Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 90
Filter
1.
Small ; : e2403159, 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38958081

ABSTRACT

Uncovering the hardening mechanisms is of great importance to accelerate the design of superhard high-entropy carbides (HECs). Herein, the hardening mechanisms of HECs by a combination of experiments and first-principles calculations are systematically explored. The equiatomic single-phase 4- to 8-cation HECs (4-8HECs) are successfully fabricated by the two-step approach involving ultrafast high-temperature synthesis and hot-press sintering techniques. The as-fabricated 4-8HEC samples possess fully dense microstructures (relative densities of up to ≈99%), similar grain sizes, clean grain boundaries, and uniform compositions. With the elimination of these morphological properties, the monotonic enhancement of Vickers hardness and nanohardness of the as-fabricated 4-8HEC samples is found to be driven by the aggravation of lattice distortion. Further studies show no evident association between the enhanced hardness of the as-fabricated 4-8HEC samples and other potential indicators, including bond strength, valence electron concentration, electronegativity mismatch, and metallic states. The work unveils the underlying hardening mechanisms of HECs and offers an effective strategy for designing superhard HECs.

2.
Burns Trauma ; 12: tkae009, 2024.
Article in English | MEDLINE | ID: mdl-38841099

ABSTRACT

Background: Given the significant impact on human health, it is imperative to develop novel treatment approaches for diabetic wounds, which are prevalent and serious complications of diabetes. The diabetic wound microenvironment has a high level of reactive oxygen species (ROS) and an imbalance between proinflammatory and anti-inflammatory cells/factors, which hamper the healing of chronic wounds. This study aimed to develop poly(L-lactic acid) (PLLA) nanofibrous membranes incorporating curcumin and silver nanoparticles (AgNPs), defined as PLLA/C/Ag, for diabetic wound healing. Methods: PLLA/C/Ag were fabricated via an air-jet spinning approach. The membranes underwent preparation and characterization through various techniques including Fourier-transform infrared spectroscopy, measurement of water contact angle, X-ray photoelectron spectroscopy, X-ray diffraction, scanning electron microscopy, assessment of in vitro release of curcumin and Ag+, testing of mechanical strength, flexibility, water absorption and biodegradability. In addition, the antioxidant, antibacterial and anti-inflammatory properties of the membranes were evaluated in vitro, and the ability of the membranes to heal wounds was tested in vivo using diabetic mice. Results: Loose hydrophilic nanofibrous membranes with uniform fibre sizes were prepared through air-jet spinning. The membranes enabled the efficient and sustained release of curcumin. More importantly, antibacterial AgNPs were successfully reduced in situ from AgNO3. The incorporation of AgNPs endowed the membrane with superior antibacterial activity, and the bioactivities of curcumin and the AgNPs gave the membrane efficient ROS scavenging and immunomodulatory effects, which protected cells from oxidative damage and reduced inflammation. Further results from animal studies indicated that the PLLA/C/Ag membranes had the most efficient wound healing properties, which were achieved by stimulating angiogenesis and collagen deposition and inhibiting inflammation. Conclusions: In this research, we successfully fabricated PLLA/C/Ag membranes that possess properties of antioxidants, antibacterial agents and anti-inflammatory agents, which can aid in the process of wound healing. Modulating wound inflammation, these new PLLA/C/Ag membranes serve as a novel dressing to enhance the healing of diabetic wounds.

3.
Adv Mater ; 36(14): e2311870, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38166175

ABSTRACT

High mechanical load-carrying capability and thermal insulating performance are crucial to thermal-insulation materials under extreme conditions. However, these features are often difficult to achieve simultaneously in conventional porous ceramics. Here, for the first time, it is reported a multiscale structure design and fast fabrication of 9-cation porous high-entropy diboride ceramics via an ultrafast high-temperature synthesis technique that can lead to exceptional mechanical load-bearing capability and high thermal insulation performance. With the construction of multiscale structures involving ultrafine pores at the microscale, high-quality interfaces between building blocks at the nanoscale, and severe lattice distortion at the atomic scale, the materials with an ≈50% porosity exhibit an ultrahigh compressive strength of up to ≈337 MPa at room temperature and a thermal conductivity as low as ≈0.76 W m-1 K-1. More importantly, they demonstrate exceptional thermal stability, with merely ≈2.4% volume shrinkage after 2000 °C annealing. They also show an ultrahigh compressive strength of ≈690 MPa up to 2000 °C, displaying a ductile compressive behavior. The excellent mechanical and thermal insulating properties offer an attractive material for reliable thermal insulation under extreme conditions.

4.
Front Immunol ; 14: 1294317, 2023.
Article in English | MEDLINE | ID: mdl-38111578

ABSTRACT

Diabetic nephropathy (DN) is a chronic inflammatory disease that affects millions of diabetic patients worldwide. The key to treating of DN is early diagnosis and prevention. Once the patient enters the clinical proteinuria stage, renal damage is difficult to reverse. Therefore, developing early treatment methods is critical. DN pathogenesis results from various factors, among which the immune response and inflammation play major roles. Ferroptosis is a newly discovered type of programmed cell death characterized by iron-dependent lipid peroxidation and excessive ROS production. Recent studies have demonstrated that inflammation activation is closely related to the occurrence and development of ferroptosis. Moreover, hyperglycemia induces iron overload, lipid peroxidation, oxidative stress, inflammation, and renal fibrosis, all of which are related to DN pathogenesis, indicating that ferroptosis plays a key role in the development of DN. Therefore, this review focuses on the regulatory mechanisms of ferroptosis, and the mutual regulatory processes involved in the occurrence and development of DN and inflammation. By discussing and analyzing the relationship between ferroptosis and inflammation in the occurrence and development of DN, we can deepen our understanding of DN pathogenesis and develop new therapeutics targeting ferroptosis or inflammation-related regulatory mechanisms for patients with DN.


Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Ferroptosis , Humans , Diabetic Nephropathies/pathology , Oxidative Stress , Kidney/pathology , Inflammation/metabolism , Diabetes Mellitus/metabolism
5.
Biomed Pharmacother ; 168: 115818, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37939612

ABSTRACT

Diabetic nephropathy (DN) is a prevalent chronic microvascular complication associated with diabetes mellitus and represents a major cause of chronic kidney disease and renal failure. Current treatment strategies for DN primarily focus on symptom alleviation, lacking effective approaches to halt or reverse DN progression. Circular RNA (circRNA), characterized by a closed-loop structure, has emerged as a novel non-coding RNA regulator of gene expression, attributed to its conservation, stability, specificity, and multifunctionality. Dysregulation of circRNA expression is closely associated with DN progression, whereby circRNA impacts kidney cell injury by modulating cell cycle, differentiation, cell death, as well as influencing the release of inflammatory factors and stromal fibronectin expression. Consequently, circRNA is considered a predictive biomarker and a potential therapeutic target for DN. This review provides an overview of the latest research progress in the classification, functions, monitoring methods, and databases related to circRNA. The paper focuses on elucidating the impact and underlying mechanisms of circRNA on kidney cells under diabetic conditions, aiming to offer novel insights into the prevention, diagnosis, and treatment of DN.


Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Humans , Diabetic Nephropathies/diagnosis , Diabetic Nephropathies/genetics , Diabetic Nephropathies/therapy , RNA, Circular/genetics , RNA, Circular/metabolism , Kidney/metabolism , Biomarkers/metabolism , Diabetes Mellitus/metabolism
6.
Front Immunol ; 14: 1274654, 2023.
Article in English | MEDLINE | ID: mdl-37954576

ABSTRACT

Diabetes mellitus is a metabolic disease that is characterized by chronic hyperglycemia due to a variety of etiological factors. Long-term metabolic stress induces harmful inflammation leading to chronic complications, mainly diabetic ophthalmopathy, diabetic cardiovascular complications and diabetic nephropathy. With diabetes complications being one of the leading causes of disability and death, the use of anti-inflammatories in combination therapy for diabetes is increasing. There has been increasing interest in targeting significant regulators of the inflammatory pathway, notably receptor-interacting serine/threonine-kinase-1 (RIPK1) and receptor-interacting serine/threonine-kinase-3 (RIPK3), as drug targets for managing inflammation in treating diabetes complications. In this review, we aim to provide an up-to-date summary of current research on the mechanism of action and drug development of RIPK1 and RIPK3, which are pivotal in chronic inflammation and immunity, in relation to diabetic complications which may be benefit for explicating the potential of selective RIPK1 and RIPK3 inhibitors as anti-inflammatory therapeutic agents for diabetic complications.


Subject(s)
Diabetes Complications , Diabetes Mellitus , Diabetic Nephropathies , Humans , Inflammation/drug therapy , Inflammation/metabolism , Diabetes Complications/drug therapy , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Threonine , Serine , Diabetes Mellitus/drug therapy , Diabetes Mellitus/etiology
7.
Mol Med ; 29(1): 135, 2023 Oct 12.
Article in English | MEDLINE | ID: mdl-37828444

ABSTRACT

Diabetic kidney disease (DKD) is the main cause of end-stage renal disease, and its clinical manifestations are progressive proteinuria, decreased glomerular filtration rate, and renal failure. The injury and death of glomerular podocytes are the keys to DKD. Currently, a variety of cell death modes have been identified in podocytes, including apoptosis, autophagy, endoplasmic reticulum (ER) stress, pyroptosis, necroptosis, ferroptosis, mitotic catastrophe, etc. The signaling pathways leading to these cell death processes are interconnected and can be activated simultaneously or in parallel. They are essential for cell survival and death that determine the fate of cells. With the deepening of the research on the mechanism of cell death, more and more researchers have devoted their attention to the underlying pathologic research and the drug therapy research of DKD. In this paper, we discussed the podocyte physiologic role and DKD processes. We also provide an overview of the types and specific mechanisms involved in each type of cell death in DKD, as well as related targeted therapy methods and drugs are reviewed. In the last part we discuss the complexity and potential crosstalk between various modes of cell death, which will help improve the understanding of podocyte death and lay a foundation for new and ideal targeted therapy strategies for DKD treatment in the future.


Subject(s)
Diabetes Mellitus , Diabetic Nephropathies , Podocytes , Humans , Diabetic Nephropathies/pathology , Podocytes/metabolism , Podocytes/pathology , Cell Death , Apoptosis , Epithelial Cells/metabolism , Diabetes Mellitus/metabolism
8.
Protein J ; 42(6): 753-765, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37690089

ABSTRACT

Excessive production of transforming growth factor ß1 (TGF-ß1) in activated hepatic stellate cells (aHSCs) promotes liver fibrosis by activating the TGF-ß1/Smad signaling pathway. Thus, specifically inhibiting the pro-fibrotic activity of TGF-ß1 in aHSCs is an ideal strategy for treating liver fibrosis. Overexpression of platelet-derived growth factor ß receptor (PDGFßR) has been demonstrated on the surface of aHSCs relative to normal cells in liver fibrosis. Interferon-gamma peptidomimetic (mIFNγ) and truncated TGF-ß receptor type II (tTßRII) inhibit the TGF-ß1/Smad signaling pathway by different mechanisms. In this study, we designed a chimeric protein by the conjugation of (1) mIFNγ and tTßRII coupled via plasma protease-cleavable linker sequences (FNPKTP) to (2) PDGFßR-recognizing peptide (BiPPB), namely BiPPB-mIFNγ-tTßRII. This novel protein BiPPB-mIFNγ-tTßRII was effectively prepared using Escherichia coli expression system. The active components BiPPB-mIFNγ and tTßRII were slowly released from BiPPB-mIFNγ-tTßRII by hydrolysis using the plasma protease thrombin in vitro. Moreover, BiPPB-mIFNγ-tTßRII highly targeted to fibrotic liver tissues, markedly ameliorated liver morphology and fibrotic responses in chronic liver fibrosis mice by both inhibiting the phosphorylation of Smad2/3 and inducing the expression of Smad7. Meanwhile, BiPPB-mIFNγ-tTßRII markedly reduced the deposition of collagen fibrils and expression of fibrosis-related proteins in acute liver fibrosis mice. Furthermore, BiPPB-mIFNγ-tTßRII showed a good safety performance in both liver fibrosis mice. Taken together, BiPPB-mIFNγ-tTßRII improved the in vivo anti-liver fibrotic activity due to its high fibrotic liver-targeting potential and the dual inhibition of the TGF-ß1/Smad signaling pathway, which may be a potential candidate for targeting therapy on liver fibrosis.

9.
Appl Microbiol Biotechnol ; 107(20): 6251-6262, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37606791

ABSTRACT

Cardiac fibrosis is a remodeling process of the cardiac interstitium, characterized by abnormal metabolism of the extracellular matrix, excessive accumulation of collagen fibers, and scar tissue hyperplasia. Persistent activation and transdifferentiation into myofibroblasts of cardiac fibroblasts promote the progression of fibrosis. Transforming growth factor-ß1 (TGF-ß1) is a pivotal factor in cardiac fibrosis. Latency-associated peptide (LAP) is essential for activating TGF-ß1 and its binding to the receptor. Thus, interference with TGF-ß1 and the signaling pathways using LAP may attenuate cardiac fibrosis. Recombinant full-length and truncated LAP were previously constructed, expressed, and purified. Their effects on cardiac fibrosis were investigated in isoproterenol (ISO)-induced cardiac fibroblasts (CFs) and C57BL/6 mice. The study showed that LAP and tLAP inhibited ISO-induced CF activation, inflammation, and fibrosis, improved cardiac function, and alleviated myocardial injury in ISO-induced mice. LAP and tLAP alleviated the histopathological alterations and inhibited the elevated expression of inflammatory and fibrosis-related markers in cardiac tissue. In addition, LAP and tLAP decreased the ISO-induced elevated expression of TGF-ß, αvß3, αvß5, p-Smad2, and p-Smad3. The study indicated that LAP and tLAP attenuated ISO-induced cardiac fibrosis via suppressing TGF-ß/Smad pathway. This study may provide a potential approach to alleviate cardiac fibrosis. KEY POINTS: • LAP and tLAP inhibited ISO-induced CF activation, inflammation, and fibrosis. • LAP and tLAP improved cardiac function and alleviated myocardial injury, inflammation, and fibrosis in ISO-induced mice. • LAP and tLAP attenuated cardiac fibrosis via suppressing TGF-ß/Smad pathway.

10.
Emerg Microbes Infect ; 12(2): 2251600, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37606967

ABSTRACT

Pigeon paramyxovirus 1 (PPMV-1) is an antigenic host variant of avian paramyxovirus 1. Sporadic outbreaks of PPMV-1 infection have occurred in pigeons in China; however, few cases of human PPMV-1 infection have been reported. The purpose of this article is to report a case of severe human PPMV-1 infection in an individual with probable post-COVID-19 syndrome (long COVID) who presented with rapidly progressing pulmonary infection. The patient was a 66-year-old man who was admitted to the intensive care unit 11 days after onset of pneumonia and recovered 64 days after onset. PPMV-1 was isolated from the patient's sputum and in cloacal smear samples from domesticated pigeons belonging to the patient's neighbour. Residual severe acute respiratory syndrome coronavirus 2 was detected in respiratory and anal swab samples from the patient. Sequencing analyses revealed that the PPMV-1 genome belonged to genotype VI.2.1.1.2.2 and had the 112RRQKRF117 motif in the cleavage site of the fusion protein, which is indicative of high virulence. This case of cross-species transmission of PPMV-1 from a pigeon to a human highlights the risk of severe PPMV-1 infection in immunocompromised patients, especially those with long COVID. Enhanced surveillance for increased risk of severe viral infection is warranted in this population.


Subject(s)
COVID-19 , Male , Animals , Humans , Aged , Columbidae , Newcastle disease virus/genetics , Post-Acute COVID-19 Syndrome , Antigenic Variation
11.
Arch Pharm Res ; 46(3): 177-191, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36905489

ABSTRACT

Truncated transforming growth factor ß receptor type II (tTßRII) is a promising anti-liver fibrotic candidate because it serves as a trap for binding excessive TGF-ß1 by means of competing with wild type TßRII (wtTßRII). However, the widespread application of tTßRII for the treatment of liver fibrosis has been limited by its poor fibrotic liver-homing capacity. Herein, we designed a novel tTßRII variant Z-tTßRII by fusing the platelet-derived growth factor ß receptor (PDGFßR)-specific affibody ZPDGFßR to the N-terminus of tTßRII. The target protein Z-tTßRII was produced using Escherichia coli expression system. In vitro and in vivo studies showed that Z-tTßRII has a superior specific fibrotic liver-targeting potential via the engagement of PDGFßR-overexpressing activated hepatic stellate cells (aHSCs) in liver fibrosis. Moreover, Z-tTßRII significantly inhibited cell migration and invasion, and downregulated fibrosis- and TGF-ß1/Smad pathway-related protein levels in TGF-ß1-stimiluated HSC-T6 cells. Furthermore, Z-tTßRII remarkably ameliorated liver histopathology, mitigated the fibrosis responses and blocked TGF-ß1/Smad signaling pathway in CCl4-induced liver fibrotic mice. More importantly, Z-tTßRII exhibits a higher fibrotic liver-targeting potential and stronger anti-fibrotic effects than either its parent tTßRII or former variant BiPPB-tTßRII (PDGFßR-binding peptide BiPPB modified tTßRII). In addition, Z-tTßRII shows no significant sign of potential side effects in other vital organs in liver fibrotic mice. Taken together, we conclude that Z-tTßRII with its a high fibrotic liver-homing potential, holds a superior anti-fibrotic activity in liver fibrosis in vitro and in vivo, which may be a potential candidate for targeted therapy for liver fibrosis.


Subject(s)
Liver Cirrhosis , Transforming Growth Factor beta1 , Mice , Animals , Transforming Growth Factor beta1/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Hepatic Stellate Cells/metabolism , Signal Transduction , Organic Chemicals/pharmacology , Transforming Growth Factor beta , Carbon Tetrachloride/adverse effects , Carbon Tetrachloride/metabolism
12.
Front Cardiovasc Med ; 10: 1135723, 2023.
Article in English | MEDLINE | ID: mdl-36970345

ABSTRACT

Diabetes is a common chronic metabolic disease, and its incidence continues to increase year after year. Diabetic patients mainly die from various complications, with the most common being diabetic cardiomyopathy. However, the detection rate of diabetic cardiomyopathy is low in clinical practice, and targeted treatment is lacking. Recently, a large number of studies have confirmed that myocardial cell death in diabetic cardiomyopathy involves pyroptosis, apoptosis, necrosis, ferroptosis, necroptosis, cuproptosis, cellular burial, and other processes. Most importantly, numerous animal studies have shown that the onset and progression of diabetic cardiomyopathy can be mitigated by inhibiting these regulatory cell death processes, such as by utilizing inhibitors, chelators, or genetic manipulation. Therefore, we review the role of ferroptosis, necroptosis, and cuproptosis, three novel forms of cell death in diabetic cardiomyopathy, searching for possible targets, and analyzing the corresponding therapeutic approaches to these targets.

13.
Fundam Res ; 3(6): 979-987, 2023 Nov.
Article in English | MEDLINE | ID: mdl-38933014

ABSTRACT

The development of high-entropy borides with combined structural and functional performance holds untold scientific and technological potential, yet relevant studies have been rarely reported. In this work, we report nanocrystalline (La0.25Ce0.25Nd0.25Eu0.25)B6 high-entropy rare-earth hexaboride (HEReB6-1) ceramics fabricated through the high-pressure sintering of self-synthesized nanopowders for the first time. The as-fabricated samples exhibited a highly dense (96.3%) nanocrystalline (94 nm) microstructure with major (001) fiber textures and good grain boundaries without any impurities, resulting in a remarkable mechanical, electrical, and thermionic emission performance. The results showed that the samples possessed outstanding comprehensive mechanical properties and a high electrical resistivity from room temperature to high temperatures; these were greater than the average values of corresponding binary rare-earth hexaborides, such as a Vickers hardness of 23.4 ± 0.6 GPa and a fracture toughness of 3.0 ± 0.4 MPa•m1/2 at room temperature. More importantly, they showed high emission current densities at elevated temperatures, which were higher than the average values of the corresponding binary rare-earth hexaborides. For instance, the maximum emission current density reached 48.3 A•cm-2 at 1873 K. Such superior performance makes the nanocrystalline HEReB6-1 ceramics highly suitable for potential applications in thermionic emission cathodes.

14.
Biomedicines ; 10(12)2022 Dec 16.
Article in English | MEDLINE | ID: mdl-36552026

ABSTRACT

Excessive accumulation of the extracellular matrix (ECM) is a crucial pathological process in chronic kidney diseases, such as diabetic nephropathy, etc. The underlying mechanisms of how to decrease ECM deposition to improve diabetic nephropathy remain elusive. The present study investigated whether cyclopentanone compound H8 alleviated ECM over-deposition and fibrosis to prevent and treat diabetic nephropathy. HK-2 cell viability after treatment with H8 was measured by an MTT assay. ECM alterations and renal fibrosis were identified in vitro and in vivo. A pharmacological antagonist was used to detect associations between H8 and the p38 mitogen-activated protein kinase (p38MAPK) signaling pathway. H8 binding was identified through computer simulation methods. Studies conducted on high glucose and transforming growth factor ß1 (TGF-ß1)-stimulated HK-2 cells revealed that the p38MAPK inhibitor SB 202190 and H8 had similar pharmacological effects. In addition, excessive ECM accumulation and fibrosis in diabetic nephropathy were remarkably improved after H8 administration in vivo and in vitro. Finally, the two molecular docking models further proved that H8 is a specific p38MAPK inhibitor that forms a hydrogen bond with the LYS-53 residue of p38MAPK. The cyclopentanone compound H8 alleviated the over-deposition of ECM and the development of fibrosis in diabetic nephropathy by suppressing the TGF-ß/p38MAPK axis.

15.
Front Mol Biosci ; 9: 965064, 2022.
Article in English | MEDLINE | ID: mdl-36090039

ABSTRACT

Alzheimer's disease (AD) accounts for two-thirds of all dementia cases, affecting 50 million people worldwide. Only four of the more than 100 AD drugs developed thus far have successfully improved AD symptoms. Furthermore, these improvements are only temporary, as no treatment can stop or reverse AD progression. A growing number of recent studies have demonstrated that iron-dependent programmed cell death, known as ferroptosis, contributes to AD-mediated nerve cell death. The ferroptosis pathways within nerve cells include iron homeostasis regulation, cystine/glutamate (Glu) reverse transporter (system xc-), glutathione (GSH)/glutathione peroxidase 4 (GPX4), and lipid peroxidation. In the regulation pathway of AD iron homeostasis, abnormal iron uptake, excretion and storage in nerve cells lead to increased intracellular free iron and Fenton reactions. Furthermore, decreased Glu transporter expression leads to Glu accumulation outside nerve cells, resulting in the inhibition of the system xc- pathway. GSH depletion causes abnormalities in GPX4, leading to excessive accumulation of lipid peroxides. Alterations in these specific pathways and amino acid metabolism eventually lead to ferroptosis. This review explores the connection between AD and the ferroptosis signaling pathways and amino acid metabolism, potentially informing future AD diagnosis and treatment methodologies.

16.
Mol Med ; 28(1): 80, 2022 07 16.
Article in English | MEDLINE | ID: mdl-35842576

ABSTRACT

BACKGROUND: Liver fibrosis is a progressive liver injury response. Transforming growth factor ß1 (TGF-ß1) is oversecreted during liver fibrosis and promotes the development of liver fibrosis. Therapeutic approaches targeting TGF-ß1 and its downstream pathways are essential to inhibit liver fibrosis. The N-terminal latency-associated peptide (LAP) blocks the binding of TGF-ß1 to its receptor. Removal of LAP is critical for the activation of TGF-ß1. Therefore, inhibition of TGF-ß1 and its downstream pathways by LAP may be a potential approach to affect liver fibrosis. METHODS: Truncated LAP (tLAP) plasmids were constructed. Recombinant proteins were purified by Ni affinity chromatography. The effects of LAP and tLAP on liver fibrosis were investigated in TGF-ß1-induced HSC-T6 cells, AML12 cells and CCl4-induced liver fibrosis mice by real time cellular analysis (RTCA), western blot, real-time quantitative PCR (RT-qPCR), immunofluorescence and pathological staining. RESULTS: LAP and tLAP could inhibit TGF-ß1-induced AML12 cells inflammation, apoptosis and EMT, and could inhibit TGF-ß1-induced HSC-T6 cells proliferation and fibrosis. LAP and tLAP could attenuate the pathological changes of liver fibrosis and inhibit the expression of fibrosis-related proteins and mRNAs in CCl4-induced liver fibrosis mice. CONCLUSION: LAP and tLAP could alleviate liver fibrosis in vitro and in vivo via inhibition of TGF-ß/Smad pathway. TLAP has higher expression level and more effective anti-fibrosis activity compared to LAP. This study may provide new ideas for the treatment of liver fibrosis.


Subject(s)
Transforming Growth Factor beta1 , Transforming Growth Factor beta , Animals , Hepatic Stellate Cells/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/metabolism , Mice , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use , Signal Transduction , Smad Proteins/metabolism , Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta1/metabolism
17.
Nutrients ; 14(11)2022 Jun 06.
Article in English | MEDLINE | ID: mdl-35684158

ABSTRACT

We investigated the effect of an 11ß-HSD1 inhibitor (H8) on hepatic steatosis and its mechanism of action. Although H8, a curcumin derivative, has been shown to alleviate insulin resistance, its effect on non-alcoholic fatty liver disease (NAFLD) remains unknown. Rats were fed a high-fat diet (HFD) for 8 weeks, intraperitoneally injected with streptozotocin (STZ) to induce NAFLD, and, then, treated with H8 (3 or 6 mg/kg/day) or curcumin (6 mg/kg/day) for 4 weeks, to evaluate the effects of H8 on NAFLD. H8 significantly alleviated HFD+STZ-induced lipid accumulation, fibrosis, and inflammation as well as improved liver function. Moreover, 11ß-HSD1 overexpression was established by transfecting animals and HepG2 cells with lentivirus, carrying the 11ß-HSD1 gene, to confirm that H8 improved NAFLD, by reducing 11ß-HSD1. An AMP-activated protein kinase (AMPK) inhibitor (Compound C, 10 µM for 2 h) was used to confirm that H8 increased AMPK, by inhibiting 11ß-HSD1, thereby restoring lipid metabolic homeostasis. A silencing-related enzyme 1 (SIRT1) inhibitor (EX572, 10 µM for 4 h) and a SIRT1 activator (SRT1720, 1 µM for 4 h) were used to confirm that H8 exerted anti-inflammatory effects, by elevating SIRT1 expression. Our findings demonstrate that H8 alleviates hepatic steatosis, by inhibiting 11ß-HSD1, which activates the AMPK/SIRT1 signaling pathway.


Subject(s)
Curcumin , Non-alcoholic Fatty Liver Disease , 11-beta-Hydroxysteroid Dehydrogenase Type 1/genetics , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , AMP-Activated Protein Kinases/metabolism , Animals , Curcumin/pharmacology , Enzyme Inhibitors/pharmacology , Lipids/pharmacology , Liver/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , Rats , Signal Transduction , Sirtuin 1/genetics , Sirtuin 1/metabolism
18.
Int J Biol Macromol ; 209(Pt A): 1516-1525, 2022 Jun 01.
Article in English | MEDLINE | ID: mdl-35452701

ABSTRACT

Elevated expressions of transforming growth factor ß1 (TGF-ß1) have been implicated in the pathogenesis of liver fibrosis, thus attenuating the excessive TGF-ß1's activity by TGF-ß1-binding peptide is an ideal strategy for the treatment of liver fibrosis. However, the application of small peptide as a pharmaceutical agent is obstacle due to difficult preparation and non-selective delivery. The I-plus sequences of circumsporozoite protein (CSP-I) possesses high affinity for heparan sulfate proteoglycans, which are primarily located on liver tissues. TGF-ß1-binding peptide P15 holds specific ability of binding to TGF-ß1. In this study, we describe an approach to efficiently preparing liver-targeting peptide P15-CSP-I, which is conjugation of the sequences of P15 to the N-terminus of CSP-I, from the cleavage of biological macromolecule SUMO-tagged P15-CSP-I. In vitro and ex vivo binding assay showed that P15-CSP-I specifically targeted to the hepatocytes and liver tissues. Moreover, P15-CSP-I inhibited cell proliferation, migration and invasion, and decreased fibrosis-related proteins expression in TGF-ß1-activated HSCs in vitro. Furthermore, P15-CSP-I ameliorated liver morphology and decreased the fibrosis responses in vivo. Taken together, P15-CSP-I may be a potential candidate for targeting therapy on liver fibrosis due to its high efficient preparation, specific liver-targeting potential and improved anti-liver fibrotic activity.


Subject(s)
Heparan Sulfate Proteoglycans , Liver , Transforming Growth Factor beta1 , Animals , Heparan Sulfate Proteoglycans/metabolism , Humans , Liver/metabolism , Liver Cirrhosis/pathology , Mice , Peptides/metabolism , Rats , SUMO-1 Protein/metabolism , Transforming Growth Factor beta1/metabolism
19.
PeerJ ; 10: e12797, 2022.
Article in English | MEDLINE | ID: mdl-35111409

ABSTRACT

BACKGROUND: Cardiac fibrosis refers to the abnormal accumulation of extracellular matrix in the heart, which leads to the formation of cardiac scars. It causes systolic and diastolic dysfunction, and ultimately leads to cardiac dysfunction and arrhythmia. TGF-ß1 is an important regulatory factor involved in cardiac fibrosis. Studies have shown that the N-terminal latency associated peptide (LAP) must be removed before TGF-ß1 is activated. We hypothesize that recombinant LAP may inhibit cardiac fibrosis induced by TGF-ß1. To evaluate anti-cardiac fibrosis activity of recombinant LAP, an experimental study was carried out and is reported here. METHODS: The pET28a-LAP plasmid was constructed and transformed into E. coli C43 (DE3) competent cells. The recombinant LAP protein was purified by Ni affinity chromatography. The cells were treated with TGF-ß1 at different concentrations for 24 h. The expression of α-SMA was detected by Western blot. RTCA was used to detect the effect of recombinant LAP on the proliferation of H9C2 cells induced by 10 ng/mL TGF-ß1. To detect the effect of LAP on the expression of fibrosis-related proteins, H9C2 cells were treated with 10 ng/mL TGF-ß1 for 24 h, then added 60 µg/mL recombinant LAP for 48 h. The LAP group was treated with 60 µg/mL recombinant LAP alone. The LAP pre-protection group was treated with 10 ng/mL TGF-ß1 and 60 µg/mL recombinant LAP at the same time. Western blot and immunofluorescence were used to detect the expression of α-SMA, collagen I and fibronectin and p-Smad2. RESULTS: The recombinant LAP was prokaryotic expressed and purified. 10 ng/mL was determined as the optimal working concentration of TGF-ß1 to induce H9C2 cells fibrosis. RTCA results showed that 60 µg/mL LAP could effectively inhibit the proliferation of H9C2 cells induced by TGF-ß1. Immunofluorescence results showed that compared with the control group, the fluorescence intensities of α-SMA, collagen I and FN increased significantly after TGF-ß1 treatment. The fluorescence intensities in the TGF-ß1+LAP group decreased significantly. Western blot results showed that 60 µg/mL LAP could inhibit the increase of α-SMA, collagen I and FN expression in H9C2 cells induced by TGF-ß1. Compared with the control, the LAP alone group has no significant difference in α-SMA and p-Smad2 expression level. The expression of α-SMA and p-Smad2 in the TGF-ß1 model group was significantly increased compared with the control group. Compared with the TGF-ß1 group, both TGF-ß1+LAP group and LAP pre-protection group significantly reduced the increase in α-SMA and p-Smad2 levels. CONCLUSIONS: Recombinant LAP was prokaryotic expressed and purified. The results showed that recombinant LAP can inhibit the cell proliferation and expression increase of α-SMA, collagen I, fibronectin and p-Smad2 in H9C2 cells induced by TGF-ß1. These results suggested that recombinant LAP might inhibit TGF-ß1-induced fibrosis of H9C2 cells through the TGF-ß/Smad pathway.


Subject(s)
Cardiomyopathies , Transforming Growth Factor beta1 , Humans , Transforming Growth Factor beta1/genetics , Fibronectins/metabolism , Escherichia coli/metabolism , Signal Transduction , Transforming Growth Factor beta/genetics , Fibrosis , Collagen Type I/metabolism
20.
Int J Biol Macromol ; 188: 941-949, 2021 Oct 01.
Article in English | MEDLINE | ID: mdl-34389395

ABSTRACT

Truncated transforming growth factor-ß receptor type II (tTßRII) is a promising anti-fibrotic candidate because it attenuates excessive transforming growth factor-ß1 (TGF-ß1) and then blocks TGF-ß1 activity in hepatic fibrosis. However, its use has been greatly limited due to the fact that it is expensive to chemically synthesize and it does not specifically target to the lesion site. In this study, we describe that platelet-derived growth factor ß receptor (PDGFßR)-binding peptide BiPPB modified tTßRII (BiPPB-tTßRII) was prepared from the cleavage of SUMO-BiPPB-tTßRII by digestion with SUMO-specific protease. Moreover, compared to the unmodified tTßRII, the target protein BiPPB-tTßRII not only highly specific targeted activated hepatic stellate cells (HSCs) and fibrotic liver tissue, but also significantly inhibited the protein levels of fibrosis-related genes in TGF-ß1-induced HSC-T6 cells and CCl4-induced liver fibrosis in mice. Furthermore, BiPPB-tTßRII markedly ameliorated liver morphology, fibrotic responses and the damage of liver function in fibrosis animal. More importantly, BiPPB-tTßRII showed a much lesser extent in binding to quiescent HSCs and non-fibrotic liver tissue. Taken together, our results suggested that the target protein BiPPB-tTßRII, with its high specific fibrotic liver-targeting potential and its improved anti-fibrotic activity in liver fibrosis, may be a potential therapeutic agent for liver fibrosis.


Subject(s)
Liver Cirrhosis/drug therapy , Liver Cirrhosis/pathology , Peptides/administration & dosage , Peptides/therapeutic use , Receptor, Platelet-Derived Growth Factor beta/metabolism , Receptor, Transforming Growth Factor-beta Type II/administration & dosage , Animals , Carbon Tetrachloride , Cell Line, Tumor , Genetic Vectors/metabolism , Mice , Recombinant Fusion Proteins/metabolism , Small Ubiquitin-Related Modifier Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...