Guo-Chang Fan - Academia.edu (original) (raw)

Papers by Guo-Chang Fan

Hereditas

Background Type 2 Diabetes Mellitus (T2DM) is an independent risk factor of hepatocellular carcin... more Background Type 2 Diabetes Mellitus (T2DM) is an independent risk factor of hepatocellular carcinoma (HCC). However, the related genes and modules to hepatocarcinogenesis and progression in T2DM remain unclear. Methods The microarray data from Gene Expression Omnibus (GEO) were analyzed to screen differentially expressed genes (DEGs) of T2DM and HCC dataset. Then, weighted gene co-expression network analysis (WGCNA) was performed on these DEGs to detect the modules and genes, respectively. Common genes in modules with clinical interests of T2DM and HCC were obtained and annotated via GOSemSim package and Metascape. Genes related to late-stage HCC and high glycated haemoglobin (HbA1c) were also identified. These genes were validated by UALCAN analysis and univariate cox regression based on The Cancer Genome Atlas (TCGA). Finally, another two independent datasets were applied to confirm the results of our study. Results A total of 1288 and 1559 DEGs of T2DM and HCC were screened, resp...

Arteriosclerosis, Thrombosis, and Vascular Biology, 2017

Introduction: Septic shock increases vascular permeability, leading to multiple organ failure and... more Introduction: Septic shock increases vascular permeability, leading to multiple organ failure and higher mortality. Reactive oxygen species (ROS) have been shown to promote both actin cytoskeleton reorganization resulting in vascular leakage and the formation of podosome, an actin-based dynamic membrane structure. Interestingly, recent studies have shown that circulating exosomes from septic patients contained higher levels of ROS than healthy ones. In this study, we hypothesized that septic exosomes can transfer exosomal ROS to endothelial cell (EC) to promote the generation of podosomes, leading to hyperpermeability. Methods: C57BL/6 mice (20-25g) were subjected to CLP surgery or injection with LPS (25 μg/g). Sham-operated or PBS-treated mice were used as controls. Exosomes were isolated from sera, collected at 3 h post-CLP or post-LPS-injection. Podosomes were identified by co-immunostaining F-actin/cortactin following stimulation with PMA, thrombin and exosomes. Transendothelial...

Frontiers in Public Health, 2021

Background:Integrated Chinese and Western medicine (integrated medicine) is routinely used in the... more Background:Integrated Chinese and Western medicine (integrated medicine) is routinely used in the treatment of coronavirus disease 2019 (COVID-19) in China. In this study, we undertook a systematic review and meta-analysis of published randomized controlled trials (RCTs) to evaluate the efficacy of integrated medicine therapy for patients with COVID-19.Methods:In this meta-analysis, we searched PubMed, Embase, Web of Science, SinoMed, China National Knowledge Infrastructure (CNKI), Chongqing VIP (CQVIP), and Wanfang databases from inception to April 12, 2021, to identify RCTs of integrated medicine in the treatment of COVID-19. The quality of RCTs was assessed by the Cochrane risk of bias tool. RevMan v5.3 and Stata software packages were used for statistical analysis.Results:Nineteen RCTs involving 1,853 patients met our inclusion criteria. Compared with patients treated by conventional Western medicine (CWM), patients treated by integrated medicine have a higher overall effective ...

Circulation, Nov 25, 2014

Introduction: Exosomes, a group of nano-vesicles secreted from living cells, are documented to in... more Introduction: Exosomes, a group of nano-vesicles secreted from living cells, are documented to increase in the circulation and are believed to promote cardiac dysfunction in sepsis patients and animal models. However, whether inhibition of exosome release could exert a cardio-protective effect in polymicrobial sepsis remains unexplored. Methods and Results: C57BL/6 mice (male, 8-week old) were pre-treated with GW4869 (dissolved in DMSO, injection i.p. at a dose of 2.5μg/g body weight), a known inhibitor of exosome secretion. Same volume of DMSO was used as controls. One hour later, cecal ligation and puncture (CLP) surgery was performed to induce polymicrobial sepsis. We found that the concentration of serum exosomes, measured by membrane markers CD63 and CD81with detection ELISA kits, was increased by 3.5-fold in DMSO-CLP mice, but no increase was detected in GW4869-CLP mice or in sham operated mice (n=4-6, p<0.01). Myocardial contractile function, assessed at 12h post-CLP using a SONOS-7500 echocardiography system, revealed that pre-injection of GW4869 significantly attenuated CLP-associated cardiac dysfunction, evidenced by an improved left ventricular ejection fraction (LVEF) and minor axis fractional shortening (LVFS), compared to DMSO controls (n=8-10, p<0.01). Myeloperoxidase (MPO) activity, a marker of myocardial inflammation, measured with a [[Unable to Display Character: ﬂ]]uorometric assay kit, also showed a significant reduction in GW4869-pre-treated mice, compared to DMSO-controls (n=5, p<0.01). Similarly, serum levels of inflammatory cytokines TNF-α and IL-1β triggered by CLP were reduced by 72% and 61%, respectively in GW4869-treated mice, compared with controls (n=6). Furthermore, we observed that 67% (n=9) of the DMSO controls, but only 20% in GW4869-treated mice (n=10) had died by 48h post-CLP. In vitro study confirmed that GW4869 limited the production of TNF-α and IL-1β in RAW 264.7 cells (a mouse macrophage cell line) challenged with endotoxin (LPS, 1μg/ml, 24 h). Conclusions: Together, this study indicates that blockade of exosome secretion could attenuate the inflammatory cytokine response as well as the consequent cardiac dysfunction and mortality in polymicrobial sepsis. Thus, our study may provide a new approach to the treatment of sepsis.

• PKA-phosphorylation of Hsp20 is elevated in human failing hearts. • Increases in phosp... more • PKA-phosphorylation of Hsp20 is elevated in human failing hearts. • Increases in phosphorylated Hsp20 in vivo are associated with fibrotic remodeling and reduced left ventricular function. • The phosphorylated Hsp20 in cardiomyocyte promotes upregulation of IL-6 and its subsequent paracrine actions on the cardiac fibroblast. • Blockade of IL-6 effects ex vivo and in vivo reduces the pro-fibrotic effects of phosphorylated Hsp20. • Targeting phosphorylated Hsp20 in the cardiomyocyte may represent a potential therapeutic strategy to mitigate fibrotic remodeling and preserve function in the failing heart.

(A) Kaplan-Meier survival curve of S16D and WT control mice. Longitudinal echo... more (A) Kaplan-Meier survival curve of S16D and WT control mice. Longitudinal echocardiographic assessment of S16D and WT mice at 2, 4, and 6 months of age: (B) LVEDV; (C) LVESV; and (D) EF. Gravimetric analysis of S16D and WT control mice at 2, 4, and 6 months of age. Ratios of (E) heart weight/body weight and (F) lung weight/body weight in S16D and WT control mice. Values are mean ± SEM. *p < 0.05; **p < 0.01; ***p < 0.001 versus WT. The number of samples (n) per group is indicated on the bar graphs. EF = ejection fraction; LVEDV = left ventricular end diastolic volume; LVESV = left ventricular end systolic volume; S16D = phosphorylated Hsp20; WT = wild type.

Journal of the American Academy of Dermatology, 2022

Circulation Research, 2011

Hsp20 has been shown to prevent stress-triggered cardiac injury. However, it remains obscure whet... more Hsp20 has been shown to prevent stress-triggered cardiac injury. However, it remains obscure whether Hsp20-elicited cardioprotection is associated with the activation of autophagy. We first assessed cardiac autophagy in a transgenic (TG) mouse model with 10-fold overexpression of Hsp20 by immunoblotting. Levels of two autophagy markers (LC3II and Beclin1) were increased by 1.6- and 2.2-fold, respectively, in Hsp20-hearts, compared to WTs. To examine whether Hsp20 activates autophagic flux in the heart, mice were i.p. injected with chloroquine (CQ, 50mg/kg), an inhibitor for autophagosome-lysosome fusion, for 4h. Cadaverine dye-binding analysis showed that autophagy levels were increased by 1.5-fold in CQ-treated Hsp20-hearts compared to saline controls. To examine whether increased autophagy levels contribute to Hsp20-induced cardioprotection, 3-methyladenine (3-MA, an inhibitor for autophgy) was i.p . injected into TG mice (30mg/kg). One hour later, hearts were subjected to global ...

Frontiers in Immunology, 2021

The defective eradication of invading pathogens is a major cause of death in sepsis. As professio... more The defective eradication of invading pathogens is a major cause of death in sepsis. As professional phagocytic cells, macrophages actively engulf/kill microorganisms and play essential roles in innate immune response against pathogens. Growth differentiation factor 3 (GDF3) was previously implicated as an important modulator of inflammatory response upon acute sterile injury. In this study, administration of recombinant GDF3 protein (rGDF3) either before or after CLP surgery remarkably improved mouse survival, along with significant reductions in bacterial load, plasma pro-inflammatory cytokine levels, and organ damage. Notably, our in vitro experiments revealed that rGDF3 treatment substantially promoted macrophage phagocytosis and intracellular killing of bacteria in a dose-dependent manner. Mechanistically, RNA-seq analysis results showed that CD5L, known to be regulated by liver X receptor α (LXRα), was the most significantly upregulated gene in rGDF3-treated macrophages. Furth...

Molecular Therapy, 2021

Tissue-resident macrophages (TRMs) are sentinel cells for maintaining tissue homeostasis and orga... more Tissue-resident macrophages (TRMs) are sentinel cells for maintaining tissue homeostasis and organ function. In this study, we discovered that LPS administration dramatically reduced TRM populations and suppressed their self-renewal capacities in multiple organs. Using loss- and gain-of-function approaches, we define Sectm1a as a novel regulator of TRM self-renewal. Specifically, at the earlier stage of endotoxemia, Sectm1a deficiency exaggerated acute inflammation-caused reduction of TRM numbers in multi-organs by suppressing their proliferation, associated with more infiltrations of inflammatory monocytes/neutrophils and more serious organ damages. By contrast, administration of recombinant Sectm1a enhanced TRM populations and improved animal survival upon endotoxin challenge. Mechanistically, we identified that Sectm1a-induced upregulation in the self-renewal capacity of TRM is dependent on GITR-activated T-helper cell expansion and cytokine production. Meanwhile, we found that TRMs may play an important role in protecting local vascular integrity during endotoxemia. Our study demonstrates that Sectm1a contributes to stabling TRM populations through maintaining their self-renewal capacities, which benefits the host immune response to acute inflammation. Therefore, Sectm1a may serve as a new therapeutic agent for the treatment of inflammatory diseases.

Advances in medical sciences, 2021

PURPOSE Several studies have demonstrated that C-type natriuretic peptide (CNP) stimulates osteob... more PURPOSE Several studies have demonstrated that C-type natriuretic peptide (CNP) stimulates osteoblastic proliferation seemly via antagonizing the expression of fibroblast growth factor (FGF)-23 in vitro. The main aim of the present study is to probe whether the post-receptor pathways of FGF-23 participate in osteogenesis caused by CNP. METHODS Osteoblasts were cultured in the absence or presence of CNP: 0, 10, and 100 pmol/L, for 24 h, 48 h and 72 h, respectively. RESULTS The findings of the present study indicated that osteoblastic proliferation was directly promoted by exogenous CNP in a dose-dependent manner; osteoblastic FGF-23 was significantly down-regulated by CNP at 24 h post-treatment; RAF-1, extracellular signal-regulated kinases (ERK), and P38 were substantially suppressed by CNP in a dose- and time-dependent manner; and signal transducer and activator of transcription (STAT)-1 was not changed on the premise of the down-regulated FGF-23 in osteoblasts treated with CN...

Frontiers in Endocrinology, 2020

Background: Chinese medicine has been used to treat diabetes symptoms for thousands of years. Dio... more Background: Chinese medicine has been used to treat diabetes symptoms for thousands of years. Dioscoreae rhizome or Shanyao is a Chinese medicinal herb that is routinely used in the treatment of diabetes mellitus (DM). Objective: The purpose of this study is to evaluate the evidence of the added benefits and safety of herbal formulae containing Shanyao in clinical studies and the possible mechanisms of Shanyao in the prevention and treatment of DM in experimental studies. Methods: We searched nine databases for randomized controlled trials (RCTs) that included Shanyao in the formulae in the treatment of type 2 DM. Furthermore, experimental studies on the prevention and treatment of DM by Shanyao in Englishand Chinese-language databases were identified. Results: Fifty-three moderate quality RCTs with herbal formulae containing Shanyao were identified. Results from meta-analysis indicated that Shanyao alone or formulae containing Shanyao in addition to conventional treatments could benefit people with type 2 DM in lowering blood glucose, blood lipids and reducing insulin resistance. Moreover, adverse events were significantly lower in the CHM plus conventional group than those in the conventional group. Shanyao may exert the benefit through various mechanisms including inhibition of a-glucosidase and DPP-IV activity, increase of endogenous GLP-1 and immune regulating activities. Conclusion: Evidence from this review suggested that there appeared to be added clinical benefits associated with the use of Shanyao for DM, whether as a food supplement or as a CHM combined with hypoglycemic agents with a good safety profile.

Clinical and Experimental Medicine, 2021

Objective Kawasaki disease (KD) is an acute systemic vasculitis and suspected to be triggered by ... more Objective Kawasaki disease (KD) is an acute systemic vasculitis and suspected to be triggered by several potential infections in which procalcitonin (PCT) experiences an increase to some extent. However, whether PCT can serve as a useful candidate for differentiating KD from sepsis, and even for predicting incomplete KD, intravenous immunoglobulin (IVIG) nonresponsiveness and coronary artery abnormalities (CAAs) remains unclear. Methods A total of 254 Chinese KD children were enrolled and divided into 6 subgroups, including complete KD, incomplete KD, IVIG-responsive KD, IVIG-nonresponsive KD, KD with CAAs and KD without CAAs. Blood samples were collected from all subjects within 24-h pre-and 48-h post-IVIG infusion, respectively. PCT, C-reactive protein, erythrocyte sedimentation rate and blood cell counts were detected. In addition, both 261 children with sepsis and 251 healthy children sex-and age-matched with KD children were enrolled in the same period. Results (1) PCT experienced the highest increase in sepsis patients before antibiotic therapy, followed by acute KD patients and the healthy controls. (2) The proportion of KD patients with a PCT concentration below 0.25 ng/ml was 11 folds higher than that of sepsis patients. (3) PCT had a sensitivity of 91.7% and a specificity of 30.3% at a cutoff value of > 0.15 ng/ml to predict IVIG nonresponsiveness, and the proportion of IVIG-nonresponders with a PCT concentration of 0.25-0.50 ng/ml was 2 folds higher than that of IVIG-responders. Conclusions The PCT concentrations below 0.25 ng/ml may be useful for discriminating KD from sepsis, and moreover, the PCT concentrations of 0.25-0.50 ng/ml may be helpful in predicting IVIG nonresponsiveness.

Shock, 2020

Macrophage, as an integral component of the immune system and the first responder to local damage... more Macrophage, as an integral component of the immune system and the first responder to local damage, is on the front line of defense against infection. Over the past century, the prevailing view of macrophage origin states that all macrophage populations resided in tissues are terminally differentiated and replenished by monocytes from bone-marrow progenitors. Nonetheless, this theory has been reformed by groundbreaking discoveries from the past decades. It is now believed that tissue-resident macrophages (TRMs) are originated from the embryonic precursors and seeded in tissue prenatally. They can replenish via self-renewal throughout the lifespan. Indeed, recent studies have demonstrated that tissue-resident macrophages should not be classified by the oversimplified macrophage polarization (M1/M2) dogma during inflammation. Moreover, multiple lines of evidence have indicated that tissue-resident macrophages play critical roles in maintaining tissue homeostasis and facilitating tissue repair through controlling infection and resolving inflammation. In this review, we summarize the properties of resident macrophages in the lung, spleen, and heart, and further highlight the impact of TRM populations on inflammation control and tissue repair. We also discuss the potential role of local proliferation in maintaining a physiologically stable TRM pool in response to acute inflammation.

Cells, 2020

Macrophages are critical for regulation of inflammatory response during endotoxemia and septic sh... more Macrophages are critical for regulation of inflammatory response during endotoxemia and septic shock. However, the mediators underlying their regulatory function remain obscure. Growth differentiation factor 3 (GDF3), a member of transforming growth factor beta (TGF-β) superfamily, has been implicated in inflammatory response. Nonetheless, the role of GDF3 in macrophage-regulated endotoxemia/sepsis is unknown. Here, we show that serum GDF3 levels in septic patients are elevated and strongly correlate with severity of sepsis and 28-day mortality. Interestingly, macrophages treated with recombinant GDF3 protein (rGDF3) exhibit greatly reduced production of pro-inflammatory cytokines, comparing to controls upon endotoxin challenge. Moreover, acute administration of rGDF3 to endotoxin-treated mice suppresses macrophage infiltration to the heart, attenuates systemic and cardiac inflammation with less pro-inflammatory macrophages (M1) and more anti-inflammatory macrophages (M2), as well a...

Acta Pharmacologica Sinica, 2018

Cell reports, Jan 19, 2018

Exposure to cold temperature is well known to upregulate heat shock protein (Hsp) expression and ... more Exposure to cold temperature is well known to upregulate heat shock protein (Hsp) expression and recruit and/or activate brown adipose tissue and beige adipocytes in humans and animals. However, whether and how Hsps regulate adipocyte function for energy homeostatic responses is poorly understood. Here, we demonstrate a critical role of Hsp20 as a negative regulator of adipocyte function. Deletion of Hsp20 enhances non-shivering thermogenesis and suppresses inflammatory responses, leading to improvement of glucose and lipid metabolism under both chow diet and high-fat diet conditions. Mechanistically, Hsp20 controls adipocyte function by interacting with the subunit of the ubiquitin ligase complex, F-box only protein 4 (FBXO4), and regulating the ubiquitin-dependent degradation of peroxisome proliferation activated receptor gamma (PPARγ). Indeed, Hsp20 deficiency mimics and enhances the pharmacological effects of the PPARγ agonist rosiglitazone. Together, our findings suggest a role...

Acta Pharmacologica Sinica, 2017

Gram-negative bacterium-released outer-membrane vesicles (OMVs) and Gram-positive bacterium-relea... more Gram-negative bacterium-released outer-membrane vesicles (OMVs) and Gram-positive bacterium-released membrane vesicles (MVs) share significant similarities with mammalian cell-derived MVs (eg, microvesicles and exosomes) in terms of structure and their biological activities. Recent studies have revealed that bacterial OMVs/MVs could (1) interact with immune cells to regulate inflammatory responses, (2) transport virulence factors (eg, enzymes, DNA and small RNAs) to host cells and result in cell injury, (3) enhance barrier function by stimulating the expression of tight junction proteins in intestinal epithelial cells, (4) upregulate the expression of endothelial cell adhesion molecules, and (5) serve as natural nanocarriers for immunogenic antigens, enzyme support and drug delivery. In addition, OMVs/MVs can enter the systemic circulation and induce a variety of immunological and metabolic responses. This review highlights the recent advances in the understanding of OMV/MV biogenesis and their compositional remodeling. In addition, interactions between OMVs/MVs and various types of mammalian cells (ie, immune cells, epithelial cells, and endothelial cells) and their pathological/preventive effects on infectious/inflammatory diseases are summarized. Finally, methods for engineering OMVs/MVs and their therapeutic potential are discussed.