaling pathway was identified as the vital pathway. Additionally, PZH profoundly reduced the levels of Cleaved caspase-3 and promoted the expression of CD31 and TGF-β1. Mechanically, PZH significantly decreased expression of NKG2-D, NOD2, and TLR2, and further inhibited the activation of downstream NF-κB signaling pathway and inhibited expression of inflammatory factors (IFN-γ and IL-1β). Importantly, we found that several active ingredients may play a significant role in diabetic wound healing, including Notoginsenoside R1, Deoxycorticosterone, Ursolic acid, and 4-Methoxyphenol. In summary, our study sheds light on the complicated mechanisms underlying the promising anti-diabetic wounds of PZH and provides the discovery of agents treating diabetic ulcers.

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Down‐regulated TINAGL1 in fibroblasts impairs wound healing in diabetes

Cited by 3 publications

References 30 publications

PDK4 facilitates fibroblast functions and diabetic wound healing through regulation of HIF‐1α protein stability and gene expression

PDK4 facilitates fibroblast functions and diabetic wound healing through regulation of HIF‐1α protein stability and gene expression

Tubulointerstitial nephritis antigen-like 1 from cancer-associated fibroblasts contribute to the progression of diffuse-type gastric cancers through the interaction with integrin β1

Integrating RNA-sequencing and network analysis to explore the mechanism of topical Pien Tze Huang treatment on diabetic wounds

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