Deping Kong’s research while affiliated with The Second Xiangya Hospital of Central South University and other places

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Publications (48)


PGD2/DP1 axis promotes liver regeneration by secreting Wnt2 in Kupffer cells in mice
  • Article

July 2024

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22 Reads

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1 Citation

Hepatology

Juanjuan Li

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Yinghong Zheng

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Zhenzhen Duan

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[...]

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Ying Yu

Background and aims The liver possesses a remarkable regenerative capacity in response to injuries or viral infections. Various growth factors and cytokines are involved in regulating liver regeneration. Prostaglandin (PG) D 2 , a pro-resolution lipid mediator, is the most abundant hepatic prostanoid. However, the role of PGD 2 in the injury-induced liver regeneration remains unclear. Approach and results Two-thirds partial hepatectomy (70% PH), massive hepatectomy (85% resection), and carbon tetrachloride-induced chronic injury were performed in mice to study the mechanisms of live regeneration. Hepatic PGD 2 production was elevated in mice after PH. Global deletion of D prostanoid receptor (DP) 1, but not DP2, slowed PH-induced liver regeneration in mice, as evidenced by lower liver weight to body weight ratio, less Ki67 ⁺ hepatocyte proliferation, and G2/M phase hepatocytes. Additionally, DP1 deficiency specifically in resident Kupffer cells (KCs), and not in endothelial cells or hepatic stellate cells, retarded liver regeneration in mice post-PH. Conversely, the overexpression of exogenous DP1 in KCs accelerated liver regeneration in mice. Mechanistically, DP1 activation promoted Wnt2 transcription in a PKA/CREB-dependent manner in resident KCs and mediated hepatocyte proliferation through Frizzled8/β-catenin signaling. Adeno-associated virus vector serotype 8 (AAV8)-mediated Frizzled8 knockdown in hepatocytes attenuated accelerated liver regeneration in KC-DP1 transgenic mice post-PH. Treatment with the DP1 receptor agonist BW245C promotes PH-induced liver regeneration in mice. Conclusions DP1 activation mediates crosstalk between KCs and hepatocytes through Wnt2, and facilitates liver regeneration. Hence, DP1 may serve as a novel therapeutic target in acute and chronic liver diseases.


HMGB2 Release Promotes Pulmonary Hypertension and Predicts Severity and Mortality of Patients With Pulmonary Arterial Hypertension

April 2024

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14 Reads

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2 Citations

Arteriosclerosis Thrombosis and Vascular Biology

BACKGROUND Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, which involves aberrant proliferation and apoptosis resistance of the pulmonary arterial smooth muscle cells (PASMCs), resembling the hallmark characteristics of cancer. In cancer, the HMGB2 (high-mobility group box 2) protein promotes the pro-proliferative/antiapoptotic phenotype. However, the function of HMGB2 in PH remains uninvestigated. METHODS Smooth muscle cell (SMC)–specific HMGB2 knockout or HMGB2-OE (HMGB2 overexpression) mice and HMGB2 silenced rats were used to establish hypoxia+Su5416 (HySu)-induced PH mouse and monocrotaline-induced PH rat models, respectively. The effects of HMGB2 and its underlying mechanisms were subsequently elucidated using RNA-sequencing and cellular and molecular biology analyses. Serum HMGB2 levels were measured in the controls and patients with pulmonary arterial (PA) hypertension. RESULTS HMGB2 expression was markedly increased in the PAs of patients with PA hypertension and PH rodent models and was predominantly localized in PASMCs. SMC-specific HMGB2 deficiency or silencing attenuated PH development and pulmonary vascular remodeling in hypoxia+Su5416-induced mice and monocrotaline-treated rats. SMC-specific HMGB2 overexpression aggravated hypoxia+Su5416-induced PH. HMGB2 knockdown inhibited PASMC proliferation in vitro in response to PDGF-BB (platelet-derived growth factor-BB). In contrast, HMGB2 protein stimulation caused the hyperproliferation of PASMCs. In addition, HMGB2 promoted PASMC proliferation and the development of PH by RAGE (receptor for advanced glycation end products)/FAK (focal adhesion kinase)-mediated Hippo/YAP (yes-associated protein) signaling suppression. Serum HMGB2 levels were significantly increased in patients with PA hypertension, and they correlated with disease severity, predicting worse survival. CONCLUSIONS Our findings indicate that targeting HMGB2 might be a novel therapeutic strategy for treating PH. Serum HMGB2 levels could serve as a novel biomarker for diagnosing PA hypertension and determining its prognosis.


Long-read nanopore RNA sequencing to identify full-length transcripts in VSMCs
a Schematic of experimental design for this study. Primary HASMCs (passage 3 to 6) were transfected with negative control miRNA or hsa-miR-221-3P (50 nM) for 36 h. Subsequently, cells were treated with vehicle control, PDGF (15 ng/mL), or TGFβ (10 ng/ml) for another 24 h and analyzed. n = 4 for each group. b Composition of different transcript types in all detected full-length transcripts. c Proportion of genes with annotated and unannotated transcripts in different gene types. d Stack plot shows the fractions of genes detected in different sequencing technologies in each sample. e Bar plot shows the number of transcripts in genes detected in ONT platform. f Length distribution of annotated and unannotated transcripts detected in ONT platform.
Differential transcripts in the miR-221, PDGF, and TGFβ groups
a Venn plot shows overlaps of detected transcripts among different sample groups. b Upset plot shows the numbers of shared transcripts that were dysregulated in different groups. c Heatmap shows the relative expression levels of differential transcripts across all samples. Transcripts are ordered by sets in b. Numbers on the left indicate the number of differential transcripts. Bar plots on the right show the significantly enriched pathways for each set of transcripts.
Aberrant alternative splicing events in VSMCs
a The percentages of different ASE types in annotated and unannotated genes. b The number of differential ASEs in each sample group. c The percentages of differential ASEs for each ASE type across different sample groups. d Heatmap shows PSI values of representative genes that were detected with top differential ASEs across samples. e Volcano plots show the difference of switching isoforms in miR-221, PDGF, and TGFβ groups. f The isoform structures, gene expression, isoform expression, and isoform usages of the PAIP1 gene in the miR-221 group. g The isoform switching details of the RARG gene in the PDGF group. h The isoform switching details of the ACTA2 gene in the TGFβ group. Error bars represent the means ± SDs. In (f-h), differential analysis of gene and isoform expression were performed by DESeq2 package, and isoform usage was by DEXSeq package. n = 4 independent samples were included in each group. Abbreviations in f-h: IDR, intrinsically disordered region; MIF4G, middle domain of eukaryotic initiation factor 4G; PAM2, PABP-interacting motif 2; zf-C4, zinc finger C4 type.
Expression levels and ORF changes in unannotated transcripts
a Box plots comparing the expression levels between annotated and unannotated transcripts in protein coding genes, lncRNAs, and pseudogenes. Each box represents the IQR and median of TPM value of each transcript, whiskers indicate 1.5 times the IQR. P, Wilcoxon’s rank-sum test. n = 443,200 annotated and n = 1,373,392 protein coding transcripts, n = 41,168 annotated and n = 39,984 unannotated lncRNA transcripts, n = 5472 annotated and n = 15,840 unannotated pseudogene transcripts, respectively. The individual expression values (data points) could be found in the Supplementary Data 8. b The length distributions of ORF from annotated and unannotated transcripts. c The percentage of transcripts with different ORF changes. d Bar plots showing the number of different ORF changes in each ASE type.
Experimental validation of the unannotated transcript CISD1-u derived from the CISD1 gene
a The validation of the unannotated transcript CISD1-u in HASMCs by 5’ RACE. Red arrows indicate the primer pairs complementary to the indicated CISD1-u novel exon-intron boundary sequences used for 5’ RACE. b The sequence validation of the unannotated transcript CISD1-u in HASMCs by Sanger sequencing. Red arrows indicate the splice junction sites, and blue arrows indicate where the primers target. c, d Validation of the splicing in novel transcript CISD1-u by percent splicing inclusion c and quantification analysis d upon the treatment of si-CISD1-u or PDGF. Red arrows in c indicate the primer pairs used for semiquantitative RT-PCR. n = 3 independent samples were used in each group. e Expression quantification of cell proliferation-related genes (Cyclin D1 and OPN) upon CISD1-u knockdown. n = 3 independent samples were used in each group. f Expression quantification of contraction-related genes (ACTA2 and TAGLN) upon CISD1-u knockdown. n = 3 independent samples were used in each group. g, h Representative western blot and quantification of the protein levels of Cyclin D1 and SMα-actin upon CISD1-u knockdown post PDGF treatment. These western blots were derived from different runs with the same sample loading. GAPDH was used as a loading control. In e–h, primary HASMCs were transfected with scramble or si-CISD1-u (50 nM) for 36 h. Subsequently, cells were treated with vehicle control or PDGF (15 ng/ml) for another 24 h for mRNAs or 48 h for protein assays. n = 3 independent samples were used in each group. i Quantitative analysis of cell proliferation assay. n = 6 independent samples were used in each group. j Representative images of wound-healing assay. Images were taken at 0 and 24 h after scratching (white lines indicate wound edges). k Quantitative analysis wound-healing assay in j. Three or four independent samples were used in each group. In i–k, primary HASMCs were transfected with scramble or si-CISD1-u (50 nM). Cells were treated with vehicle control or PDGF (15 ng/ml) for another 24 h and subject to CCK8 cell proliferation assay or scratch-wound assay. Error bars represent the means ± SDs. P: two-way ANOVA with Bonferroni post hoc analysis.
Nanopore long-read RNA sequencing reveals functional alternative splicing variants in human vascular smooth muscle cells
  • Article
  • Full-text available

October 2023

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45 Reads

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5 Citations

Communications Biology

Vascular smooth muscle cells (VSMCs) are the major contributor to vascular repair and remodeling, which showed high level of phenotypic plasticity. Abnormalities in VSMC plasticity can lead to multiple cardiovascular diseases, wherein alternative splicing plays important roles. However, alternative splicing variants in VSMC plasticity are not fully understood. Here we systematically characterized the long-read transcriptome and their dysregulation in human aortic smooth muscle cells (HASMCs) by employing the Oxford Nanopore Technologies long-read RNA sequencing in HASMCs that are separately treated with platelet-derived growth factor, transforming growth factor, and hsa-miR-221-3P transfection. Our analysis reveals frequent alternative splicing events and thousands of unannotated transcripts generated from alternative splicing. HASMCs treated with different factors exhibit distinct transcriptional reprogramming modulated by alternative splicing. We also found that unannotated transcripts produce different open reading frames compared to the annotated transcripts. Finally, we experimentally validated the unannotated transcript derived from gene CISD1, namely CISD1-u, which plays a role in the phenotypic switch of HASMCs. Our study characterizes the phenotypic modulation of HASMCs from an insight of long-read transcriptome, which would promote the understanding and the manipulation of HASMC plasticity in cardiovascular diseases.

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Tumor Acidic Microenvironment-Responsive Promodulator Iron Oxide Nanoparticles for Photothermal-Enhanced Chemodynamic Immunotherapy of Cancer

January 2023

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23 Reads

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17 Citations

ACS Biomaterials Science & Engineering

Cancer nanomedicine combined with immunotherapy has emerged as a promising strategy for the treatment of cancer. However, precise regulation of the activation of antitumor immunity in targeting tissues for safe and effective cancer immunotherapy remains challenging. Herein, we report a tumor acidic microenvironment-responsive promodulator iron oxide nanoparticle (termed as FGR) with pH-activated action for photothermal-enhanced chemodynamic immunotherapy of cancer. FGR is formed via surface-modifying iron oxide nanoparticles with a dextran-conjugated Toll-like receptor agonist (R848) containing an acid-labile bond. In an acidic tumor microenvironment, the acid-responsive bonds are hydrolyzed to trigger the specific release of R848 to promote the maturation of dendritic cells. In addition, iron oxide nanoparticles within FGR exert photothermal and chemodynamic effects under near-infrared laser irradiation to directly kill tumor cells and induce immunogenic cell death. The synergistic effect of the released immunogenic factors and the acid-activated TLR7/8 pathway stimulates the formation of strong antitumor immunity, resulting in increased infiltration of cytotoxic CD8+ T cells into tumor tissues. As a result, FGR achieves acid-responsive on-demand release and activation of modulators in tumor sites and mediates photothermal-enhanced chemodynamic immunotherapy to inhibit the growth and metastasis of melanoma. Therefore, this work proposes a general strategy for designing prodrug nanomedicines to accurately regulate cancer immunotherapy.


Tumor immunosuppressive microenvironment modulating hydrogels for second near-infrared photothermal-immunotherapy of cancer

December 2022

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49 Reads

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13 Citations

Materials Today Bio

Immunotherapy has recently been seen as a hopeful therapeutic device to inhibit tumor growth and metastasis, while the curative efficacy is limited by intrinsic immunosuppressive tumor microenvironment. Herein, we reported a tumor immunosuppressive microenvironment modulating hydrogel (TIMmH) platform to achieve second near-infrared (NIR-II) photothermal therapy (PTT) combined immunotherapy for durable inhibition of breast cancer. This TIMmH platform was synthesized through co-loading of NIR-II photothermal nanoagent and an immunoadjuvant cytosine-phosphateguanosine oligodeoxynucleotides (CpG ODNs) into the alginate hydrogel (ALG). Upon the administration of ALG into the tumor, the TIMmH was in situ formed via the coordination effect with Ca²⁺, locally encapsulating the semiconducting polymer nanoparticles (SPIIN) and CpG in the colloid, achieving to prolong the accumulation time and prevent the premature damage and release of immunotherapeutic agents. Upon 1064-nm photoirradiation, the TIMmHSD was able to elevate the intratumoral temperature for the ablation of tumors, which could induce the apoptosis of tumor cells and achieve thermal immune activation by regulating of an immunosuppressive microenvironment. The TIMmH-mediated combined treatment effectively suppressed the growths of breast cancers, and even acquired a sustained inhibition of the lung metastasis. This study provides a novel tumor immunosuppressive microenvironment modulating hydrogel platform with NIR-II photoexcited capacity for the safe, effective and durable lung metastasis-inhibiting breast cancer treatment.


Systematic characterization of cancer transcriptome at transcript resolution

November 2022

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190 Reads

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12 Citations

Transcribed RNAs undergo various regulation and modification to become functional transcripts. Notably, cancer transcriptome has not been fully characterized at transcript resolution. Herein, we carry out a reference-based transcript assembly across >1000 cancer cell lines. We identify 498,255 transcripts, approximately half of which are unannotated. Unannotated transcripts are closely associated with cancer-related hallmarks and show clinical significance. We build a high-confidence RNA binding protein (RBP)-transcript regulatory network, wherein most RBPs tend to regulate transcripts involved in cell proliferation. We identify numerous transcripts that are highly associated with anti-cancer drug sensitivity. Furthermore, we establish RBP-transcript-drug axes, wherein PTBP1 is experimentally validated to affect the sensitivity to decitabine by regulating KIAA1522-a6 transcript. Finally, we establish a user-friendly data portal to serve as a valuable resource for understanding cancer transcriptome diversity and its potential clinical utility at transcript level. Our study substantially extends cancer RNA repository and will facilitate anti-cancer drug discovery. Modification of transcribed mRNAs enables regulation of transcription but its extent in cancer cells is incompletely understood. Here, the authors analyse transcript assembly in over 1000 cancer cell lines and find unannotated transcripts are common, and are associated with drug sensitivity.


A prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy

June 2022

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50 Reads

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59 Citations

Acta Biomaterialia

Immunotherapy has been used for cancer treatment, while it faces the common dilemmas of low therapeutic efficacy and serious immunotoxicity. In this study, we report the construction of a tumor microenvironment and near-infrared (NIR) light dual-responsive prodrug hydrogel for cancer synergistic immunotherapy in a more effective and safe manner. Such prodrug hydrogels were in-situ formed via calcium-induced gelation of alginate solution containing protoporphyrin IX (PpIX)‐modified iron oxide (Fe3O4) nanoparticles and programmed death ligand 1 antibody (aPD-L1) prodrug nanoparticles crosslinked by reactive oxygen species (ROS)-responsive linkers. PpIX served as a photosensitizer to produce singlet oxygen (¹O2) under NIR laser irradiation for photodynamic therapy (PDT), and Fe3O4 nanoparticles mediated chemodynamic therapy (CDT) to generate hydroxyl radical (·OH) via Fenton reaction in the tumor microenvironment. In view of the cumulative actions of PDT and CDT, amplified ROS was generated to not only induce immunogenic cell death (ICD), but also destroy ROS-responsive linkers to achieve on-demand release of aPD-L1 from prodrug nanoparticles. Boosted antitumor immunity was elicited in tumor-bearing mice due to the aPD-L1-mediated immune checkpoint blocking. As a result, the prodrug hydrogel-based synergistic immunotherapy could almost treat bilateral tumors and prevent lung and liver metastasis using 4T1 tumor mouse models. This study thus offers a dual-responsive prodrug hydrogel platform for precision cancer immunotherapy. Statement of significance Via calcium-induced gelation of alginate, we constructed a prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy. Such hydrogels can achieve on-demand release of aPD-L1 upon photoactivation in the tumor microenvironment. Through mediating photodynamic and chemodynamic therapy, the prodrug hydrogels can induce enhanced immunogenic cell death and synergistically improve the efficacy of aPD-L1-mediated immune checkpoint blocking. The prodrug hydrogel-based synergistic therapy almost deracinates the primary and distant tumors, and prevents lung and liver metastasis in tumor mouse models.


Prostaglandin D2 signaling and cardiovascular homeostasis

April 2022

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31 Reads

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18 Citations

Journal of Molecular and Cellular Cardiology

Cardiovascular diseases are the leading cause of death worldwide. A chronic inflammatory response is a common pathological alteration in diverse cardiovascular diseases. Prostaglandin (PG) D2, a key lipid mediator derived from arachidonic acid metabolism, promotes resolution of inflammation and regulated T cell function through its receptors. Accumulated evidence has shown that dysregulated PGD2 signaling is involved in the pathogenesis of cardiovascular diseases, including atherosclerosis, hypertension, pulmonary hypertension, abdominal aortic aneurysm, and myocardial ischemia. Here, we summarized the recent progresses on PGD2 in cardiovascular homeostasis and discussed potential therapeutic translation by targeting PGD2 signaling.


Liposome-based nanocomplexes with pH-sensitive second near-infrared photothermal property for combinational immunotherapy

December 2021

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21 Reads

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13 Citations

Applied Materials Today

Natural killer (NK) cell-mediated immunotherapy has shown a great promise for treatments of tumors, while some strategies that can improve its therapeutic efficacy and reduce potential adverse events are highly desired. We herein report a pH-sensitive second near-infrared (NIR-II) photothermal liposomal nanocomplex for enhanced NK cell-based immunotherapy of breast cancer. Such nanocomplex (LNCDS) consists of charge-transfer nanoparticles (CTN) with pH-sensitive NIR-II photothermal effect, deoxyribonuclease I (DNase I), NK cell stimulant (SIS3) and a surface coated thermal-responsive liposome shell. Upon 1064 nm laser irradiation, LNCDS generates mild heat in a controlled manner, which results in destruction of thermal-responsive liposome shell to allow on-demand release of stimulants and DNase I in tumor sites. The released DNase I not only kills cancer cells, but also induces immunogenic cell death (ICD), which synergizes with the action of the released SIS3 to promote activation of NK cells and cytotoxic T lymphocytes, contributing to enhanced therapeutic efficacy of immunotherapy. As a result, a single treatment of LNCDS upon NIR-II photoactivation greatly inhibits the growths of subcutaneously implanted primary and distant tumors in a breast cancer murine model, and even completely prevents lung metastasis. This study thus offers a photo-controlled drug delivery nanosystem for efficacy and precise NK cell-mediated immunotherapy of cancer. Graphical abstract


Fig. 1 Decreased phosphorylation of PRKAR2A in UC patients and mice with DSS-induced colitis. a The expression of PRKAR1A and PRKAR2A in different tissues of WT mice. b Colon tissues of WT mice were stained with DAPI (blue), antibody to Pan-keratin (green), and antibody to PRKAR2A (red). Representative immunofluorescent images and merged images are shown. Bar = 20 μm. c Representative images of immunofluorescent staining for p-PRKAR2A(ser99) in colon tissues collected from human and mice. Nuclei were counterstained with DAPI. d Semi-quantification of the level of p-PRKAR2A in human (UC patients (n = 5) and uninflamed controls (n = 3)) and mice (treated (n = 5) and untreated (n = 5) with DSS). Data shown in a-d are representative of two independent experiments. Data are presented as mean ± SEM. Student's t test was used to do the analysis. ***P < 0.001, bar = 50 μm.
Fig. 3 Ablation of Prkar2a in IECs protects against DSS-induced colitis. a Flow cytometric analysis of Epcam+CD45− intestinal epithelial cell frequencies in colonic epithelial cells isolated from Prkar2a IECKO mice. Cells were gated on Epcam and CD45. b Colonic epithelial cells from Prkar2a IEC-KO mice and Prkar2a fl mice were collected and subjected for western blot with PRKAR2A antibody. Experiments in a, b were repeated at least three times. c-g Prkar2a fl (n = 6) and Prkar2a IEC-KO (n = 7) mice were treated with 2% DSS for 1 week followed by 2 days normal drinking water. c Weight loss was monitored daily and is displayed as the percentage of the initial body weight. d Stool score was measured every day during colitis development. e At day 9, colons were removed and colon lengths were determined. f Histological analysis of distal colon tissues at day 9 of experimental colitis. g Representative images of distal colon at day 9. Scale bar = 50 μm. h The survival curve of Prkar2a fl (n = 16) and Prkar2a IEC-KO (n = 12) mice. Mice were treated with 3% DSS for 1 week and the mortality was monitored over 14 days. Log-rank (Mantel-Cox) test was used to do the analysis. Data shown in c-h are representative of three independent experiments. All graphs show mean ± SEM. Student's t test (e, f) or two-way ANOVA (c, d) was used to compare experimental groups. ***P < 0.001; **P < 0.01.
Fig. 6 Prkar2a deficiency inhibits STAT3 activation through an IL-6-independent pathway. a Western blot analysis of STAT3 activation in colon tissues collected from Prkar2a −/− (n = 4) and WT mice (n = 4) at day 6 of DSS-induced colitis. Data are representative of at least three independent experiments. b Immunoblot analysis of the indicated proteins in colon tissues from WT mice at day 0 (n = 2), day 3 (n = 3), and day 6 (n = 4) of DSS-induced colitis. Data are representative of two independent experiments. c Western blot analysis of the indicated proteins in CCD841 cell line after stimulation with F/I. Data are representative of at least three independent experiments. d Immunoblot analysis of the indicated proteins in RKO cells transfected with siRNA against PRKAR2A or a scramble control and then stimulated with recombinant human IL-6 (10 ng/mL) for 30 min. e Immunoblot analysis of the indicated proteins in CCD841 cells transfected with siRNA against PRKAR2A or a scramble control and then stimulated with recombinant human IL-6 (10 ng/mL) for 30 min. f Immunoblot analysis of the indicated proteins in SW480 cells after stable knockdown of PRKAR2A followed by stimulation with recombinant human IL-6 for 30 min. Data shown in d-f are representative of two independent experiments conducted in duplicate. Student's t test (a, e, f) or two-way ANOVA (b) or one-way ANOVA (d) was used to do the analysis. ***P < 0.001; *P < 0.05. ns not significant.
Fig. 7 PRKAR2A orchestrates type I IFN-induced signaling pathway. a-c Colon tissues from WT (n = 3) and Prkar2a −/− mice (n = 3) were subjected to RNA-seq. a Heatmap of RNA-seq data shows at least twofold upregulated or downregulated expression of genes in colon tissues from WT and Prkar2a −/− mice. b GO analysis of the upregulated and downregulated genes in colon tissues in Prkar2a −/− mice. c Volcano plot of the RNA-seq data. d Quantitative PCR analysis of PRKAR2A, OAS2, APOL9A, ISG15, IRF7, and USP18 mRNA levels in colon tissues from Prkar2a −/− (n = 3) and WT mice (n = 3). e PRKAR2A expression was stably knocked down in SW480 cells. The cells were then stimulated with IFN-α (200 ng/mL) or IFN-γ (50 ng/mL) for 30 min, and the indicated proteins were detected by western blot. f Expression of PRKAR2A was knocked down by siRNA in CCD841 cells. The cells were stimulated with or without IFN-α (200 ng/mL) for 30 min, and the indicated proteins were detected by western blot. Data shown in d-f are representative of three independent experiments conducted in duplicate. Error bars represent mean ± SEM. Student's t test was used to compare the experimental groups. *P < 0.05, **P < 0.01.
Fig. 8 Inhibiting ISGs partly reverses the protection against DSS-colitis in Prkar2a −/− mice. a RT-qPCR analysis ISGs (IRF7, ISG15, OAS2, USP18, and APOL9A) in colon tissues of Prkar2a −/− mice treated (n = 3) or untreated (n = 3) with TSA. Data are representative of two independent experiments conducted in duplicate. b-e Prkar2a −/− mice (n = 5), TSA-treated Prkar2a −/− mice (n = 5), and WT mice (n = 5) were challenged with 1.5% DSS for 6 days followed by 2 days of normal water to induce experimental colitis. b Weight loss was determined daily and is displayed relative to initial weight. c Histological scores. d Representative H&E-stained images of colon sections. Scale bar = 50 µm. e At day 9, the mice were sacrificed and colons were removed to calculate the length. Data shown in b-e are representative of three independent experiments. Results are presented as mean ± SEM. Student's t test (a) or one-way ANOVA (c, e) or two-way ANOVA (b) was used to compare the experimental groups. *P < 0.05, **P < 0.01, ***P < 0.001.
PRKAR2A deficiency protects mice from experimental colitis by increasing IFN-stimulated gene expression and modulating the intestinal microbiota

August 2021

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88 Reads

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7 Citations

Mucosal Immunology

Protein kinase A (PKA) plays an important role in regulating inflammation via its catalytic subunits. Recently, PKA regulatory subunits have been reported to directly modulate some signaling pathways and alleviate inflammation. However, the role of PKA regulatory subunits in colonic inflammation remains unclear. Therefore, we conducted this study to investigate the role of the PKA regulatory subunit PRKAR2A in colitis. We observed that PRKAR2A deficiency protected mice from dextran sulfate sodium (DSS)-induced experimental colitis. Our experiments revealed that the intestinal epithelial cell-specific deletion of Prkar2a contributed to this protection. Mechanistically, the loss of PRKAR2A in Prkar2a −/− mice resulted in an increased IFN-stimulated gene (ISG) expression and altered gut microbiota. Inhibition of ISGs partially reversed the protective effects against DSS-induced colitis in Prkar2a −/− mice. Antibiotic treatment and cross-fostering experiments demonstrated that the protection against DSS-induced colitis in Prkar2a −/− mice was largely dependent on the gut microflora. Altogether, our work demonstrates a previously unidentified function of PRKAR2A in promoting DSS-induced colitis.


Citations (25)


... Pulmonary hypertension (PH) is a progressive disease caused by various etiologies and complex pathogenetic mechanisms, which leads to alterations in pulmonary function, increased pulmonary vascular resistance, and elevated pulmonary artery pressure [1,2]. These changes result in right ventricular dysfunction, ultimately causing right heart failure and death. ...

Reference:

Exploring the diagnostic and immune infiltration roles of disulfidptosis related genes in pulmonary hypertension
HMGB2 Release Promotes Pulmonary Hypertension and Predicts Severity and Mortality of Patients With Pulmonary Arterial Hypertension
  • Citing Article
  • April 2024

Arteriosclerosis Thrombosis and Vascular Biology

... Due to the complexity of posttranscriptional modifications, the same gene can produce different transcripts in different states [55]. The expression of some transcripts may not be consistent with that of their host gene [56,57]. Therefore, it is necessary to carry out transcriptlevel studies. ...

Nanopore long-read RNA sequencing reveals functional alternative splicing variants in human vascular smooth muscle cells

Communications Biology

... Similarly, Chen et al. reported a pH-activated promodulator of iron oxide nanoparticles that respond to tumor acidic microenvironment for photothermal-enhanced chemodynamic immunotherapy of cancer. These nanoparticles induce immunogenic cell death and directly destroy the cancer cells [11]. ...

Tumor Acidic Microenvironment-Responsive Promodulator Iron Oxide Nanoparticles for Photothermal-Enhanced Chemodynamic Immunotherapy of Cancer
  • Citing Article
  • January 2023

ACS Biomaterials Science & Engineering

... transcriptional machinery to previously inaccessible genomic regions 14 . Global disruptions in the RNA regulatory machinery in cancer 15 may also result in the appearance and stabilization of RNA fragments not commonly observed in normal tissues 16 . ...

Systematic characterization of cancer transcriptome at transcript resolution

... AlG is a natural polysaccharide compound derived from brown algae with good biocompatibility and degradability, as well as the unique property of cross-linking with divalent cations to form gels (Zhang et al., 2021a). in the presence or addition of ca 2+ , the negatively charged AlG and ca 2+ crosslink under the electrostatic complexation of opposite charges to form a hydrogel, which is a convenient and rapid gelation process and does not produce any toxic substances . Shen et al. (2022) prepared AlG-based injectable hydrogel loaded with SPiiN (NiR-ii absorbent) and cpG (immune adjuvant), and the precursor mixture solution formed by simple mixing of AlG with SPiiN and cpG was injected into the tumor resection site, where the hydrogel was formed in situ by interacting with ca 2+ in the tumor microenvironment. the hydrogel can serve as an excellent carrier for cpG, overcoming the problems of low cpG cell uptake, easy degradation and damage, insufficient content in the tumor area, and short residence time, and enhancing the depth of NiR laser penetration, thus effectively inhibiting breast cancer tumor recurrence and metastasis after surgery. ...

Tumor immunosuppressive microenvironment modulating hydrogels for second near-infrared photothermal-immunotherapy of cancer

Materials Today Bio

... Consequently, CDT provides several benefits over traditional treatment options, including minimal invasiveness, high selectivity, and fewer side effects. The natural concentration of H 2 O 2 typically ranges from 10 to 50 µM [137]. However, this concentration alone is not enough to produce the necessary quantity of hydroxyl radicals for the successful operation of CDT. ...

A prodrug hydrogel with tumor microenvironment and near-infrared light dual-responsive action for synergistic cancer immunotherapy
  • Citing Article
  • June 2022

Acta Biomaterialia

... 27 Noteworthy, prostaglandin D2 has anti-inflammatory and regulation of cardiovascular homeostasis effects. 28 Therefore, in the context of Corilagin, elevated serum levels of arachidonic acid may play an important role in protecting the cardiovascular system. ...

Prostaglandin D2 signaling and cardiovascular homeostasis
  • Citing Article
  • April 2022

Journal of Molecular and Cellular Cardiology

... Similar to this strategy, selenium nanoparticles (Se NPs) were explored to upregulate the expressions of activation receptor-NKG2D on NK cells and its ligand-NKG2DL on tumor cells (Fig. 12C) [257]. Nanomaterials can be also used as therapeutic agents to kill tumors and release stimulants to activate NK cells for combined immunotherapy of tumor [258,259]. ...

Liposome-based nanocomplexes with pH-sensitive second near-infrared photothermal property for combinational immunotherapy
  • Citing Article
  • December 2021

Applied Materials Today

... Interferons (IFNs) are generated in response to viral infection, stimulating the cells to produce antiviral activities and inducing the extensive synthesis of interferon-stimulated genes (ISGs) with antiviral functions (Pellefigues et al. 2017). IFNs are classified into three main categories: type I IFN, type II IFN, and type III IFN, based on their different triggering techniques and sequence homology (Liu et al. 2019;Li et al. 2020;Duncan et al. 2021;Wei et al. 2021). Human type I and type III interferons (IFNs) are commonly considered unique endogenous antiviral agents, largely distinguished by their distribution in tissues and their specific target cells (Gui et al. 2017). ...

PRKAR2A deficiency protects mice from experimental colitis by increasing IFN-stimulated gene expression and modulating the intestinal microbiota

Mucosal Immunology

... 8 O colágeno é um componente primário da estrutura do tecido e seu acúmulo excessivo pode levar à deposição anormal da matriz extracelular, reduzindo assim a complacência cardíaca e prejudicando sua função. 9 À medida que a fibrose progride, as funções sistólica e diastólica do coração ficam ainda mais comprometidas, resultando em insuficiência cardíaca e afetando significativamente a qualidade de vida dos pacientes. ...

ER‐anchored CRTH2 antagonizes collagen biosynthesis and organ fibrosis via binding LARP6

The EMBO Journal