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1.
Molecules ; 27(9)2022 Apr 24.
Article in English | MEDLINE | ID: covidwho-1810048

ABSTRACT

Cepharanthine (CEP) has excellent anti-SARS-CoV-2 properties, indicating its favorable potential for COVID-19 treatment. However, its application is challenged by its poor dissolubility and oral bioavailability. The present study aimed to improve the bioavailability of CEP by optimizing its solubility and through a pulmonary delivery method, which improved its bioavailability by five times when compared to that through the oral delivery method (68.07% vs. 13.15%). An ultra-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS) method for quantification of CEP in rat plasma was developed and validated to support the bioavailability and pharmacokinetic studies. In addition, pulmonary fibrosis was recognized as a sequela of COVID-19 infection, warranting further evaluation of the therapeutic potential of CEP on a rat lung fibrosis model. The antifibrotic effect was assessed by analysis of lung index and histopathological examination, detection of transforming growth factor (TGF)-ß1, interleukin-6 (IL-6), α-smooth muscle actin (α-SMA), and hydroxyproline level in serum or lung tissues. Our data demonstrated that CEP could significantly alleviate bleomycin (BLM)-induced collagen accumulation and inflammation, thereby exerting protective effects against pulmonary fibrosis. Our results provide evidence supporting the hypothesis that pulmonary delivery CEP may be a promising therapy for pulmonary fibrosis associated with COVID-19 infection.


Subject(s)
COVID-19 , Pulmonary Fibrosis , Animals , Benzylisoquinolines , Biological Availability , Bleomycin/pharmacology , COVID-19/complications , COVID-19/drug therapy , Chromatography, Liquid , Humans , Lung , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/etiology , Rats , Tandem Mass Spectrometry , Transforming Growth Factor beta1/metabolism
2.
Cells ; 11(8)2022 Apr 13.
Article in English | MEDLINE | ID: covidwho-1785544

ABSTRACT

Cardiovascular disease (CVD) is the leading cause of death worldwide. Current data suggest that patients with cardiovascular diseases experience more serious complications with coronavirus disease-19 (COVID-19) than those without CVD. In addition, severe COVID-19 appears to cause acute cardiac injury, as well as long-term adverse remodeling of heart tissue. Cardiac fibroblasts and myofibroblasts, being crucial in response to injury, may play a pivotal role in both contributing to and healing COVID-19-induced cardiac injury. The role of cardiac myofibroblasts in cardiac fibrosis has been well-established in the literature for decades. However, with the emergence of the novel coronavirus SARS-CoV-2, new cardiac complications are arising. Bursts of inflammatory cytokines and upregulation of TGF-ß1 and angiotensin (AngII) are common in severe COVID-19 patients. Cytokines, TGF-ß1, and Ang II can induce cardiac fibroblast differentiation, potentially leading to fibrosis. This review details the key information concerning the role of cardiac myofibroblasts in CVD and COVID-19 complications. Additionally, new factors including controlling ACE2 expression and microRNA regulation are explored as promising treatments for both COVID-19 and CVD. Further understanding of this topic may provide insight into the long-term cardiac manifestations of the COVID-19 pandemic and ways to mitigate its negative effects.


Subject(s)
COVID-19 , Cardiovascular Diseases , COVID-19/complications , Cardiovascular Diseases/metabolism , Fibroblasts/metabolism , Humans , Myocardium/metabolism , Myofibroblasts/metabolism , Pandemics , SARS-CoV-2 , Transforming Growth Factor beta1/metabolism
3.
Int J Mol Sci ; 23(7)2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1785739

ABSTRACT

Di-(2-ethylhexyl) phthalate (DEHP) is a frequently used plasticizer that may be linked to the development of endometriosis, a common gynecological disorder with a profound impact on quality of life. Despite its prevalence, vital access to treatment has often been hampered by a lack of understanding of its pathogenesis as well as reliable disease models. Recently, epithelial-mesenchymal transition (EMT) has been suggested to have a significant role in endometriosis pathophysiology. In this study, we found that DEHP treatment enhanced proliferation, migration, and inflammatory responses, along with EMT and stemness induction in human endometrial and endometriotic cells. The selective transforming growth factor-ß (TGF-ß) receptor type 1/2 inhibitor LY2109761 reversed the DEHP-induced cell proliferation and migration enhancement as well as the increased expression of crucial molecules involved in inflammation, EMT, and stemness, indicating that DEHP-triggered phenomena occur via the TGF-ß/Smad signaling pathway. Our study clearly defines the role of DEHP in the etiology and pathophysiological mechanisms of endometriosis and establishes an efficient disease model for endometriosis using a biomimetic 3D cell culture technique. Altogether, our data provide novel etiological and mechanistic insights into the role of DEHP in endometriosis pathogenesis, opening avenues for developing novel preventive and therapeutic strategies for endometriosis.


Subject(s)
Diethylhexyl Phthalate , Endometriosis , Cell Proliferation , Diethylhexyl Phthalate/metabolism , Diethylhexyl Phthalate/toxicity , Endometriosis/pathology , Epithelial Cells/metabolism , Epithelial-Mesenchymal Transition , Female , Humans , Phthalic Acids , Quality of Life , Signal Transduction , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1/metabolism , Transforming Growth Factors/metabolism
4.
Front Immunol ; 12: 825358, 2021.
Article in English | MEDLINE | ID: covidwho-1662589

ABSTRACT

Coronavirus disease 2019 (COVID-19) raises the issue of how hypoxia destroys normal physiological function and host immunity against pathogens. However, there are few or no comprehensive omics studies on this effect. From an evolutionary perspective, animals living in complex and changeable marine environments might develop signaling pathways to address bacterial threats under hypoxia. In this study, the ancient genomic model animal Takifugu obscurus and widespread Vibrio parahaemolyticus were utilized to study the effect. T. obscurus was challenged by V. parahaemolyticus or (and) exposed to hypoxia. The effects of hypoxia and infection were identified, and a theoretical model of the host critical signaling pathway in response to hypoxia and infection was defined by methods of comparative metabolomics and proteomics on the entire liver. The changing trends of some differential metabolites and proteins under hypoxia, infection or double stressors were consistent. The model includes transforming growth factor-ß1 (TGF-ß1), hypoxia-inducible factor-1α (HIF-1α), and epidermal growth factor (EGF) signaling pathways, and the consistent changing trends indicated that the host liver tended toward cell proliferation. Hypoxia and infection caused tissue damage and fibrosis in the portal area of the liver, which may be related to TGF-ß1 signal transduction. We propose that LRG (leucine-rich alpha-2-glycoprotein) is widely involved in the transition of the TGF-ß1/Smad signaling pathway in response to hypoxia and pathogenic infection in vertebrates as a conserved molecule.


Subject(s)
Hypoxia/metabolism , Signal Transduction/physiology , Takifugu/metabolism , Takifugu/microbiology , Vibrio Infections/metabolism , Vibrio parahaemolyticus/pathogenicity , Animals , Epidermal Growth Factor/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Metabolomics/methods , Proteomics/methods , Transforming Growth Factor beta1/metabolism , Vibrio Infections/microbiology
5.
Am J Chin Med ; 49(8): 1965-1999, 2021.
Article in English | MEDLINE | ID: covidwho-1599109

ABSTRACT

Pulmonary fibrosis (PF) is a chronic and irreversible interstitial lung disease that even threatens the lives of some patients infected with COVID-19. PF is a multicellular pathological process, including the initial injuries of epithelial cells, recruitment of inflammatory cells, epithelial-mesenchymal transition, activation and differentiation of fibroblasts, etc. TGF-[Formula: see text]1 acts as a key effect factor that participates in these cellular processes of PF. Recently, much attention was paid to inhibiting TGF-[Formula: see text]1 mediated cell processes in the treatment of PF with Chinese herbal medicines (CHM), an important part of traditional Chinese medicine. Here, this review first summarized the effects of TGF-[Formula: see text]1 in different cellular processes of PF. Then, this review summarized the recent research on CHM (compounds, multi-components, single medicines and prescriptions) to directly and/or indirectly inhibit TGF-[Formula: see text]1 signaling (TLRs, PPARs, micrRNA, etc.) in PF. Most of the research focused on CHM natural compounds, including but not limited to alkaloids, flavonoids, phenols and terpenes. After review, the research perspectives of CHM on TGF-[Formula: see text]1 inhibition in PF were further discussed. This review hopes that revealing the inhibiting effects of CHM on TGF-[Formula: see text]1-mediated cellular processes of PF can promote CHM to be better understood and utilized, thus transforming the therapeutic activities of CHM into practice.


Subject(s)
Cell Physiological Phenomena/drug effects , Drugs, Chinese Herbal/therapeutic use , Pulmonary Fibrosis/drug therapy , Signal Transduction/drug effects , Transforming Growth Factor beta1/antagonists & inhibitors , COVID-19/complications , COVID-19/metabolism , COVID-19/virology , Humans , Medicine, Chinese Traditional/methods , Phytotherapy/methods , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/metabolism , SARS-CoV-2/physiology , Transforming Growth Factor beta1/metabolism
6.
Int J Mol Sci ; 23(1)2021 Dec 24.
Article in English | MEDLINE | ID: covidwho-1580700

ABSTRACT

Acute respiratory distress syndrome (ARDS) followed by repair with lung remodeling is observed in COVID-19. These findings can lead to pulmonary terminal fibrosis, a form of irreversible sequelae. There is evidence that TGF-ß is intimately involved in the fibrogenic process. When activated, TGF-ß promotes the differentiation of fibroblasts into myofibroblasts and regulates the remodeling of the extracellular matrix (ECM). In this sense, the present study evaluated the histopathological features and immunohistochemical biomarkers (ACE-2, AKT-1, Caveolin-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 tissue expression) involved in the TGF-ß1 signaling pathways and pulmonary fibrosis. The study consisted of 24 paraffin lung samples from patients who died of COVID-19 (COVID-19 group), compared to 10 lung samples from patients who died of H1N1pdm09 (H1N1 group) and 11 lung samples from patients who died of different causes, with no lung injury (CONTROL group). In addition to the presence of alveolar septal fibrosis, diffuse alveolar damage (DAD) was found to be significantly increased in the COVID-19 group, associated with a higher density of Collagen I (mature) and III (immature). There was also a significant increase observed in the immunoexpression of tissue biomarkers ACE-2, AKT-1, CD44v6, IL-4, MMP-9, α-SMA, Sphingosine-1, and TGF-ß1 in the COVID-19 group. A significantly lower expression of Caveolin-1 was also found in this group. The results suggest the participation of TGF-ß pathways in the development process of pulmonary fibrosis. Thus, it would be plausible to consider therapy with TGF-ß inhibitors in those patients recovered from COVID-19 to mitigate a possible development of pulmonary fibrosis and its consequences for post-COVID-19 life quality.


Subject(s)
COVID-19/metabolism , Pulmonary Fibrosis/metabolism , Signal Transduction , Transforming Growth Factor beta/metabolism , Actins/metabolism , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Caveolin 1/metabolism , Collagen Type I/metabolism , Collagen Type III/metabolism , Female , Humans , Hyaluronan Receptors/metabolism , Immunohistochemistry , Influenza A Virus, H1N1 Subtype/metabolism , Influenza, Human/metabolism , Influenza, Human/pathology , Interleukin-4/metabolism , Male , Matrix Metalloproteinase 9/metabolism , Middle Aged , Proto-Oncogene Proteins c-akt/metabolism , Pulmonary Fibrosis/complications , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/pathology , Retrospective Studies , Transforming Growth Factor beta1/metabolism
7.
Front Immunol ; 12: 740260, 2021.
Article in English | MEDLINE | ID: covidwho-1506482

ABSTRACT

Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventricular myocardium of deceased COVID-19 patients, compared with matched controls. We also detected increased mRNA levels of soluble interleukin-1 receptor-like 1 (sIL1-RL1) and transforming growth factor ß1 (TGF-ß1) in the left ventricular myocardium of deceased COVID-19 patients. Biochemical analysis of blood sampled from patients admitted to the emergency department (ED) with COVID-19 revealed highly elevated levels of TGF-ß1 mRNA in these patients compared to controls. Left ventricular strain measured by echocardiography as a marker of pre-existing cardiac fibrosis correlated strongly with blood TGF-ß1 mRNA levels and predicted disease severity in COVID-19 patients. In the left ventricular myocardium and lungs of COVID-19 patients, we found increased neuropilin-1 (NRP-1) RNA levels, which correlated strongly with the prevalence of pulmonary SARS-CoV-2 nucleocapsid. Cardiac and pulmonary fibrosis may therefore predispose these patients to increased cellular viral entry in the lung, which may explain the worse clinical outcome observed in our cohort. Our study demonstrates that patients at risk of clinical deterioration can be identified early by echocardiographic strain analysis and quantification of blood TGF-ß1 mRNA performed at the time of first medical contact.


Subject(s)
COVID-19/physiopathology , Heart Ventricles/pathology , Myocardium/pathology , Pulmonary Fibrosis/physiopathology , SARS-CoV-2/physiology , Adult , Aged , COVID-19/immunology , Female , Fibrosis , Heart Ventricles/metabolism , Humans , Interleukin-1 Receptor-Like 1 Protein/genetics , Interleukin-1 Receptor-Like 1 Protein/metabolism , Male , Middle Aged , Myocardium/metabolism , Neuropilin-1/genetics , Neuropilin-1/metabolism , Pulmonary Fibrosis/immunology , Risk , Severity of Illness Index , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Viral Load
8.
PLoS One ; 16(6): e0252758, 2021.
Article in English | MEDLINE | ID: covidwho-1261297

ABSTRACT

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been implicated in the pathogenesis of experimental kidney disease. ACE2 is on the X chromosome, and in mice, deletion of ACE2 leads to the development of focal segmental glomerulosclerosis (FSGS). The relationship between sex and renal ACE2 expression in humans with kidney disease is a gap in current knowledge. METHODS: We studied renal tubulointerstitial microarray data and clinical variables from subjects with FSGS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) study. We compared relationships between ACE2 expression and age, estimated glomerular filtration rate (eGFR), urinary albumin to creatinine ratio (UACR), interstitial fibrosis, tubular atrophy, and genes implicated in inflammation and fibrosis in male and female subjects. RESULTS: ACE2 mRNA expression was lower in the tubulointerstitium of males compared to females (P = 0.0026). Multiple linear regression analysis showed that ACE2 expression was related to sex and eGFR but not to age or treatment with renin angiotensin system blockade. ACE2 expression is also related to interstitial fibrosis, and tubular atrophy, in males but not in females. Genes involved in inflammation (CCL2 and TNF) correlated with ACE2 expression in males (TNF: r = -0.65, P < 0.0001; CCL2: r = -0.60, P < 0.0001) but not in females. TGFB1, a gene implicated in fibrosis correlated with ACE2 in both sexes. CONCLUSIONS: Sex is an important determinant of ACE2 expression in the tubulointerstitium of the kidney in FSGS. Sex also influences the relationships between ACE2, kidney fibrosis, and expression of genes involved in kidney inflammation.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Glomerulosclerosis, Focal Segmental/metabolism , Adolescent , Adult , Angiotensin-Converting Enzyme 2/genetics , Chemokine CCL2/genetics , Chemokine CCL2/metabolism , Child , Female , Glomerulosclerosis, Focal Segmental/genetics , Glomerulosclerosis, Focal Segmental/pathology , Humans , Kidney/metabolism , Male , Middle Aged , Sex Factors , Transforming Growth Factor beta1/genetics , Transforming Growth Factor beta1/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism
9.
Am J Physiol Lung Cell Mol Physiol ; 320(2): L246-L253, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1088311

ABSTRACT

The COVID-19 pandemic is an ongoing threat to public health. Since the identification of COVID-19, the disease caused by SARS-CoV-2, no drugs have been developed to specifically target SARS-CoV-2. To develop effective and safe treatment options, a better understanding of cellular mechanisms underlying SARS-CoV-2 infection is required. To fill this knowledge gap, researchers require reliable experimental systems that express the host factor proteins necessary for the cellular entry of SARS-CoV-2. These proteins include the viral receptor, angiotensin-converting enzyme 2 (ACE2), and the proteases, transmembrane serine protease 2 (TMPRSS2) and furin. A number of studies have reported cell-type-specific expression of the genes encoding these molecules. However, less is known about the protein expression of these molecules. We assessed the suitability of primary human bronchial epithelial (HBE) cells maintained in an air-liquid interface (ALI) as an experimental system for studying SARS-CoV-2 infection in vitro. During cellular differentiation, we measured the expression of ACE2, TMPRSS2, and furin over progressive ALI days by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence staining. We also explored the effect of the fibrotic cytokine TGF-ß on the expression of these proteins in well-differentiated HBE cells. Like ACE2, TMPRSS2 and furin proteins are localized in differentiated ciliated cells, as confirmed by immunofluorescence staining. These data suggest that well-differentiated HBE cells maintained in ALI are a reliable in vitro system for investigating cellular mechanisms of SARS-CoV-2 infection. We further identified that the profibrotic mediators, TGF-ß1 and TGF-ß2, increase the expression of furin, which is a protease required for the cellular entry of SARS-CoV-2.


Subject(s)
Bronchi/metabolism , COVID-19/etiology , Furin/metabolism , SARS-CoV-2 , Transforming Growth Factor beta1/metabolism , Transforming Growth Factor beta2/metabolism , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Bronchi/cytology , Bronchi/drug effects , Cell Differentiation , Cells, Cultured , Disease Susceptibility , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Furin/genetics , Gene Expression/drug effects , Host Microbial Interactions/drug effects , Host Microbial Interactions/genetics , Host Microbial Interactions/physiology , Humans , Models, Biological , Pandemics , RNA, Messenger/genetics , RNA, Messenger/metabolism , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Transforming Growth Factor beta1/pharmacology , Transforming Growth Factor beta2/pharmacology , Virus Internalization
10.
Med Hypotheses ; 149: 110534, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1082320

ABSTRACT

Bilirubin has been proven to possess significant anti-inflammatory, antioxidant and antiviral activities. Recently, it has been postulated as a metabolic hormone. Further, moderately higher levels of bilirubin are positively associated with reduced risk of cardiovascular diseases, diabetes, metabolic syndrome and obesity. However, due to poor solubility the therapeutic delivery of bilirubin remains a challenge. Nanotechnology offers unique advantages which may be exploited for improved delivery of bilirubin to the target organ with reduced risk of systemic toxicity. Herein, we postulate the use of intravenous administration or inhalational delivery of bilirubin nanomedicine (BNM) to combat systemic dysfunctions associated with COVID-19, owing to the remarkable preclinical efficacy and optimistic results of various clinical studies of bilirubin in non-communicable disorders. BNM may be used to harness the proven preclinical pharmacological efficacy of bilirubin against COVID-19 related systemic complications.


Subject(s)
Bilirubin/therapeutic use , COVID-19/therapy , Nanomedicine/methods , Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Antiviral Agents/therapeutic use , Biliverdine/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome , Humans , Inflammation , MAP Kinase Signaling System , Models, Theoretical , NF-kappa B p50 Subunit/metabolism , Risk , Signal Transduction , Transforming Growth Factor beta1/metabolism
11.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1066781

ABSTRACT

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. Here, we demonstrated that lungs originating from different types of patients with PF, including coronavirus disease 2019, systemic sclerosis-associated interstitial lung disease, and idiopathic PF, and from mice following bleomycin (BLM)-induced PF are characterized by the altered methyl-CpG-binding domain 2 (MBD2) expression in macrophages. Depletion of Mbd2 in macrophages protected mice against BLM-induced PF. Mbd2 deficiency significantly attenuated transforming growth factor-ß1 (TGF-ß1) production and reduced M2 macrophage accumulation in the lung following BLM induction. Mechanistically, Mbd2 selectively bound to the Ship promoter in macrophages, by which it repressed Ship expression and enhanced PI3K/Akt signaling to promote the macrophage M2 program. Therefore, intratracheal administration of liposomes loaded with Mbd2 siRNA protected mice from BLM-induced lung injuries and fibrosis. Together, our data support the possibility that MBD2 could be a viable target against PF in clinical settings.


Subject(s)
COVID-19/metabolism , DNA-Binding Proteins/metabolism , Macrophages/metabolism , Pulmonary Fibrosis/metabolism , Animals , Bleomycin/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , Fibrosis , Gene Expression Profiling , Gene Expression Regulation , Humans , Liposomes/chemistry , Lung Diseases, Interstitial/metabolism , Lung Neoplasms/metabolism , Macrophages/virology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pulmonary Fibrosis/virology , RNA, Small Interfering/metabolism , Scleroderma, Systemic/metabolism , Signal Transduction , Transforming Growth Factor beta1/metabolism
12.
Med Sci Monit ; 26: e927240, 2020 Dec 01.
Article in English | MEDLINE | ID: covidwho-985826

ABSTRACT

BACKGROUND Infants and young children with acute respiratory distress syndrome (ARDS) have acute progressive hypoxic respiratory failure caused by a variety of extrapulmonary pathogenic factors and cardiogenic factors. Diffuse alveolar injury and pulmonary fibrosis both are pathological features of ARDS. This study investigated the effect of Rehmannia Radix extract (RRE) on pulmonary fibrosis of infants with ARDS. MATERIAL AND METHODS The human lung fibroblasts cell line HFL1 was treated with various concentrations of Rehmannia Radix extract in different groups for different times. Flow cytometry and TUNEL assay were performed to detect cell apoptosis, and CCK8 assay was utilized to analyze cell proliferation. TGF-ß1 expression was detected by real-time quantitative PCR, and protein-level expressions of Caspase3, TGF-ß1, Bcl-2, and Smad3 were measured by western blot and immunohistochemical staining in cells or tissues. TGF-ß1 was overexpressed by recombinant human TGF-ß1 (2 ng/mL) and the treated cells and culture supernatant were harvested for analysis in each step. Bleomycin was used to induce a mouse model of pulmonary fibrosis and was confirmed by HE pathological sections. RESULTS Flow cytometry and TUNEL results showed that RRE promoted the apoptosis of HFL1 cells in a concentration-dependent manner, and it inhibited the proliferation of HFL1 cells. Upregulation of TGF-ß1 reversed the effects of RRE in HFL1 cells. RRE alleviated pulmonary fibrosis in mice through downregulating Bcl-2, TGF-ß1, and Smad3 expression. CONCLUSIONS RRE promoted apoptosis and inhibited proliferation of HFL1, and then arrested the progression of pulmonary fibrosis. RRE had a significant inhibitory effect on TGF-ß1 and Smad3. These results suggest that RRE directly prevents the development of pulmonary fibrosis by affecting the expression of TGF-ß1 and Smad3.


Subject(s)
Plant Extracts/therapeutic use , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/drug therapy , Rehmannia/chemistry , Transforming Growth Factor beta1/metabolism , Animals , Apoptosis/drug effects , Bleomycin , Cell Line , Cell Proliferation/drug effects , Disease Progression , Humans , Mice , Plant Extracts/pharmacology , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology
13.
Exp Lung Res ; 47(2): 67-77, 2021.
Article in English | MEDLINE | ID: covidwho-948635

ABSTRACT

OBJECTIVE: Patients with idiopathic pulmonary fibrosis (IPF) are still suffering from unfavorable survival. BTB and CNC homology1 (Bach1) is a regulator of oxidative stress and participates in the pathogenesis of multiple lung diseases. Thus, this study aimed to determine the effect of Bach1 knockdown on fibrosis and inflammation in pulmonary fibrosis (PF) mice and cell models. METHODS: Bleomycin induced PF mice were constructed and treated with Bach1 siRNA adenovirus (BLM + Bach1 siRNA group), control siRNA adenovirus (BLM + Control siRNA group) or normal saline (BLM group), then lung tissues were collected for Bach1 expression detection, H&E staining and Masson's trichrome staining. Afterwards, collagen type I alpha 1 chain (COL1A1) and interleukin-6 (IL-6) expressions in serum and bronchoalveolar lavage fluid (BALF) were examined. Subsequently, mouse lung fibroblasts (MLFs) were collected from PF mice and treated with TGF-ß1 to construct PF cell model, which was treated with Bach1 siRNA adenovirus (TGF-ß1 + Bach1 siRNA group) and MAP kinase (ERK) inhibitor U0126 alone (TGF-ß1 + U0126 group) or in combination (TGF-ß1 + U0126 + Bach1 siRNA group), then alpha-smooth muscle actin (α-SMA), fibronectin 1 (Fn1), COL1A1, IL-6 expressions and cell viability were detected. RESULTS: Lung tissue Bach1 mRNA and protein expressions were upregulated in PF mice compared to control mice. Bach1 knockdown reduced lung fibrosis (displayed by Masson's trichrome staining) and inflammation (displayed by H&E staining), then downregulated serum and BALF expressions of COL1A1 and IL-6 in PF mice. Subsequently, in PF cell model, Bach1 knockdown blocked ERK pathway, but did not affect Smads, c-Jun N-terminal kinase (JNK) or thymoma viral proto-oncogene 1 (Akt) pathways. Further experiments revealed that Bach1 knockdown repressed cell viability, α-SMA, Fn1, IL-6 and COL1A1 expressions in PF cell model, then ERK inhibition by U0126 enhanced these effects. CONCLUSIONS: Bach1 is involved in the PF pathogenesis via modulating ERK signaling pathway.


Subject(s)
Basic-Leucine Zipper Transcription Factors/genetics , Idiopathic Pulmonary Fibrosis , MAP Kinase Signaling System , Animals , Bleomycin , Humans , Inflammation , Lung/metabolism , Mice , Transforming Growth Factor beta1/metabolism
14.
Virology ; 552: 43-51, 2021 01 02.
Article in English | MEDLINE | ID: covidwho-843443

ABSTRACT

This study focused on intestinal restitution including phenotype switching of absorptive enterocytes and the abundance of different enterocyte subtypes in weaned pigs after porcine epidemic diarrhea virus (PEDV) infection. At 10 days post-PEDV-inoculation, the ratio of villus height to crypt depth in both jejunum and ileum had restored, and the PEDV antigen was not detectable. However, enterocytes at the villus tips revealed epithelial-mesenchymal transition (EMT) in the jejunum in which E-cadherin expression decreased while expression of N-cadherin, vimentin, and Snail increased. Additionally, there was reduced expression of actin in microvilli and Zonula occludens-1 (ZO-1) in tight junctions. Moreover, the protein concentration of transforming growth factor ß1 (TGFß1), which mediates EMT and cytoskeleton alteration, was increased. We also found a decreased number of Peyer's patch M cells in the ileum. These results reveal incomplete restitution of enterocytes in the jejunum and potentially impaired immune surveillance in the ileum after PEDV infection.


Subject(s)
Coronavirus Infections/veterinary , Enterocytes/pathology , Epithelial-Mesenchymal Transition , Gastroenteritis, Transmissible, of Swine/pathology , Peyer's Patches/pathology , Porcine epidemic diarrhea virus/pathogenicity , Animals , Cadherins/metabolism , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Gastroenteritis, Transmissible, of Swine/immunology , Gastroenteritis, Transmissible, of Swine/virology , Ileum/immunology , Ileum/pathology , Intestinal Mucosa/pathology , Jejunum/immunology , Jejunum/pathology , Microvilli/pathology , Swine , Tight Junctions/pathology , Transforming Growth Factor beta1/metabolism , Weaning
15.
Phytother Res ; 35(2): 974-986, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-804475

ABSTRACT

Pulmonary fibrosis is a key feature of COVID-19, Chinese herbal medicine Arenaria kansuensis has been used for curing pulmonary disease and antivirus for a long time and it has the potential against COVID-19. In this work, protective effect of A. kansuensis ethanol extract (AE) on pulmonary fibrosis was evaluated through paraquat (PQ)-induced pulmonary fibrosis animal model. Results showed that AE could significantly improve the survival rate, increase the body weight and reduce the lung index of mice at the raw drug doses of 700 and 350 mg/kg. Histopathological observation results showed that the destruction degree of lung tissue structure in mice was significantly improved with the increase of AE dosage. Collagen deposition in lung interstitium was significantly reduced. The marker protein alpha-SMA involved in PF were significantly inhibited through repressing TGF-beta1/Smads pathway. The degree of inflammatory infiltration was significantly reduced and inflammatory cytokines were significantly inhibited in mice through inhibiting the NF-kB-p65. Besides, oxidant stress level including upregulated ROS and down-regulated SOD and GSH was efficiently improved by AE through upregulation of Nrf2 and downregulation of NOX4. In summary, this study firstly showed that the protective effect of AE on pulmonary fibrosis was partly due to activation of Nrf2 pathway and the inhibition of NF-kB/TGF-beta1/Smad2/3 pathway.


Subject(s)
Arenaria Plant/chemistry , Drugs, Chinese Herbal/pharmacology , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/metabolism , Acute Lung Injury , Animals , Arenaria Plant/physiology , COVID-19/complications , COVID-19/drug therapy , COVID-19/pathology , Cytokines/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Ethanol/chemistry , Female , Male , Mice , Mice, Inbred C57BL , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Oxidative Stress/drug effects , Paraquat , Phytotherapy , Pulmonary Edema/drug therapy , Pulmonary Edema/pathology , Pulmonary Fibrosis/chemically induced , Pulmonary Fibrosis/pathology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Signal Transduction/drug effects , Smad2 Protein/metabolism , Smad3 Protein/metabolism , Survival Rate , Transforming Growth Factor beta1/metabolism
16.
Sci Adv ; 6(35): eaba7910, 2020 08.
Article in English | MEDLINE | ID: covidwho-760200

ABSTRACT

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.


Subject(s)
Adaptor Proteins, Vesicular Transport/metabolism , Antiviral Agents/pharmacology , Cinnamates/pharmacology , Coronavirus Infections/drug therapy , HIV Infections/drug therapy , Influenza, Human/drug therapy , Pneumonia, Viral/drug therapy , ortho-Aminobenzoates/pharmacology , A549 Cells , Animals , Betacoronavirus/drug effects , Binding Sites/genetics , COVID-19 , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus Infections/pathology , Dogs , HEK293 Cells , HIV Infections/pathology , HIV-1/drug effects , Host-Pathogen Interactions/drug effects , Humans , Influenza A virus/drug effects , Influenza, Human/pathology , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Middle East Respiratory Syndrome Coronavirus/drug effects , Pandemics , Pneumonia, Viral/pathology , Protein Binding/genetics , Protein Transport/drug effects , RNA, Viral/genetics , Receptor, Interferon alpha-beta/genetics , SARS-CoV-2 , Transforming Growth Factor beta1/metabolism , Vero Cells , Virus Replication/drug effects , Zika Virus/drug effects , Zika Virus Infection/pathology
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