Phenotypic Conversion Research Articles

Glucocorticoid regulation of the mTORC1 pathway modulates CD4+ T cell responses during infection.

Conventional glucocorticoid (GC) treatment poses significant risks for opportunistic infections due to its suppressive impact on CD4+ T cells. This study aimed to explore the mechanisms by which GCs modulate the functionality of CD4+ Tcells during infection. We consistently measured FOXP3, inflammatory cytokines and phospho-S6 ribosomal protein levels in CD4+ T cells from patients undergoing conventional GC treatment. Using Foxp3EGFP animals, we investigated the dynamicactivation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway and its correlation with the immunoregulatory function of CD4+ T cells under the influence of GCs. GCs dynamically altered the expression pattern of FOXP3 in CD4+ T cells, promoting their acquisition of an active T regulatory (Treg) cell phenotype upon stimulation. Mechanistically, GCs undermined the kinetics of the mTORC1 pathway, which was closely correlated with phenotype conversion and functional properties of CD4+ T cells. Dynamic activation of the mTORC1 signaling modified the GC-dampened immunoregulatory capacity of CD4+ T cells by phenotypically and functionally bolstering the FOXP3+ Treg cells. Interventions targeting the mTORC1 pathway effectively modulated the GC-dampened immunoregulatory capacity of CD4+ T cells. These findings highlight a novel mTORC1-mediated mechanism underlying CD4+ T cell immunity in the context of conventional GC treatment.

DAP12 deletion causes age-related motor function impairment but promotes functional recovery after sciatic nerve crush injury

DNAX activating protein of 12 kDa (DAP12)-deficiency mice showed impaired differentiation of oligodendrocytes and reduced myelin in the central nervous system. Whether DAP12 is expressed by Schwann cells and its roles in the peripheral nervous system (PNS) remains unknown. In this study, expression of DAP12 was detected in Schwann cells in vivo and in vitro. The DAP12-knockout (KO) mice showed age-related motor deficits and thinner myelin in the sciatic nerve than WT mice but significantly faster clinical recovery after sciatic nerve crush injury. In sciatic nerves of DAP12 KO and WT mice, proteomic profiles analysis identified 158 differentially expressed proteins (DEPs) at 8-week-old, 29 DEPs at 54-week-old and 33 DEPs at two weeks after crush injury. Typically, of the DEPs at 54-week-old, up-regulated Lgmn and down-regulated RecK and Yap1 were associated with myelin loss in the sciatic nerve of DAP12 KO mice. Upregulation of nicotinamide nucleotide transhydrogenase and haptoglobin were associated with the accumulation of macrophages in the crushed sciatic nerve of DAP12 KO mice. After crush injury, there were significantly more M1 macrophages at one-week and more M2 macrophages at two-week in sciatic nerve of DAP12 KO mice than WT mice, indicating that DAP12 deletion promotes the phenotype conversion of macrophages from M1 to M2. Collectively, our findings suggest that DAP12 may exert dual roles in the PNS including promoting the physiological myelin formation and maintenance of Schwann cells but delaying nerve repair after injury by modulating the recruitment of macrophages and phenotype conversion.

Notch signaling dependent monocyte conversion alleviates immune-mediated neuropathies by regulating RBP-J/NR4A1 axis

Monocytes in peripheral blood and sciatic nerves play vital roles in immune-mediated neuropathies such as Guillain-Barré syndrome (GBS). Different subpopulations of monocytes, including classical and non-classical, exhibit distinct functions as well as phenotypic conversion potentials. However, the mechanisms underlying their development during immune-mediated neuropathy remain unclear. Notch signaling participates in monocyte differentiation and function. In this study, we used a myeloid-specific Notch signaling activation transgenic mouse (NICcA) and investigated the role of Notch signaling in monocytes during experimental autoimmune neuritis (EAN) in a mouse model of GBS. Clinical score assessment and histopathological examination revealed that sciatic nerve injury was attenuated in NICcA EAN mice compared to that in control mice. Flow cytometry and immunofluorescence staining suggested that increasing Ly6Clo monocytes in the peripheral blood and nerve tissue might contribute to the alleviation of neuritis in NICcA mice. Meanwhile, an in vitro study suggested that bone marrow-derived monocytes from NICcA mice are more inclined toward Ly6Clo cells than Ly6Chi cells. Differential expression of monocyte development-associated genes was detected in NICcA and wild-type mice using RNA sequencing. The expression of Nr4a1 is upregulated remarkably when Notch signaling is activated. Treatment with Nr4a1 antagonist on NICcA mice-derived monocytes compromise their Ly6Clo tendency. Consistently, a relationship between monocyte conversion and disease severity was observed in blood samples from patients with GBS. In conclusion, our current study showed that monocyte conversion modulated by Notch signaling plays an essential role in the EAN mouse model.

The influence of three-dimensional structure on naïve T cell homeostasis and aging.

A breakdown in cellular homeostasis is thought to drive naïve T cell aging, however the link between naïve T cell homeostasis and aging in humans is poorly understood. To better address this, we developed a lymphoid organoid system that maintains resting naïve T cells for more than 2weeks, in conjunction with high CD45RA expression. Deep phenotypic characterization of naïve T cells across age identified reduced CD45RA density as a hallmark of aging. A conversion from CD45RAhigh naive cells to a CD45RAlow phenotype was reproduced within our organoid system by structural breakdown, but not by stromal cell aging or reduced lymphocyte density, and mediated by alternative CD45 splicing. Together, these data suggest that external influences within the lymph node microenvironment may cause phenotypic conversion of naïve T cells in older adults.

Epithelial-mesenchymal transition-related long noncoding RNAs in gastric carcinoma.

As an evolutionarily phenotypic conversion program, the epithelial-mesenchymal transition (EMT) has been implicated in tumour deterioration and has facilitated the metastatic ability of cancer cells via enhancing migration and invasion. Gastric cancer (GC) remains a frequently diagnosed non-skin malignancy globally. Most GC-associated mortality can be attributed to metastasis. Recent studies have shown that EMT-related long non-coding RNAs (lncRNAs) play a critical role in GC progression and GC cell motility. In addition, lncRNAs are associated with EMT-related transcription factors and signalling pathways. In the present review, we comprehensively described the EMT-inducing lncRNA molecular mechanisms and functional perspectives of EMT-inducing lncRNAs in GC progression. Taken together, the statements of this review provided a clinical implementation in identifying lncRNAs as potential therapeutic targets for advanced GC.

Induction of ferroptosis promotes vascular smooth muscle cell phenotypic switching and aggravates neointimal hyperplasia in mice

BackgroundStent implantation-induced neointima formation is a dominant culprit in coronary artery disease treatment failure after percutaneous coronary intervention. Ferroptosis, an iron-dependent regulated cell death, has been associated with various cardiovascular diseases. However, the effect of ferroptosis on neointima formation remains unclear.MethodsThe mouse common right carotid arteries were ligated for 16 or 30 days, and ligated tissues were collected for further analyses. Primary rat vascular smooth muscle cells (VSMCs) were isolated from the media of aortas of Sprague-Dawley (SD) rats and used for in vitro cell culture experiments.ResultsFerroptosis was positively associated with neointima formation. In vivo, RAS-selective lethal 3 (RSL3), a ferroptosis activator, aggravated carotid artery ligation-induced neointima formation and promoted VSMC phenotypic conversion. In contrast, a ferroptosis inhibitor, ferrostatin-1 (Fer-1), showed the opposite effects in mice. In vitro, RSL3 promoted rat VSMC phenotypic switching from a contractile to a synthetic phenotype, evidenced by increased contractile markers (smooth muscle myosin heavy chain and calponin 1), and decreased synthetic marker osteopontin. The induction of ferroptosis by RSL3 was confirmed by the increased expression level of ferroptosis-associated gene prostaglandin-endoperoxide synthase 2 (Ptgs2). The effect of RSL3 on rat VSMC phenotypic switching was abolished by Fer-1. Moreover, N-acetyl-l-cysteine (NAC), the reactive oxygen species inhibitor, counteracted the effect of RSL3 on the phenotypic conversion of rat VSMCs.ConclusionsFerroptosis induces VSMC phenotypic switching and accelerates ligation-induced neointimal hyperplasia in mice. Our findings suggest inhibition of ferroptosis as an attractive strategy for limiting vascular restenosis.

Emerging Role of Non-Coding RNAs in Aortic Dissection.

Aortic dissection (AD) is a fatal cardiovascular acute disease with high incidence and mortality, and it seriously threatens patients’ lives and health. The pathogenesis of AD mainly includes vascular inflammation, extracellular matrix degradation, and phenotypic conversion as well as apoptosis of vascular smooth muscle cells (VSMCs); however, its detailed mechanisms are still not fully elucidated. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are an emerging class of RNA molecules without protein-coding ability, and they play crucial roles in the progression of many diseases, including AD. A growing number of studies have shown that the dysregulation of ncRNAs contributes to the occurrence and development of AD by modulating the expression of specific target genes or the activity of related proteins. In addition, some ncRNAs exhibit great potential as promising biomarkers and therapeutic targets in AD treatment. In this review, we systematically summarize the recent findings on the underlying mechanism of ncRNA involved in AD regulation and highlight their clinical application as biomarkers and therapeutic targets in AD treatment. The information reviewed here will be of great benefit to the development of ncRNA-based therapeutic strategies for AD patients.

Reprogramming—Evolving Path to Functional Surrogate β-Cells

Numerous cell sources are being explored to replenish functional β-cell mass since the proof-of -concept for cell therapy of diabetes was laid down by transplantation of islets. Many of these cell sources have been shown to possess a degree of plasticity permitting differentiation along new lineages into insulin-secreting β-cells. In this review, we explore emerging reprograming pathways that aim to generate bone fide insulin producing cells. We focus on small molecules and key transcriptional regulators that orchestrate phenotypic conversion and maintenance of engineered cells.

Association between non-alcoholic fatty liver disease and metabolically healthy deterioration across different body shape phenotypes at baseline and change patterns

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome (MetS), and the relationship between NAFLD and metabolic deterioration remains unclear. This study aimed to investigate dynamic changes in metabolically healthy phenotypes and to assess the impact of non-alcoholic fatty liver disease (NAFLD) on the conversion from metabolically healthy (MH) to metabolically unhealthy (MU) phenotypes across body shape phenotypes and phenotypic change patterns. We defined body shape phenotypes using both the body mass index (BMI) and waist circumference (WC) and defined metabolic health as individuals scoring ≤ 1 on the NCEP-ATP III criteria, excluding WC. A total of 12,910 Chinese participants who were MH at baseline were enrolled in 2013 and followed-up in 2019 or 2020. During a median follow-up of 6.9 years, 27.0% (n = 3,486) of the MH individuals developed an MU phenotype. According to the multivariate Cox analyses, NAFLD was a significant predictor of conversion from the MH to MU phenotype, independent of potential confounders (HR: 1.12; 95% confidence interval: 1.02–1.22). For the MH-normal weight group, the relative risk of NAFLD in phenotypic conversion was 1.21 (95% CI 1.03–1.41, P = 0.017), which was relatively higher than that of MH-overweight/obesity group (HR: 1.14, 95% CI 1.02–1.26, P = 0.013). Interestingly, the effect of NAFLD at baseline on MH deterioration was stronger in the “lean” phenotype group than in the “non-lean” phenotype group at baseline and in the “fluctuating non-lean” phenotype change pattern group than in the “stable non-lean” phenotype change pattern group during follow-up. In conclusion, lean NAFLD is not as benign as currently considered and requires more attention during metabolic status screening.

Long non-coding RNAs: Modulators of phenotypic transformation in vascular smooth muscle cells.

Long non-coding RNA (lncRNAs) are longer than 200 nucleotides and cannot encode proteins but can regulate the expression of genes through epigenetic, transcriptional, and post-transcriptional modifications. The pathophysiology of smooth muscle cells can lead to many vascular diseases, and studies have shown that lncRNAs can regulate the phenotypic conversion of smooth muscle cells so that smooth muscle cells proliferate, migrate, and undergo apoptosis, thereby affecting the development and prognosis of vascular diseases. This review discusses the molecular mechanisms of lncRNA as a signal, bait, stent, guide, and other functions to regulate the phenotypic conversion of vascular smooth muscle cells, and summarizes the role of lncRNAs in regulating vascular smooth muscle cells in atherosclerosis, hypertension, aortic dissection, vascular restenosis, and aneurysms, providing new ideas for the diagnosis and treatment of vascular diseases.

DCBLD2 regulates vascular hyperplasia by modulating the platelet derived growth factor receptor-β endocytosis through Caveolin-1 in vascular smooth muscle cells.

DCBLD2 is a neuropilin-like transmembrane protein that is up-regulated during arterial remodeling in humans, rats, and mice. Activation of PDGFR-β via PDGF triggers receptor phosphorylation and endocytosis. Subsequent activation of downstream signals leads to the stimulation of phenotypic conversion of VSMCs and arterial wall proliferation, which are common pathological changes in vascular remodeling diseases such as atherosclerosis, hypertension, and restenosis after angioplasty. In this study, we hypothesized that DCBLD2 regulates neointimal hyperplasia through the regulation of PDGFR-β endocytosis of vascular smooth muscle cells (VSMCs) through Caveolin-1 (Cav-1). Compared with wild-type (WT) mice or control littermate mice, the germline or VSMC conditional deletion of the Dcbld2 gene resulted in a significant increase in the thickness of the tunica media in the carotid artery ligation. To elucidate the underlying molecular mechanisms, VSMCs were isolated from the aorta of WT or Dcbld2-/- mice and were stimulated with PDGF. Western blotting assays demonstrated that Dcbld2 deletion increased the PDGF signaling pathway. Biotin labeling test and membrane-cytosol separation test showed that after DCBLD2 was knocked down or knocked out, the level of PDGFR-β on the cell membrane was significantly reduced, while the amount of PDGFR-β in the cytoplasm increased. Co-immunoprecipitation experiments showed that after DCBLD2 gene knock-out, the binding of PDGFR-β and Cav-1 in the cytoplasm significantly increased. Double immunofluorescence staining showed that PDGFR-β accumulated Cav-1/lysosomes earlier than for control cells, which indicated that DCBLD2 gene knock-down or deletion accelerated the endocytosis of PDGF-induced PDGFR-β in VSMCs. In order to confirm that DCBLD2 affects the relationship between Cav-1 and PDGFR-β, proteins extracted from VSMCs cultured in vitro were derived from WT and Dcbld2-/- mice, whereas co-immunoprecipitation suggested that the combination of DCBLD2 and Cav-1 reduced the bond between Cav-1 and PDGFR-β, and DCBLD2 knock-out was able to enhance the interaction between Cav-1 and PDGFR-β. Therefore, the current results suggest that DCBLD2 may inhibit the caveolae-dependent endocytosis of PDGFR-β by anchoring the receptor on the cell membrane. Based on its ability to regulate the activity of PDGFR-β, DCBLD2 may be a novel therapeutic target for the treatment of cardiovascular diseases.

Cornuside Is a Potential Agent against Alzheimer's Disease via Orchestration of Reactive Astrocytes.

Cornuside is an iridoid glycoside from Cornus officinalis, with the activities of anti-inflammatory, antioxidant, anti-mitochondrial dysfunction, and neuroprotection. In the present research, a triple-transgenic mice model of AD (3 × Tg-AD) was used to explore the beneficial actions and potential mechanism of cornuside on the memory deficits. We found that cornuside prominently alleviated neuronal injuries, reduced amyloid plaque pathology, inhibited Tau phosphorylation, and repaired synaptic damage. Additionally, cornuside lowered the release of interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO), lowered the level of malondialdehyde (MDA), and increased the activity of superoxide dismutase (SOD) and the level of glutathione peroxidase (GSH-Px). Cornuside also significantly reduced the activation of astrocytes and modulated A1/A2 phenotypes by the AKT/Nrf2/NF-κB signaling pathway. We further confirmed that LY294002 and Nrf2 silencing could block the cornuside-mediated phenotypic switch of C6 cells induced by microglia conditioned medium (MCM) in response to lipopolysaccharide (LPS), which indicated that the effects of cornuside in astrocyte activation are dependent on AKT/Nrf2/NF-κB signaling. In conclusion, cornuside may regulate the phenotypic conversion of astrocytes, inhibit neuroinflammation and oxidative stress, improve synaptic plasticity, and alleviate cognitive impairment in mice through the AKT/Nrf2/NF-κB axis. Our present work provides an experimental foundation for further research and development of cornuside as a candidate drug for AD management.

Docetaxel-loaded M1 macrophage-derived exosomes for a safe and efficient chemoimmunotherapy of breast cancer

The conversion of tumor-promoting M2 macrophage phenotype to tumor-suppressing M1 macrophages is a promising therapeutic approach for cancer treatment. However, the tumor normally provides an abundance of M2 macrophage stimuli, which creates an M2 macrophage-dominant immunosuppressive microenvironment. In our study, docetaxel (DTX) as chemotherapeutic modularity was loaded into M1 macrophage-derived exosomes (M1-Exo) with M1 proinflammatory nature to establish DTX-M1-Exo drug delivery system. We found that DTX-M1-Exo induced naïve M0 macrophages to polarize to M1 phenotype, while failed to repolarize to M2 macrophages upon Interleukin 4 restimulation due to impaired mitochondrial function. This suggests that DTX-M1-Exo can achieve long-term robust M1 activation in immunosuppressive tumor microenvironment. The in vivo results further confirmed that DTX-M1-Exo has a beneficial effect on macrophage infiltration and activation in the tumor tissues. Thus, DTX-M1-Exo is a novel macrophage polarization strategy via combined chemotherapy and immunotherapy to achieve great antitumor therapeutic efficacy.

Biodegradable Hollow-Structured Nanozymes Modulate Phenotypic Polarization of Macrophages and Relieve Hypoxia for Treatment of Osteoarthritis.

Nanozymes are widely applied for treating various major diseases, including neurological diseases and tumors. However, the biodegradability of nanozymes remains a great challenge, which hinders their further clinical translation. Based on the microenvironment of osteoarthritis (OA), a representative pH-responsive biodegradable hollow-structured manganese Prussian blue nanozyme (HMPBzyme) is designed and applied for treatment of OA. HMPBzyme with good pH-responsive biodegradability, biocompatibility, and multi-enzyme activities is constructed by bovine serum albumin bubbles as a template-mediated biomineralization strategy. HMPBzyme suppresses hypoxia-inducible factor-1α(HIF-1α)expression and decreases reactive oxygen species (ROS) level in the in vitro experiment. Furthermore, HMPBzyme markedly suppresses the expression of ROS and alleviates the degeneration of cartilage in OA rat models. The results indicate that the biodegradable HMPBzyme inhibits oxidative damage and relieves hypoxia synergistically to suppress inflammation and promote the anabolism of cartilage extracellular matrix by protecting mitochondrial function and down-regulating the expression of HIF-1α, which modulates the phenotypic conversion of macrophages from pro-inflammatory M1 subtype to anti-inflammatory M2 subtype for OA treatment. This research lays a solid foundation for the design, construction, and biomedical application of biodegradable nanozymes and promotes the application of nanozymes in biomedicine.

Vagus nerve stimulation promotes the M1-to-M2 transition via inhibition of TLR4/NF-κB in microglial to rescue the reperfusion injury

ObjectiveTo specify the effect of vagus nerve stimulation (VNS) on microglial polarization following ischemic-reperfusion and further investigate its underlying mechanism. Materials and methodsSprague-Dawley rats were randomly divided into the sham, ischemic reperfusion group (IR), IR+VNS groups. VNS intervention lasting for 1 hour was administered after 30 minutes of occlusion. We analyzed the expression of Arginase 1 (Arg1), the number of M2 microglial in the peri-infarction cortex and assessed the neurological scores at the 1, 3, 7 days after reperfusion to determine the research time point. Then, we assessed polarization status of microglial, the infarct volume, neurological scores, the cellular distribution of Toll-like Receptor 4 (TLR4), the TLR4-associated pathway protein and the p-NF-κB in microglial at 3 days after reperfusion. ResultsWe found that VNS could increase the specific marker of M2 Arg1 and upregulate the M2 microglial after reperfusion, and the increase of Arg1, M2 microglial and the neurological scores was largest at the 3 days after reperfusion. VNS treatment significantly reduced the number and percent of M1, improved the number and percent of M2 and upregulated the M2 to M1 ratio without changing the number of total microglial at the 3 days after reperfusion. Moreover, VNS reduced the infarct volume and neurological deficits. In addition, VNS significantly reduced the microglial-specific TLR4, inhibited the activated TLR4/MyD88/NF-κB pathway following ischemic-reperfusion, and ultimately suppressed the p-NF-κB in microglial. ConclusionOur study revealed that VNS can promote the M1-to-M2 phenotype conversion to alleviate inflammatory response and brain injury through inhibition of TLR4/MyD88/NF-κB pathway in microglia following ischemic-reperfusion.

Bioinspired Nanovesicles Convert the Skeletal Endothelium-Associated Secretory Phenotype to Treat Osteoporosis.

Recently, bone marrow endothelial cells (BMECs) were found to play an important role in regulating bone homeostasis. However, few studies utilized BMECs to treat bone metabolic diseases including osteoporosis. Here, we reported bioinspired nanovesicles (BNVs) prepared from human induced pluripotent stem cells-derived endothelial cells under hypoxia culture through an extrusion approach. Abundant membrane C-X-C motif chemokine receptor 4 conferred these BNVs bone-targeting ability and the endothelial homology facilitated the BMEC tropism. Due to their unique endogenous miRNA cargos, these BNVs re-educated BMECs to secret cytokines favoring osteogenesis and anti-inflammation. Owing to the conversion of secretory phenotype, the osteogenic differentiation of bone mesenchymal stem cells was facilitated, and the M1-macrophage-dominant pro-inflammatory microenvironment was ameliorated in osteoporotic bones. Taken together, this study proposed BMEC-targeting nanovesicles treating osteoporosis via converting the skeletal endothelium-associated secretory phenotype.

Interaction Between Intrinsic Renal Cells and Immune Cells in the Progression of Acute Kidney Injury.

A growing number of studies have confirmed that immune cells play various key roles in the pathophysiology of acute kidney injury (AKI) development. After the resident immune cells and intrinsic renal cells are damaged by ischemia and hypoxia, drugs and toxins, more immune cells will be recruited to infiltrate through the release of chemokines, while the intrinsic cells promote macrophage polarity conversion, and the immune cells will promote various programmed deaths, phenotypic conversion and cycle arrest of the intrinsic cells, ultimately leading to renal impairment and fibrosis. In the complex and dynamic immune microenvironment of AKI, the bidirectional interaction between immune cells and intrinsic renal cells affects the prognosis of the kidney and the progression of fibrosis, and determines the ultimate fate of the kidney.

Keratin5-cytoskeleton-BMP4 network regulates cell phenotype conversions during cardiac regeneration

The reconstruction of a blood supply system and myocardial recovery from inflamamtory reactions in the infract zone remains a challenge in cardiac regeneration after myocardial infarction. Here, we observed that the local myocardial cells and the clotted blood cells undergo cellular remodeling via cytoplasmic exocytosis and nuclear reorganization in zebrafish hearts after resection of the ventricular apex. The subsequent tissue regeneration processes were visualized by detection of the spatiotemporal expression of three tissue specific genes (α-SMA which marks for vasculature/fibrogenesis, Flk1for angiogenesis/hematopoiesis, and Pax3a for remusculogensis), and two histone modification markers (H3K9Ac and H3K9Me3 for chromatin remodeling). By analyzing the composition of the blastema tissue fractions we found that Krt5 peptide could promote F-actin assembly, BMP4-pSmad2/5/8 signaling activity, and H3K9Me3-mediated chromatin accessibility at the blastema representative genes in the cultured zebrafish embryonic fibroblasts. Further in vivo tests demonstrated that Krt5 interacted with beta actin, and promoted Gata3 expression and Flk1-GFP marked blastema angiogenesis. These results proposed a new Krt5-cytoskeleton-BMP4 mechanotransduction mechanism in the epithelial-dependent and cell phenotype conversion-based tissue regeneration.

Histone deacetylase 3 promotes alveolar epithelial–mesenchymal transition and fibroblast migration under hypoxic conditions

Epithelial–mesenchymal transition (EMT), a process by which epithelial cells undergo a phenotypic conversion that leads to myofibroblast formation, plays a crucial role in the progression of idiopathic pulmonary fibrosis (IPF). Recently, it was revealed that hypoxia promotes alveolar EMT and that histone deacetylases (HDACs) are abnormally overexpressed in the lung tissues of IPF patients. In this study, we showed that HDAC3 regulated alveolar EMT markers via the AKT pathway during hypoxia and that inhibition of HDAC3 expression by small interfering RNA (siRNA) decreased the migration ability and invasiveness of diseased human lung fibroblasts. Furthermore, we found that HDAC3 enhanced the migratory and invasive properties of fibroblasts by positively affecting the EMT process, which in turn was affected by the increased and decreased levels of microRNA (miR)-224 and Forkhead Box A1 (FOXA1), respectively. Lastly, we found this mechanism to be valid in an in vivo system; HDAC3 siRNA administration inhibited bleomycin-induced pulmonary fibrosis in mice. Thus, it is reasonable to suggest that HDAC3 may accelerate pulmonary fibrosis progression under hypoxic conditions by enhancing EMT in alveolar cells through the regulation of miR-224 and FOXA1. This entire process, we believe, offers a novel therapeutic approach for pulmonary fibrosis.

Oxidative Stress in Calcific Aortic Valve Stenosis: Protective Role of Natural Antioxidants.

Calcific aortic valve stenosis (CAVS) is the most prevalent heart valvular disease worldwide and a slowly progressive disorder characterized by thickening of the aortic valve, calcification, and subsequent heart failure. Valvular calcification is an active cell regulation process in which valvular interstitial cells involve phenotypic conversion into osteoblasts/chondrocytes-like cells. The underlying pathophysiology is complicated, and there have been no pharmacological treatments for CAVS to date. Recent studies have suggested that an increase in oxidative stress is the major trigger of CAVS, and natural antioxidants could ameliorate the detrimental effects of reactive oxygen species in the pathogenesis of CAVS. It is imperative to review the current findings regarding the role of natural antioxidants in CAVS, as they can be a promising therapeutic approach for managing CAVS, a disorder currently without effective treatment. This review summarizes the current findings on molecular mechanisms associated with oxidative stress in the development of valvular calcification and discusses the protective roles of natural antioxidants in the prevention and treatment of CAVS.