Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 2.512
Filter
1.
Adv Healthc Mater ; : e2401466, 2024 Aug 01.
Article in English | MEDLINE | ID: mdl-39087398

ABSTRACT

Aortic dissection (AD) is a severe cardiovascular disease necessitating active therapeutic strategies for early intervention and prevention. Nucleic acid drugs, known for their potent molecule-targeting therapeutic properties, offer potential for genetic suppression of AD. Piwi-interacting RNAs, a class of small RNAs, hold promise for managing cardiovascular diseases. Limited research on these RNAs and AD exists. This study demonstrates that an antagomir targeting heart-apoptosis-associated piRNA (HAAPIR) effectively regulates vascular remodeling, mitigating AD occurrence and progression through the myocyte enhancer factor 2D (Mef2D) and matrix metallopeptidase 9 (MMP9) pathways. Green tea-derived plant exosome-like nanovesicles (PELNs) are used for oral administration of antagomir. The antagomir-HAAPIR-nanovesicle complex, after purification and optimization, exhibits a high packing rate, while the antagomir is resistant to enzyme digestion. Administered to mice, the complex targets the aortic lesion, reducing AD incidence and improving survival. Moreover, MMP9 and Mef2D expression decrease significantly, inhibiting the phenotypic conversion of human aortic smooth muscle cells. PELNs encapsulate the antagomir-HAAPIR complex, maintaining stability, mediating transport into the bloodstream, and delivering Piwi-interacting RNAs to AD sites. Thus, HAAPIR is a potential target for persistent clinical AD prevention and treatment, and nanovesicle-encapsulated nucleic acids offer a promising cardiovascular disease treatment, providing insights for other therapeutic targets.

2.
Oncol Rep ; 52(4)2024 Oct.
Article in English | MEDLINE | ID: mdl-39092577

ABSTRACT

Following the publication of this article, an interested reader drew to the authors' attention that, for the cell migration assay data shown in Fig. 3C on p. 1287, the '2.5 µg/ml' and '5.0 µg/ml' panels appeared to be overlapping, such that these data were apparently derived from the same original source where they were intended to show the results from differently performed experiments. Upon asking the authors to provide an explanation, after having referred back to their original data, the authors realized that they had made an inadvertent error in assembling this figure. The revised version of Fig. 3, now showing the correct data for the '5.0 µg/ml' experiment, is shown on the next page. Note that the error made in assembling the data in Fig. 3 did not greatly affect either the results or the conclusions reported in this paper, and all the authors agree to the publication of this corrigendum. The authors regret that this error went unnoticed prior to the publication of their article, and are grateful to the Editor of Oncology Reports for granting them this opportunity to publish a corrigendum. They also apologize to the readership for any inconvenience caused. [Oncology Reports 33: 1284­1290, 2015; DOI: 10.3892/or.2014.3682].

3.
Steroids ; : 109487, 2024 Aug 04.
Article in English | MEDLINE | ID: mdl-39106908

ABSTRACT

Gastric cancer (GC)-diabetes co-morbidity is nowadays growing into a rising concern. However, no separate treatment procedures have been outlined for such patients. Phytochemicals and their derivatives can therefore be used as therapeutics as they have greater effectiveness, reduced toxicity, and a reduced likelihood of developing multi-drug resistance in cancer treatments. The present study intended to assess the therapeutic efficacy of Shatavarin-IV - a major steroidal saponin from the roots of Asparagus racemosus, in human gastric adenocarcinoma cell line under hyperglycemic conditions and explore its mechanism of action in controlling GC progression. For the present study, AGS cells were incubated in high glucose-containing media and the effects of Shatavarin-IV therein have been evaluated. Cell proliferation, confocal microscopic imaging, flow-cytometric analysis for cell cycle and apoptosis, immunoblotting, zymography, reverse zymography, wound-healing, colony formation, and invasion assays were performed. Shatavarin-IV has a prominent effect on AGS cell proliferation; with IC50 of 2.463 µâ€¯M under hyperglycemic conditions. Shatavarin-IV induces cell cycle arrest at the G0/G1 phase, thereby preventing hyperglycemia-induced excessive cell proliferation that later on leads to apoptotic cell death at 36 h of incubation. Shatavarin-IV further inhibits the migratory and invasive potential of AGS cells by altering the expression patterns of different EMT markers. It also inhibits MMP-9 while promoting TIMP-1 activity and expression; thereby regulating ECM turnover. This is the first report demonstrating the therapeutic efficacy of Shatavarin-IV against AGS cells grown in hyperglycemic conditions, implicating new insights into the treatment paradigm of patients with GC-diabetes co-morbidity.

4.
Anim Cells Syst (Seoul) ; 28(1): 381-391, 2024.
Article in English | MEDLINE | ID: mdl-39100550

ABSTRACT

Allergic asthma, a type of chronic airway inflammation, is a global health concern because of its increasing incidence and recurrence rates. Camellia sinensis L. yields a variety type of teas, which are also used as medicinal plants in East Asia and are known to have antioxidant, anti-inflammatory, and immune-potentiating properties. Here, we examined the constituents of C. sinensis L. extract (CSE) and evaluated the protective effects of CSE on allergic asthma by elucidating the underlying mechanism. To induce allergic asthma, we injected the sensitization solution (mixture of ovalbumin (OVA) and aluminum hydroxide) into mice intraperitoneally on days 0 and 14. Then, the mice were exposed to 1% OVA by a nebulizer on days 21 to 23, while intragastric administration of CSE (30 and 100 mg/kg) was performed each day on days 18 to 23. We detected five compounds in CSE, including (-)-epigallocatechin, caffeine, (-)-epicatechin, (-)-epigallocatechin gallate, and (-)-epicatechin gallate. Treatment with CSE remarkably decreased the airway hyperresponsiveness, OVA-specific immunoglobulin E level, and inflammatory cell and cytokine levels of mice, with a decrease in inflammatory cell infiltration and mucus production in lung tissue. Treatment with CSE also decreased the phosphorylation of nuclear factor-κB (NF-κB) and the expression of matrix-metalloproteinase (MMP)-9 in asthmatic mice. Our results demonstrated that CSE reduced allergic airway inflammation caused by OVA through inhibition of phosphorylated NF-κB and MMP-9 expression.

5.
Transl Androl Urol ; 13(7): 1239-1255, 2024 Jul 31.
Article in English | MEDLINE | ID: mdl-39100821

ABSTRACT

Background: M2 macrophages can promote the progression of castration-resistant prostate cancer (CRPC), but the specific mechanism is still unclear. Therefore, we are preliminarily exploring the molecular mechanism by which M2 macrophages regulate the progression of CRPC. Methods: The genes positively correlated with CRPC and with the most significant differences in the GEO32269 dataset were obtained. Database and immunofluorescence experiments were used to validate the localization of secreted phosphoprotein 1 (SPP1) in localized prostate cancer (PCa), hormone-sensitive prostate cancer (HSPC), and CRPC tumor tissues. The function of SPP1 in M2 macrophages was verified through cell scratch, Transwell, and an orthotopic PCa model. PCa database and Western blot were used to verify the relationship between SPP1 and matrix metallopeptidase 9 (MMP9), as well as the ability of MMP9 in M2 macrophages to promote epithelial-mesenchymal transition (EMT) in PCa cells. Results: The primary localization of SPP1 in prostate and CRPC tissues is in macrophages. Silencing SPP1 expression in M2 macrophages promotes their polarization towards the M1 phenotype and significantly inhibits the malignant progression of PCa in vitro and in vivo. SPP1 promotes the expression of MMP9 through the PI3K/AKT signaling pathway in M2 macrophages. Furthermore, MMP9 enhances the EMT and migratory capabilities of PC3 cells by activating the TGFß signaling pathway. Conclusions: We have found that the high expression of SPP1 in M2 macrophages promotes the progression of CRPC through cell-cell interactions. These findings can contribute to the development of novel therapeutic approaches for combating this deadly disease.

6.
Heliyon ; 10(12): e32592, 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38952360

ABSTRACT

Background: Resveratrol is a natural phenolic compound widely found in plants. Previous studies have suggested its neuroprotective role in cerebral ischemia due to its anti-oxidative, anti-inflammatory, and anti-apoptotic effects. Intranasal administration of resveratrol enhances its capacity to penetrate the blood-brain barrier, increasing therapeutic efficacy and safety. Objective: We aimed to examine the therapeutic potential of intranasal administration of resveratrol treatment in rats exposed to cerebral ischemia. Methods: Sixty-four male rats were divided into three groups: the sham group, which was exposed to only surgical stress; the vehicle and resveratrol groups, which received intranasal vehicle or 50 mg/kg resveratrol for 7 days following middle cerebral artery occlusion, respectively. We assessed the modified neurologic severity scores, wire hanging tests, blood-brain barrier disruption, brain water content, and infarct volume. Levels of matrix metalloproteinase-9, nuclear factor-kappa B, B-cell lymphoma protein 2, and B-cell lymphoma protein 2-associated X messenger RNA expression were examined. Results: At 3- and 7-days post-ischemia, rats receiving intranasal resveratrol had lower modified neurological severity scores and a smaller brain infarct volume than the rats receiving vehicle. Additionally, the intranasal resveratrol-treated rats showed significantly prolonged wire-hanging performance at the 7-day mark post-ischemia compared to the vehicle group. The blood-brain barrier disruption and brain water content were significantly lower in the resveratrol group than in the vehicle group. Furthermore, the resveratrol-treated group displayed lower expression of Matrix Metalloproteinase-9 and Nuclear Factor-Kappa B in contrast to the vehicle group, while the difference in expression levels of B-cell lymphoma protein 2-associated X and B-cell lymphoma protein 2 were not significant. Conclusion: Intranasal administration of resveratrol showed neuroprotective effects on ischemic stroke by improving neurobehavioral function, reducing blood-brain barrier disruption, cerebral edema, and infarct volume. This treatment also downregulated Matrix Metalloproteinase-9 and Nuclear Factor-Kappa B expression, indicating its potential as a therapeutic option for ischemic stroke.

7.
Antioxidants (Basel) ; 13(7)2024 Jun 28.
Article in English | MEDLINE | ID: mdl-39061853

ABSTRACT

The fruit juice industry generates a significant amount of waste, with a strong impact on the environment and the economy. Therefore, researchers have been focusing on the characterization of resources considered as food waste. This work provides information about the lipophilic and polar metabolites of pear pomace flours (PPFs) as a tool that can shed more light on the bioactive potential of this residue. Using UPLC-PDA, UPLC-FLR, and GC-MS, the study identified and quantified PPF's polar and non-polar metabolites. Essential, conditional, and non-essential amino acids were found, with asparagine being the most abundant. Isoprenoids, including lutein, zeaxanthin, and carotene isomers, ranged from 10.8 to 22.9 mg/100 g dw. Total flavonoids and phenolic compounds were 520.5-636.4 mg/100 g dw and 536.9-660.1 mg/100 g dw, respectively. Tocotrienols and tocopherols were identified, with concentrations of 173.1-347.0 mg/100 g dw and 468.7-913.4 mg/100 g dw. Fatty acids were the major non-polar compounds. All fractions significantly reduced matrix metalloproteinase-9 (MMP-9) activity. Although PPF had lower antioxidant potential (3-6 mmol Trolox/100 g dw), it inhibited AChE and BuChE by 23-30% compared to physostigmine salicylate. These findings suggest that pear pomace waste can be repurposed into functional products with valuable bioactive properties by re-introducing it in the food chain.

8.
Life (Basel) ; 14(7)2024 Jun 26.
Article in English | MEDLINE | ID: mdl-39063556

ABSTRACT

Matrix metalloproteinase (MMP)-2 and -9, which degrade type IV collagen, are linked to cancer invasion and metastasis. Gene polymorphisms in MMP-2 and MMP-9 can influence their function, impacting cancer development and progression. This study analyzed the association between polymorphisms MMP-2 rs243865 (C-1306T), rs2285053 (C-735T), and MMP-9 rs3918242 (C-1562T) with serum concentrations of these enzymes in upper tract urothelial cancer (UTUC) patients. We conducted a case-control study with 218 UTUC patients and 580 healthy individuals in Taiwan. Genotyping was performed using PCR/RFLP on DNA from blood samples, and MMP-2 and MMP-9 serum levels and mRNA expressions in 30 UTUC patients were measured using ELISA and real-time PCR. Statistical analysis showed that MMP-2 rs2285053 and MMP-9 rs3918242 genotypes were differently distributed between UTUC patients and controls (p = 0.0199 and 0.0020). The MMP-2 rs2285053 TT genotype was associated with higher UTUC risk compared to the CC genotype (OR = 2.20, p = 0.0190). Similarly, MMP-9 rs3918242 CT and TT genotypes were linked to increased UTUC risk (OR = 1.51 and 2.92, p = 0.0272 and 0.0054). In UTUC patients, TT carriers of MMP-2 rs2285053 and MMP-9 rs3918242 showed higher mRNA and protein levels (p < 0.01). These findings suggest that MMP-2 rs2285053 and MMP-9 rs3918242 genotypes are significant markers for UTUC risk and metastasis in Taiwan.

9.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(6): 1209-1216, 2024 Jun 20.
Article in Chinese | MEDLINE | ID: mdl-38977352

ABSTRACT

OBJECTIVE: To investigate the expression of Nanog and its regulatory relationship with MMP-2/MMP-9 proteins in esophageal squamous cell carcinoma (ESCC). METHODS: We detected Nanog and MMP-2/MMP-9 protein expressions in 127 ESCC tissues and 82 adjacent normal tissues using immunohistochemistry and explored their correlations with the clinicopathological parameters and prognosis of the patients. GEO database was utilized to analyze the pathways enriched with the stemness-related molecules including Nanog, and TIMER online tool was used to analyze the correlations among TßR1, MMP-2, and MMP-9 in esophageal cancer. RESULTS: Nanog and MMP-2/MMP-9 proteins were significantly upregulated in ESCC tissues and positively intercorrelated. Their expression levels were closely correlated with infiltration depth and lymph node metastasis of ESCC but not with age, gender, or tumor differentiation. The patients with high expressions of Nanog and MMP-2/MMP-9 had significantly shorter survival time. Bioinformatics analysis showed enrichment of stemness-associated molecules in the TGF-ß signaling pathway, and the expressions of MMP-2/MMP-9 and TßR1 were positively correlated. In cultured ESCC cells, Nanog knockdown significantly decreased the expression of TßR1, p-Smad2/3, MMP-2, and MMP-9 and strongly inhibited cell migration. CONCLUSION: The high expressions of Nanog, MMP-2, and MMP-9, which are positively correlated, are closely related with invasion depth, lymph node metastasis, and prognosis of ESCC. Nanog regulates the expressions of MMP-2/MMP-9 proteins through the TGF-ß signaling pathway, and its high expression promotes migration of ESCC cells.


Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Lymphatic Metastasis , Matrix Metalloproteinase 2 , Matrix Metalloproteinase 9 , Nanog Homeobox Protein , Neoplasm Invasiveness , Signal Transduction , Transforming Growth Factor beta , Humans , Esophageal Squamous Cell Carcinoma/metabolism , Esophageal Squamous Cell Carcinoma/pathology , Nanog Homeobox Protein/metabolism , Nanog Homeobox Protein/genetics , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Esophageal Neoplasms/genetics , Transforming Growth Factor beta/metabolism , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase 2/metabolism , Prognosis , Male , Female
10.
Biomater Adv ; 163: 213937, 2024 Oct.
Article in English | MEDLINE | ID: mdl-38968788

ABSTRACT

PURPOSE: In chronic hyperglycemia, the advanced glycation end product (AGE) interacts with its receptor (RAGE) and contributes to impaired wound healing by inducing oxidative stress, generating dysfunctional macrophages, and prolonging the inflammatory response. Additionally, uncontrolled levels of proteases, including metallomatrix protease-9 (MMP-9), in the diabetic wound bed degrade the extracellular matrix (ECM) and biological cues that augment healing. A multifunctional antimicrobial hydrogel (Immuno-gel) containing RAGE and MMP-9 inhibitors can regulate the wound microenvironment and promote scar-free healing. RESULTS: Immuno-gel was characterized and the wound healing efficacy was determined in vitro cell culture and in vivo diabetic Wistar rat wound model using ELISA, Western blot, and Immunofluorescence staining. The Immuno-gel exhibited a highly porous morphology with excellent in vitro cytocompatibility. AGE-stimulated macrophages treated with the Immuno-gel released higher levels of pro-healing cytokines in vitro. In the hydrogel-wound interface of diabetic Wistar rats, Immuno-gel treatment significantly reduced MMP-9 and NF-κB expression and enhanced pro-healing (M2) macrophage population and pro-healing cytokines. CONCLUSION: Altogether, this study suggests that Immuno-gel simultaneously attenuates macrophage dysfunction through the inhibition of AGE/RAGE signaling and reduces MMP-9 overexpression, both of which favor scar-free healing. The combinatorial treatment with RAGE and MMP-9 inhibitors via Immuno-gel simultaneously modulates the diabetic wound microenvironment, making it a promising novel treatment to accelerate diabetic wound healing.


Subject(s)
Diabetes Mellitus, Experimental , Glycation End Products, Advanced , Hydrogels , Matrix Metalloproteinase 9 , Rats, Wistar , Receptor for Advanced Glycation End Products , Signal Transduction , Wound Healing , Animals , Matrix Metalloproteinase 9/metabolism , Glycation End Products, Advanced/metabolism , Wound Healing/drug effects , Hydrogels/pharmacology , Receptor for Advanced Glycation End Products/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Rats , Signal Transduction/drug effects , Macrophages/drug effects , Macrophages/metabolism , Macrophages/immunology , Male , Mice
11.
Adv Med Sci ; 69(2): 362-367, 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39059469

ABSTRACT

PURPOSE: Matrix metalloproteinases (MMPs) catalyze degradation of extracellular matrix proteins. The activity of MMPs is controlled by tissue inhibitors of metalloproteinases (TIMPs). An imbalance in the MMP-9/TIMP-1 ratio has been linked with chronic periodontitis (CP). Photodynamic therapy (PDT) uses visible light, photosensitizer and oxygen to eradicate pathogens. The aim of the study was to evaluate the presence of MMP-9 and TIMP-1 in gingival crevicular fluid (GCF) in chronic periodontitis patients before and after nonsurgical periodontal therapy with additional PDT. METHODS: Nineteen patients, each with CP, were included in the study. After periodontal examination one site with a probing depth (PD) â€‹≥ â€‹4 â€‹mm was selected. The patients received scaling and root planing (SRP) with additional PDT by means of HELBO® diode minilaser. Prior to treatment, and after 3 and 6 months, the following parameters were estimated from the same site: PD, gingival recession (GR), clinical attachment level (CAL), plaque index (PI), bleeding on probing (BOP) and sulcus fluid flow rate (SFFR). The levels of MMP-9 and TIMP-1 in GCF were determined. RESULTS: Compared to baseline, the levels of MMP-9 and TIMP-1 did not show statistically significant differences after 3 and 6 months. According to Spearman's rank correlations, MMP-9 was positively correlated with SFFR at all time points. PD, CAL and PI showed a statistically significant decrease compared to baseline (p â€‹< â€‹0.001). SFFR decreased but not significantly. CONCLUSION: Nonsurgical periodontal therapy in conjunction with PDT was clinically effective but it had no effect on the levels of MMP-9 and TIMP-1 in GCF.

12.
Viruses ; 16(7)2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39066315

ABSTRACT

To explore whether the p17 protein of oncolytic avian reovirus (ARV) mediates cell migration and invadopodia formation, we applied several molecular biological approaches for studying the involved cellular factors and signal pathways. We found that ARV p17 activates the p53/phosphatase and tensin homolog (PTEN) pathway to suppress the focal adhesion kinase (FAK)/Src signaling and downstream signal molecules, thus inhibiting cell migration and the formation of invadopodia in murine melanoma cancer cell line (B16-F10). Importantly, p17-induced formation of invadopodia could be reversed in cells transfected with the mutant PTENC124A. p17 protein was found to significantly reduce the expression levels of tyrosine kinase substrate 5 (TKs5), Rab40b, non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), and matrix metalloproteinases (MMP9), suggesting that TKs5 and Rab40b were transcriptionally downregulated by p17. Furthermore, we found that p17 suppresses the formation of the TKs5/NCK1 complex. Coexpression of TKs5 and Rab40b in B16-F10 cancer cells reversed p17-modulated suppression of the formation of invadopodia. This work provides new insights into p17-modulated suppression of invadopodia formation by activating the p53/PTEN pathway, suppressing the FAK/Src pathway, and inhibiting the formation of the TKs5/NCK1 complex.


Subject(s)
Cell Movement , Focal Adhesion Kinase 1 , Orthoreovirus, Avian , Podosomes , Signal Transduction , Animals , Mice , Orthoreovirus, Avian/physiology , Orthoreovirus, Avian/genetics , Cell Line, Tumor , Podosomes/metabolism , Focal Adhesion Kinase 1/metabolism , Focal Adhesion Kinase 1/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Oncolytic Viruses/physiology , Oncolytic Viruses/genetics , src-Family Kinases/metabolism , src-Family Kinases/genetics , Viral Proteins/metabolism , Viral Proteins/genetics , Melanoma, Experimental/therapy , Melanoma, Experimental/pathology , Tumor Suppressor Protein p53/metabolism , Tumor Suppressor Protein p53/genetics , PTEN Phosphohydrolase/metabolism , PTEN Phosphohydrolase/genetics
13.
Heliyon ; 10(13): e33636, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39071605

ABSTRACT

Numerous side effects of breast cancer drugs have prompted researchers to explore more into new therapeutic approaches derived from natural substances. In this context, our study focused on uncovering the potential of East Kalimantan propolis from Trigona apicalis for breast cancer treatment including the underlying mechanisms through bioinformatics approached. We conducted integrated in vitro and bioinformatics analysis of network pharmacology, molecular docking, molecular dynamics and MM-GBSA analysis. Initially, in vitro cytotoxic assay demonstrated the anti-breast cancer activity potential of ethanol extract of East Kalimantan propolis, particularly its ethyl acetate fraction, which exhibited similar activity to doxorubicin, as indicated by their IC50 value. This study revealed eight propolis compounds, consisting of flavonoids and phenolic acids, in East Kalimantan propolis. By integrating microarray datasets (GSE29431, GSE36295, and GSE42568) analysis with potential targets derived from propolis compounds, 39 shared target genes were identified. Subsequently, GO and KEGG pathway, protein-protein interaction (PPI) network, core hub genes and gene expression analysis revealed three major targets, namely, PTGS2, CXCL2, and MMP9. Among them, only MMP9 was highly expressed in breast cancer than normal. Moreover, molecular docking revealed the six of propolis compounds which exhibited pronounced binding affinity towards MMP-9, better than marimastat as control drug. Dynamic simulation confirmed the stability of chrysin and quercetin as best compounds. Additionally, MM-GBSA analysis revealed a relative binding energy for chrysin (-25.6403 kcal/mol) that was comparable to marimastat (-27.3827 kcal/mol). In conclusion, this study reveals how East Kalimantan Propolis affect breast cancer and emphasizes MMP9 as a key target for future therapeutics.

14.
Cell Signal ; : 111312, 2024 Jul 27.
Article in English | MEDLINE | ID: mdl-39074714

ABSTRACT

Matrix metalloproteinases (MMPs) are a group of zinc-dependent proteolytic metalloenzymes that are involved in numerous pathological conditions, including nephropathy. MMP9, a member of the MMPs family, is categorized as a constituent of the gelatinase B subgroup, and its involvement in extracellular matrix (ECM) remodeling and renal fibrosis highlights its importance in the development and progression of renal diseases. The exact role of MMP9 in the development of kidney diseases is still controversial. This study investigated the dual role of MMP9 in kidney injury, discussing its implications in the pathogenesis of kidney diseases and investigating the design and mechanism of MMP9 inhibitors based on previous studies. This study provides an effective basis for the development of novel and selective MMP9 inhibitors for treating renal diseases.

15.
Neurobiol Dis ; 200: 106614, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39067491

ABSTRACT

Perineuronal nets (PNNs) are extracellular matrix structures that surround excitable neurons and their proximal dendrites. PNNs play an important role in neuroprotection against oxidative stress. Oxidative stress within motor neurons can act as a trigger for neuronal death, and this has been implicated in motor neuron degeneration in amyotrophic lateral sclerosis (ALS). We therefore characterised PNNs around alpha motor neurons and the possible contributing cellular factors in the mutant TDP-43Q331K transgenic mouse, a slow onset ALS mouse model. PNNs around alpha motor neurons showed significant loss at mid-stage disease in TDP-43Q331K mice compared to wild type strain control mice. PNN loss coincided with an increased expression of matrix metallopeptidase-9 (MMP-9), an endopeptidase known to cleave PNNs, within the ventral horn. During mid-stage disease, increased numbers of microglia and astrocytes expressing MMP-9 were present in the ventral horn of TDP-43Q331K mice. In addition, TDP-43Q331K mice showed increased levels of aggrecan, a PNN component, in the ventral horn by microglia and astrocytes during this period. Elevated aggrecan levels within glia were accompanied by an increase in fractalkine expression, a chemotaxic protein responsible for the recruitment of microglia, in alpha motor neurons of onset and mid-stage TDP-43Q331K mice. Following PNN loss, alpha motor neurons in mid-stage TDP-43Q331K mice showed increased 3-nitrotyrosine expression, an indicator of protein oxidation. Together, our observations along with previous PNN research provide suggests a possible model whereby microglia and astrocytes expressing MMP-9 degrade PNNs surrounding alpha motor neurons in the TDP-43Q331K mouse. This loss of nets may expose alpha-motor neurons to oxidative damage leading to degeneration of the alpha motor neurons in the TDP-43Q331K ALS mouse model.

16.
Protein Sci ; 33(8): e5128, 2024 Aug.
Article in English | MEDLINE | ID: mdl-39074261

ABSTRACT

Extracellular proteolysis critically regulates cellular and tissue responses and is often dysregulated in human diseases. The crosstalk between proteolytic processing and other major post-translational modifications (PTMs) is emerging as an important regulatory mechanism to modulate protease activity and maintain cellular and tissue homeostasis. Here, we focus on matrix metalloproteinase (MMP)-mediated cleavages and N-acetylgalactosamine (GalNAc)-type of O-glycosylation, two major PTMs of proteins in the extracellular space. We investigated the influence of truncated O-glycan trees, also referred to as Tn antigen, following the inactivation of C1GALT1-specific chaperone 1 (COSMC) on the general and MMP9-specific proteolytic processing in MDA-MB-231 breast cancer cells. Quantitative assessment of the proteome and N-terminome using terminal amine isotopic labelling of substrates (TAILS) technology revealed enhanced proteolysis by MMP9 within the extracellular proteomes of MDA-MB-231 cells expressing Tn antigen. In addition, we detected substantial modifications in the proteome and discovered novel ectodomain shedding events regulated by the truncation of O-glycans. These results highlight the critical role of mature O-glycosylation in fine-tuning proteolytic processing and proteome homeostasis by modulating protein susceptibility to proteolytic degradation. These data suggest a complex interplay between proteolysis and O-GalNAc glycosylation, possibly affecting cancer phenotypes.


Subject(s)
Proteolysis , Humans , Glycosylation , Cell Line, Tumor , Matrix Metalloproteinase 9/metabolism , Antigens, Tumor-Associated, Carbohydrate/metabolism , Galactosyltransferases/metabolism , Galactosyltransferases/genetics , Protein Processing, Post-Translational , Proteome/metabolism , Proteome/analysis , Molecular Chaperones
17.
Comput Biol Chem ; 112: 108149, 2024 Jul 14.
Article in English | MEDLINE | ID: mdl-39053173

ABSTRACT

Bladder cancer (BC) is the 10th most common tumour with a high incidence and recurrence rate worldwide; however, the current therapies present limitations as, regularly, not all patients benefit from treatment. Therefore, the search for new, active marine phenolic acids with anti-tumour properties is imperative. In this study, we subjected marine phenolic acids to in silico investigations such as network pharmacology, molecular docking, and molecular dynamics simulation (MD) to identify a plausible pathway and the lead compound that inhibits BC. According to the network pharmacology analysis, eight hub genes (PLAU, MMP2, ITGB3, MAPK1, PTPN11, ESR1, TLR4, MMP9) were found and linked to the enrichment of hsa05205: proteoglycans in cancer, and four hub genes (MMP1, MMP2, MAPK1, MMP9) were involved in the enrichment of hsa05219: BC. Subsequently, molecular docking studies showed that the marine phenolic acids exhibit a strong binding affinity for the target protein, matrix metalloproteinase-9 (MPP9). Among these 14 marine phenolic acids, chicoric acid showed the highest binding affinity of -67.1445 kcal/mol and formed hydrogen bonds with the residues of Ala189, Gln227, Leu188, His226, Ala242, Arg249, Ala191, and Gly186 in the active site of the MPP9 protein. Then, molecular dynamics simulation revealed that chicoric acid formed a stable protein-ligand complex with RMSD and RMSF values of 0.72 nm and 0.53 nm, respectively. Furthermore, the PCA method was employed to understand the dynamical behaviour in the conformational space of MPP9 protein bound to chicoric acid, and the results showed the good conformational space behaviour of MPP9 protein. Moreover, chicoric acid showed a free binding energy value of -32.62 kcal/mol, which indicated it could be a BC inhibitor. Overall, chicoric acid demonstrated potential anti-BC activity through MPP9 protein inhibition.

18.
Iran J Basic Med Sci ; 27(9): 1180-1186, 2024.
Article in English | MEDLINE | ID: mdl-39055867

ABSTRACT

Objectives: Using histopathological and immunohistochemical methods, we aimed to examine the dose-dependent effects of chronic caffeine consumption on the recovery of burn wounds in an in vivo rat model. Materials and Methods: Forty-five rats were randomly assigned to a high-dose group (20 mg/kg per day for eight weeks; n=15), a low-dose group (10 mg/kg per day for eight weeks; n=15), or a control group (n=15). The burn model was created in rats. The groups were separated into three subgroups (n=5) based on the day after injury (7th, 14th, or 21st day). The wound area, wound closure percentage, and histopathological and immunohistochemical reactivity were evaluated. Results: Successful wound healing was noted in rats treated with low doses of caffeine, similar to the control group. Pathology revealed low re-epithelization, low inflammation, and high granulation in the high-dose group. In addition, there was a significant difference between the control and high-dose groups regarding the immunohistochemical reactivity of αVß3 integrin, vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) (P<0.05). Conclusion: We demonstrated that chronic caffeine consumption in rats adversely affects the recovery process of wounds in a dose-dependent manner. This effect may occur through delayed wound healing via the molecules MMP-9, αVß3 integrin, and VEGF. Treatment that modulates these molecules can lead to enhanced and quicker recovery of damaged skin in coffee lovers.

19.
Rev Invest Clin ; 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39047236

ABSTRACT

Background: Hepatocellular carcinoma (HCC) is one of the most aggressive cancers worldwide. Curzerene is a sesquiterpene and component of Curcuma rhizomes and has anti-tumor and anti-inflammatory properties. Objective: The study aimed to investigate the effects of curzerene on the malignant phenotypes and tumor growth in HCC. Methods: Various concentrations of curzerene were used to treat human HCC cells (Huh7 and HCCLM3). Cell viability, apoptosis, cell cycle, invasion, and migration were detected by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry, Transwell, and wound healing assays. Cell cycle-, apoptosis-, and signaling pathway-related proteins were analyzed by Western blot analysis. A mouse xenograft model was established to analyze the anti-tumor effects of curzerene in vivo. Results: Curzerene repressed the proliferation, invasion, and migration of Huh7 and HCCLM3 cells. Curzerene also induced G2/M cycle arrest and cell apoptosis. Curzerene downregulated the CDK1, cyclin B1, PCNA, Bcl-2, matrix metallopeptidases (MMP)2, and MMP9 protein expression and upregulated the Bax, cleaved caspase3, and cleaved poly ADPribose polymerase protein expression in HCC cells. Curzerene restrained the phosphorylation of PI3K, AKT, and the Mammalian target of rapamycin (mTOR) in Huh7 and HCCLM3 cells. The in vivo data revealed that curzerene inhibited HCC tumor growth and decreased the expression of phosphorylated mTOR in xenograft mouse models. Conclusion: Curzerene inhibited cell malignancy in vitro and tumor growth in vivo in HCC, suggesting that curzerene may be a candidate agent for anti-HCC therapy.

20.
Heliyon ; 10(13): e33217, 2024 Jul 15.
Article in English | MEDLINE | ID: mdl-39027501

ABSTRACT

Background: Diabetic nephropathy represents a significant microvascular complication of diabetes, characterized by extracellular matrix accumulation, loss of cell-cell junctions, microalbuminuria, and diminished creatinine clearance. Despite its prevalence, therapeutic options dedicated to this condition are currently lacking. Natural products like bioflavonoids have garnered attention for their potential therapeutic benefits. The present study aimed to evaluate the efficacy of a bioflavonoid combination, including ginger extract, soy extract, and hesperetin, in a diabetic rat model. Methods: Diabetes was initiated in the rat pups via intraperitoneal injection of streptozotocin on the fifth postnatal day. After six weeks, rats exhibiting blood sugar levels exceeding 160 mg/dL were allocated into diabetic control and treatment groups, with eight animals each. A subset of rats received citrate buffer as a control. The treatment group received the bioflavonoid combination orally for twenty-four weeks. Various parameters, including glycemic levels, urinary parameters, antioxidant status, mRNA expression via Western blot, gel zymography, and immunohistochemistry, were assessed at the study's conclusion. Results: The bioflavonoid combination demonstrated significant reductions in hyperglycemia and various urinary parameters compared to controls. Notably, it modulated MMP-9/TIMP-1 expression, upregulated GLUT-4, and downregulated TGF-ß. Additionally, the combination enhanced total antioxidant capacity, indicating potential antioxidative benefits. Conclusions: This study highlights the therapeutic potential of a bioflavonoid combination (ginger extract, soy extract, and hesperetin) in improving renal function in diabetic nephropathy. By modulating key factors such as MMP-9/TIMP-1, TGF-ß, and GLUT-4, this combination presents a promising avenue for further exploration in managing diabetic nephropathy. These findings underscore the importance of natural products as potential therapeutic agents in addressing diabetic complications.

SELECTION OF CITATIONS
SEARCH DETAIL
...