First Affiliated Hospital of Chinese PLA General Hospital

Diversity and plasticity are two hallmarks of macrophages. M1 macrophages (classically activated macrophages) are pro-inflammatory and have a central role in host defense against infection, while M2 macrophages (alternatively activated macrophages) are associated with responses to anti-inflammatory reactions and tissue remodeling, and they represent two terminals of the full spectrum of macrophage activation. Transformation of different phenotypes of macrophages regulates the initiation, development, and cessation of inflammatory diseases. Here we reviewed the characters and functions of macrophage polarization in infection, atherosclerosis, obesity, tumor, asthma, and sepsis, and proposed that targeting macrophage polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of inflammatory diseases.

Mesenchymal stem cell (MSC)-derived exosomes have diverse functions in regulating wound healing and inflammation; however, the molecular mechanism of human umbilical cord MSC (hUCMSC)-derived exosomes in regulating burn-induced inflammation is not well understood. We found that burn injury significantly increased the inflammatory reaction of rats or macrophages exposed to lipopolysaccharide (LPS), increased tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) levels and decreased IL-10 levels. hUCMSC-exosome administration successfully reversed this reaction. Further studies showed that miR-181c in the exosomes played a pivotal role in regulating inflammation. Compared to control hUCMSC-exosomes, hUCMSC-exosomes overexpressing miR-181c more effectively suppressed the TLR4 signaling pathway and alleviated inflammation in burned rats. Administration of miR-181c-expressing hUCMSC-exosomes or TLR4 knockdown significantly reduced LPS-induced TLR4 expression by macrophages and the inflammatory reaction. In summary, miR-181c expression in hUCMSC-exosomes reduces burn-induced inflammation by downregulating the TLR4 signaling pathway.

C-reactive protein (CRP) is an acute-phase protein synthesized by hepatocytes in response to pro-inflammatory cytokines during inflammatory/infectious processes. CRP exists in conformationally distinct forms such as the native pentameric CRP and monomeric CRP (mCRP) and may bind to distinct receptors and lipid rafts and exhibit different functional properties. It is known as a biomarker of acute inflammation, but many large-scale prospective studies demonstrate that CRP is also known to be associated with chronic inflammation. This review is focused on discussing the clinical significance of CRP in chronic inflammatory and neurodegenerative diseases, such as cardiovascular disease, type 2 diabetes mellitus, age-related macular degeneration, hemorrhagic stroke, Alzheimer's disease, and Parkinson's disease, including recent advances on the implication of CRP and its forms specifically on the pathogenesis of these diseases. Overall, we highlight the advances in these areas that may be translated into promising measures for the diagnosis and treatment of inflammatory diseases.

In Brief Study Design. We collected the specimens of lumbar intervertebral disc (i.e., the symptomatic degenerative disc) from patients with discogenic low back pain to study the histopathologic features and growth factor expressions. Objectives. To study the pathogenesis of disc degeneration, meanwhile discriminating between common disc degeneration (aging disc) (i.e., black asymptomatic disc, not clinically relevant) and painful disc degeneration (i.e., symptomatic disc, clinically relevant). Summary of Background Data. The pathogenesis of intervertebral disc degeneration is poorly understood, mainly because of the difficulty to establish the experimental model with good reproducibility. Recently, the popularity of spinal fusion leads to more opportunities to obtain disc specimens, which could be applied to explore the pathogenesis of disc degeneration with modern biologic techniques. Methods. There were 21 specimens of lumbar intervertebral discs from 15 patients with discogenic low back pain during posterior lumbar interbody fusion, 16 aging discs from patients without low back pain, and 10 normal discs as control collected for the study of their histopathologic features, as well as the expressions of basic fibroblast growth factor (bFGF) and its receptor (Flg), transforming growth factor-β1 (TGF-β1) and its receptor (TGF-βRI) by immunohistochemistry. The distribution of macrophages and mast cells was also noted. Proliferating cell nuclear antigen was assessed to evaluate proliferating activities of disc cells. Results. The distinct histologic characteristic of the disc from the patient with discogenic low back pain was the ingrowth of vascularized granulation tissue along torn fissures, extending from the external layer of the anulus fibrosus into the nucleus pulposus. The immunohistochemical staining showed that there were strong expressions of bFGF and TGF-β1 and their receptors, as well as a strong expression of proliferating cell nuclear antigen in the zones of granulation tissue in the painful discs. However, there were only weak expressions in the nongranulation tissue zones in the painful discs and aging discs, and no expression in the control discs. In addition, abundant macrophages and mast cells were found in the granulation tissue zones of painful discs but absent in the nongranulation tissue zones of painful discs or aging discs and the normal control discs. Conclusions. The findings indicated that degeneration of the painful disc might originate from the injury and subsequent repair of anulus fibrosus. Growth factors, such as bFGF and TGF-β1, macrophages and mast cells might play a key role in the repair of the injured anulus fibrosus and subsequent disc degeneration. There were 21 specimens of painful lumbar intervertebral discs collected for the study of the pathogenesis of disc degeneration. The studies found that the distinct histologic characteristic of the painful disc was the ingrowth of vascularized granulation tissue along torn fissures, extending from the external layer of the anulus fibrosus into the nucleus pulposus. There were strong expressions of basic fibroblast growth factor and transforming growth factor-β1 and their receptors, as well as a strong expression of proliferating cell nuclear antigen in the zones of granulation tissue in the painful discs. In addition, abundant macrophages and mast cells were found in the same area. The findings indicated that the degeneration of painful disc might originate from the injury and subsequent repair of anulus fibrosus.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are clinically severe respiratory disorders, and there are currently no Food and Drug Administration-approved drug therapies. Melatonin is a well-known anti-inflammatory molecule, which has proven to be effective in ALI induced by many conditions. Emerging studies suggest that the NLRP3 inflammasome plays a critical role during ALI. How melatonin directly blocks activation of the NLRP3 inflammasome in ALI remains unclear. In this study, using an LPS-induced ALI mouse model, we found intratracheal (i.t.) administration of melatonin markedly reduced the pulmonary injury and decreased the infiltration of macrophages and neutrophils into lung. During ALI, the NLRP3 inflammasome is significantly activated with a large amount of IL-1β and the activated caspase-1 occurring in the lung. Melatonin inhibits the activation of the NLRP3 inflammasome by both suppressing the release of extracellular histones and directly blocking histone-induced NLRP3 inflammasome activation. Notably, i.t. route of melatonin administration opens a more efficient therapeutic approach for treating ALI.

MicroRNAs (miRNAs) have been shown to be dysregulated in virus-related cancers; however, miRNA regulation of virus-related cancer development and progression remains poorly understood. Here, we report that miR-148a is repressed by hepatitis B virus (HBV) X protein (HBx) to promote cancer growth and metastasis in a mouse model of hepatocellular carcinoma (HCC). Hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP) is an important regulator of cancer cell growth. We used miRNA target prediction programs to identify miR-148a as a regulator of HPIP. Expression of miR-148a in hepatoma cells reduced HPIP expression, leading to repression of AKT and ERK and subsequent inhibition of mTOR through the AKT/ERK/FOXO4/ATF5 pathway. HBx has been shown to play a critical role in the molecular pathogenesis of HBV-related HCC. We found that HBx suppressed p53-mediated activation of miR-148a. Moreover, expression of miR-148a was downregulated in patients with HBV-related liver cancer and negatively correlated with HPIP, which was upregulated in patients with liver cancer. In cultured cells and a mouse xenograft model, miR-148a reduced the growth, epithelial-to-mesenchymal transition, invasion, and metastasis of HBx-expressing hepatocarcinoma cells through inhibition of HPIP-mediated mTOR signaling. Thus, miR-148a activation or HPIP inhibition may be a useful strategy for cancer treatment.

BACKGROUND: Severe burns are a common and highly lethal trauma. The key step for severe burn therapy is to promote the wound healing as early as possible, and reports indicate that mesenchymal stem cell (MSC) therapy contributes to facilitate wound healing. In this study, we investigated effect of human umbilical cord MSCs (hUC-MSCs) could on wound healing in a rat model of severe burn and its potential mechanism. METHODS: Adult male Wistar rats were randomly divided into sham, burn, and burn transplanted hUC-MSCs. GFP labeled hUC-MSCs or PBS was intravenous injected into respective groups. The rate of wound closure was evaluated by Image Pro Plus. GFP-labeled hUC-MSCs were tracked by in vivo bioluminescence imaging (BLI), and human-specific DNA expression in wounds was detected by PCR. Inflammatory cells, neutrophils, macrophages, capillaries and collagen types I/III in wounds were evaluated by histochemical staining. Wound blood flow was evaluated by laser Doppler blood flow meter. The levels of proinflammatory and anti-inflammatory factors, VEGF, collagen types I/III in wounds were analyzed using an ELISA. RESULTS: We found that wound healing was significantly accelerated in the hUC-MSC therapy group. The hUC-MSCs migrated into wound and remarkably decreased the quantity of infiltrated inflammatory cells and levels of IL-1, IL-6, TNF-α and increased levels of IL-10 and TSG-6 in wounds. Additionally, the neovascularization and levels of VEGF in wounds in the hUC-MSC therapy group were markedly higher than those in other control groups. The ratio of collagen types I and III in the hUC-MSC therapy group were markedly higher than that in the burn group at indicated time after transplantation. CONCLUSION: The study suggests that hUC-MSCs transplantation can effectively improve wound healing in severe burned rat model. Moreover, these data might provide the theoretical foundation for the further clinical application of hUC-MSC in burn areas.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy and lacks effective treatment. We aimed to understand molecular mechanisms of the intertwined interactions between tumour stromal components in metastasis and to provide a new paradigm for PDAC therapy. DESIGN: Two unselected cohorts of 154 and 20 patients with PDAC were subjected to correlation between interleukin (IL)-33 and CXCL3 levels and survivals. Unbiased expression profiling, and genetic and pharmacological gain-of-function and loss-of-function approaches were employed to identify molecular signalling in tumour-associated macrophages (TAMs) and myofibroblastic cancer-associated fibroblasts (myoCAFs). The role of the IL-33-ST2-CXCL3-CXCR2 axis in PDAC metastasis was evaluated in three clinically relevant mouse PDAC models. RESULTS: IL-33 was specifically elevated in human PDACs and positively correlated with tumour inflammation in human patients with PDAC. CXCL3 was highly upregulated in IL-33-stimulated macrophages that were the primary source of CXCL3. CXCL3 was correlated with poor survival in human patients with PDAC. Mechanistically, activation of the IL-33-ST2-MYC pathway attributed to high CXCL3 production. The highest level of CXCL3 was found in PDAC relative to other cancer types and its receptor CXCR2 was almost exclusively expressed in CAFs. Activation of CXCR2 by CXCL3 induced a CAF-to-myoCAF transition and α-smooth muscle actin (α-SMA) was uniquely upregulated by the CXCL3-CXCR2 signalling. Type III collagen was identified as the CXCL3-CXCR2-targeted adhesive molecule responsible for myoCAF-driven PDAC metastasis. CONCLUSIONS: Our work provides novel mechanistic insights into understanding PDAC metastasis by the TAM-CAF interaction and targeting each of these signalling components would provide an attractive and new paradigm for treating pancreatic cancer.

INTRODUCTION: Young patients receiving chemotherapy occasionally face infertility and premature ovarian failure (POF). Numerous investigations reported that adipose-derived stem cells (ADSCs) transplantation could ameliorate the structure and function of injured tissues. The aim of this study was to explore the therapeutic efficacy of ADSC transplantation for chemotherapy-induced ovarian damage. METHODS: Female mice were injected intraperitoneally with 50 mg/kg cyclophosphamide (CTX). After 15 consecutive days of injection, ADSCs were transplanted either directly into bilateral ovaries or via intravenous injection, and the ovaries were excised after either 1 week or 1 month of treatment. The follicles were counted and categorized, and ovarian histologic sections were stained for TUNEL. Ovarian function was evaluated by monitoring ovulation. ADSC tracking, microarray analyses, and real-time polymerase chain reaction (PCR) were used to assess the inner mechanism of injury and repair. RESULTS: The ovarian function of mice exposed to CTX injection improved after ADSC transplantation. The population of follicles at different stages and ovulation significantly increased after the treatment. Immunofluorescence revealed reduced TUNEL staining. The tracking of ADSCs revealed that these cells did not directly differentiate into the follicle component. Microarray analyses indicated that changes in different groups of genes might affect follicle formation or ovulation. CONCLUSIONS: ADSC transplantation improved ovarian function. Our results suggest a potential mechanism for ADSC therapy.

The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. Here, we demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Further more, we identify cordycepin, a natural nucleoside analogue, as a potent drug to block radiation ulcer (skin, intestine, tongue) in rats/mice by preventing cell senescence through the increase of NRF2 nuclear expression (the assay used is mainly on skin). Finally, cordycepin is also revealed to activate AMPK by binding with the α1 and γ1 subunit near the autoinhibitory domain of AMPK, then promotes p62-dependent autophagic degradation of Keap1, to induce NRF2 dissociate from Keap1 and translocate to the nucleus. Taken together, our findings identify cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents, and activation of AMPK or NRF2 may thus represent therapeutic targets for preventing cell senescence and radiation ulcer.

BACKGROUND AND PURPOSE: There has been a nonstandard surgical procedure and extensive international controversy in minimally invasive surgery (MIS) for the management of spontaneous supratentorial intracerebral hemorrhage. This meta-analysis assessed the effectiveness of MIS as compared with other treatment options, including conservative medical treatment and conventional craniotomy, in patients with supratentorial intracerebral hemorrhage. METHODS: PubMed, Embase, Cochrane Controlled Trials Register (CCTR), Web of Science, European Association for Grey Literature Exploitation (EAGLE), National Technical Information Service (NTIS), Current Controlled Trials, Clinical Trials, International Clinical Trials Registry, Internet Stroke Center, Chinese Biomedical Literature Database (CBM), Chinese National Knowledge Infrastructure (CNKI) (last searched December 2011) were searched. Randomized controlled trials on MIS in patients with computed tomography-confirmed supratentorial intracerebral hemorrhage were included. We excluded low-quality randomized controlled trials. The death or dependence at the end of follow-up was defined as the primary outcome, and the death at the end of follow-up was defined as the secondary outcome. RESULTS: The 313 randomized controlled trials met the included criteria. We only analyzed 12 high-quality randomized controlled trials involving 1955 patients. The quality of the included trials was consistently high. OR of the primary outcome and secondary outcome of MIS both showed significant reductions (OR, 0.54, P<0.00001; OR, 0.53, P<0.00001). CONCLUSIONS: Patients with supratentorial intracerebral hemorrhage may benefit more from MIS than other treatment options. The most likely candidates to benefit from MIS are both sexes, age of 30 to 80 years with superficial hematoma, Glasgow Coma Scale score of ≥9, hematoma volume between 25 and 40 mL, and within 72 hours after onset of symptoms. Our study could help select appropriate patients for MIS and guide clinicians to optimize treatment strategies in supratentorial intracerebral hemorrhage.

The apoptotic or necrotic death of renal tubule epithelial cells is the main pathogenesis of renal ischemia-reperfusion-induced acute kidney injury (AKI). Pyroptosis is a programmed cell death pathway that depends on the activation of the caspase cascade and IL-1 cytokine family members. However, the role of pyroptosis in AKI induced by ischemia-reperfusion remains unclear. In this study, we found that the levels of the pyroptosis-related proteins, including caspase-1, caspase-11, and IL-1β, were significantly increased after 6 h of renal ischemia-reperfusion injury (IRI) and peaked at 12 h after IRI. Enhanced pyroptosis was accompanied by elevated renal structural and functional injury. Similarly, hypoxia-reoxygenation injury (HRI) also induced pyroptosis in renal tubule epithelial NRK-52E cells, which was characterized by increased pore formation and elevated lactate dehydrogenase release. In addition, obvious upregulation of the endoplasmic reticulum (ER) stress biomarkers glucose-regulated protein 78 and C/EBP homologous protein (CHOP) preceded the incidence of pyroptosis in cells treated with IRI or HRI. Pretreatment with a low dose of tunicamycin, an inducer of ER stress, relieved IRI-induced pyroptosis and renal tissue injury. Silencing of CHOP by small interfering RNA significantly decreased HRI-induced pyroptosis of NRK-52E cells, as evidenced by reduced caspase-11 activity and IL-1β generation. Therefore, we conclude that pyroptosis of renal tubule epithelial cells is a key event during IRI and that CHOP-caspase-11 triggered by overactivated ER stress may be an essential pathway involved in pyroptosis.

Impaired local cellular immunity contributes to the pathogenesis of persistent high-risk human papillomavirus (HR-HPV) infection and related cervical intraepithelial neoplasia (CIN), but the underlying molecular mechanisms remain unclear. Recently, the programmed death 1/programmed death 1 ligand (PD-1/PD-L1; CD279/CD274) pathway was demonstrated to play a critical role in attenuating T-cell responses and promoting T-cell tolerance during chronic viral infections. In this study, we examined the expression of PD-1 and PD-L1 on cervical T cells and dendritic cells (DCs), respectively, from 40 women who were HR-HPV-negative (-) or HR-HPV-positive (+) with CIN grades 0, I and II-III. We also measured interferon-γ, interleukin-12 (IL-12) and IL-10 in cervical exudates. The most common HPV type was HPV 16, followed by HPV 18, 33, 51 and 58. PD-1 and PD-L1 expression on cervical T cells and DCs, respectively, was associated with HR-HPV positivity and increased in parallel with increasing CIN grade. The opposite pattern was observed for CD80 and CD86 expression on DCs, which decreased in HR-HPV+ patients in parallel with increasing CIN grade. Similarly, reduced levels of the T helper type 1 cytokines interferon-γ and IL-12 and increased levels of the T helper type 2 cytokine IL-10 in cervical exudates correlated with HR-HPV positivity and CIN grade. Our results suggest that up-regulation of the inhibitory PD-1/PD-L1 pathway may negatively regulate cervical cell-mediated immunity to HPV and contribute to the progression of HR-HPV-related CIN. These results may aid in the development of PD-1/PD-L1 pathway-based strategies for immunotherapy of HR-HPV-related CIN.

The SEPT9 gene methylation assay is the first FDA-approved blood assay for colorectal cancer (CRC) screening. Fecal immunochemical test (FIT), FIT-DNA test and CEA assay are also in vitro diagnostic (IVD) tests used in CRC screening. This meta-analysis aims to review the SEPT9 assay performance and compare it with other IVD CRC screening tests. By searching the Ovid MEDLINE, EMBASE, CBMdisc and CJFD database, 25 out of 180 studies were identified to report the SEPT9 assay performance. 2613 CRC cases and 6030 controls were included, and sensitivity and specificity were used to evaluate its performance at various algorithms. 1/3 algorithm exhibited the best sensitivity while 2/3 and 1/1 algorithm exhibited the best balance between sensitivity and specificity. The performance of the blood SEPT9 assay is superior to that of the serum protein markers and the FIT test in symptomatic population, while appeared to be less potent than FIT and FIT-DNA tests in asymptomatic population. In conclusion, 1/3 algorithm is recommended for CRC screening, and 2/3 or 1/1 algorithms are suitable for early detection for diagnostic purpose. The SEPT9 assay exhibited better performance in symptomatic population than in asymptomatic population.

Abstract Delayed wound healing has a profound impact on patients, healthcare, and society. Platelet‐rich plasma (PRP) gel, as a preparation for regenerative medicine, has proven to be of clinical value in various wound treatments. Nevertheless, its weak mechanical properties and consequent burst release effect have restricted its application and efficacy. Here, an engineered PRP dual‐network hydrogel (named DN gel) based on sodium alginate is constructed through a simple “one‐step” activation process. Its improved gelling property and sustained release of growth factors may be beneficial for clinical use. Evaluations in rats indicate that DN gel promote wound healing in terms of rapid re‐epithelialization, up‐regulated growth factor levels and early transitions in the wound healing and angiogenesis stages. As a proof of concept, DN gel also exhibits superior healing efficiency in a porcine wound model. These results demonstrate the great potential of transforming this hydrogel into the next generation of PRP‐based bioactive wound dressing.

Recent studies have begun to reveal critical roles of microRNAs (miRNAs) in the pathogenesis of cardiac hypertrophy and dysfunction. In this study, we tested whether a transforming growth factor-β (TGF-β)-regulated miRNA played a pivotal role in the development of cardiac hypertrophy and heart failure (HF). We observed that miR-27b was upregulated in hearts of cardiomyocyte-specific Smad4 knockout mice, which developed cardiac hypertrophy. In vitro experiments showed that the miR-27b expression could be inhibited by TGF-β1 and that its overexpression promoted hypertrophic cell growth, while the miR-27b suppression led to inhibition of the hypertrophic cell growth caused by phenylephrine (PE) treatment. Furthermore, the analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-27b revealed that miR-27b overexpression was sufficient to induce cardiac hypertrophy and dysfunction. We validated the peroxisome proliferator-activated receptor-γ (PPAR-γ) as a direct target of miR-27b in cardiomyocyte. Consistently, the miR-27b transgenic mice displayed significantly lower levels of PPAR-γ than the control mice. Furthermore, in vivo silencing of miR-27b using a specific antagomir in a pressure-overload-induced mouse model of HF increased cardiac PPAR-γ expression, attenuated cardiac hypertrophy and dysfunction. The results of our study demonstrate that TGF-β1-regulated miR-27b is involved in the regulation of cardiac hypertrophy, and validate miR-27b as an efficient therapeutic target for cardiac diseases.

Electrospinning is a method in which materials in solution are formed into nano‐ and micro‐sized continuous fibers. Recent interest in this technique stems from both the topical nature of nanoscale material fabrication and the considerable potential for use of these nanoscale fibres in a range of applications including, amongst others, a range of biomedical applications processes such as drug delivery and the use of scaffolds to provide a framework for tissue regeneration in both soft and hard tissue applications systems. The objectives of this review are to describe the theory behind the technique, examine the effect of changing the process parameters on fiber morphology, and discuss the application and impact of electrospinning on the fields of vascular, neural, bone, cartilage, and tendon/ligament tissue engineering.

With the development of cancer immunotherapy, cancer vaccine has become a novel modality for cancer treatment, and the important role of adjuvant has been realized recently. Chitin, chitosan, and their derivatives have shown their advantages as adjuvants for cancer vaccine. In this paper, the adjuvant properties of chitin and chitosan were discussed, and some detailed information about glycated chitosan and chitosan nanoparticles was also presented to illustrate the trend for future development.

BACKGROUND: Current treatment options for human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in-situ hybridization-negative patients. Here, we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer. METHODS: Patients with HER2-overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety. RESULTS: Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%-33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7-4.9 months) and 7.9 months (95% CI: 6.7-9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48-related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48-related. CONCLUSIONS: RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.

Basal autophagy is tightly regulated by transcriptional and epigenetic factors to maintain cellular homeostasis. Dysregulation of cardiac autophagy is associated with heart diseases, including cardiac hypertrophy, but the mechanism governing cardiac autophagy is rarely identified. To analyze the in vivo function of miR-199a in cardiac autophagy and cardiac hypertrophy, we generated cardiac-specific miR-199a transgenic mice and showed that overexpression of miR-199a was sufficient to inhibit cardiomyocyte autophagy and induce cardiac hypertrophy in vivo. miR-199a impaired cardiomyocyte autophagy in a cell-autonomous manner by targeting glycogen synthase kinase 3β (GSK3β)/mammalian target of rapamycin (mTOR) complex signaling. Overexpression of autophagy related gene 5 (Atg5) attenuated the hypertrophic effects of miR-199a overexpression on cardiomyocytes, and activation of autophagy using rapamycin was sufficient to restore cardiac autophagy and decrease cardiac hypertrophy in miR-199a transgenic mice. These results reveal a novel role of miR-199a as a key regulator of cardiac autophagy, suggesting that targeting miRNAs controlling autophagy as a potential therapeutic strategy for cardiac disease.