High Expression of KIFC1 in Glioma Correlates with Poor Prognosis.

OBJECTIVE: Kinesin family member C1 (KIFC1), a non-essential kinesin-like motor protein, has been found to serve a crucial role in supernumerary centrosome clustering and the progression of several human cancer types. However, the role of KIFC1 in glioma has been rarely reported. Thus, the present study aimed to investigate the role of KIFC1 in glioma progression. METHODS: Online bioinformatics analysis was performed to determine the association between KIFC1 expression and clinical outcomes in glioma. Immunohistochemical staining was conducted to analyze the expression levels of KIFC1 in glioma and normal brain tissues. Furthermore, KIFC1 expression was knocked in the glioma cell lines, U251 and U87MG, and the functional roles of KIFC1 in cell proliferation, invasion and migration were analyzed using cell multiplication, wound healing and Transwell invasion assays, respectively. The autophagic flux and expression levels matrix metalloproteinase-2 (MMP2) were also determined using imaging flow cytometry, western blotting and a gelation zymography assay. RESULTS: The results revealed that KIFC1 expression levels were significantly upregulated in glioma tissues compared with normal brain tissues, and the expression levels were positively associated with tumor grade. Patients with glioma with low KIFC1 expression levels had a more favorable prognosis compared with patients with high KIFC1 expression levels. In vitro, KIFC1 knockdown not only inhibited the proliferation, migration and invasion of glioma cells, but also increased the autophagic flux and downregulated the expression levels of MMP2. CONCLUSION: Upregulation of KIFC1 expression may promote glioma progression and KIFC1 may serve as a potential prognostic biomarker and possible therapeutic target for glioma.

HER2-targeted, enzyme-activated liposomes show superior in vivo efficacy in an ovarian cancer model.

Liposomes carrying chemotherapeutic drugs can accumulate passively in solid tumors at high levels. However, additional targeting of the liposomes towards e.g. receptors expressed on cancer cells may improve their interaction and therapeutic properties. In this study, we designed a liposomal delivery system, which utilizes the intrinsic characteristics of HER2-positive tumors to ensure efficient delivery of oxaliplatin to the cancer cells. On the liposome surface, trastuzumab, an antibody specific to the HER2 receptor, was shown to facilitate internalization by the cancer cells. A polyethylene glycol (PEG) layer on the liposome surface provides protection from mononuclear phagocyte system uptake. To optimize the interaction between liposomes and cancer cells, a protease-sensitive cleavable peptide linker was inserted at the base of each PEG. The PEG layer is then cleaved off by intra- and extracellular matrix metalloproteinases (MMPs) upon accumulation in the tumor. Our data demonstrate that the removal of PEG significantly destabilizes the liposomes and leads to substantial oxaliplatin release. The proposed beneficial effect of combining antibody-mediated internalization with MMP sensitivity was confirmed in a series of in vivo studies using ovarian cancer xenograft models. The results demonstrated that HER2-targeted MMP-sensitive liposomes have superior anticancer activity compared to non-targeted and non-cleavable liposomes.

Expression of matrix metalloproteinase-9 (MMP-9) in human skin within 1 hour after injury through immunohistochemical staining: a pilot study.

Matrix metalloproteinase-9 (MMP-9) is involved in tissue remodeling and in skin wound healing. The present study focuses on the MMP-9 expression in epidermal wound healing within 1 h after injury, to test whether MMP-9 can be used to estimate the time of injury in forensic practice.A sample consisting of 5 individuals undergoing surgery was analyzed. With the consent of the patients, sections of skin were removed from the surgical wound at predefined time intervals. For each subject, 8 sections were taken, one for each time interval defined at 0 '- 1' - 3 '- 5' - 10 '- 15' - 30 '- 60' minutes. The specimens were immunostained with MMP-9, and the number of positively stained cells was examined.The number of positively stained cells showed an increasing trend as a function of time. Less than 30 positively stained cells were found in all cases within 3 min. At the post-infliction time of 5 min, the number of positively stained cells exceeded 30 in 3 out of 5 cases. The number of MMP-positive cells exceeded 40 in all cases in over 10 min.In the light of these results, the count of MMP-9 positive cells might be a useful marker in the wound-age estimation within 1 h in forensic setting. More research is required to collect more samples and to compare samples from the hyperacute phase with those from several days after injury.

Green tea extract suppresses airway inflammation via oxidative stress-driven MAPKs/MMP-9 signaling in asthmatic mice and human airway epithelial cells.

Introduction: The anti-inflammatory effect of green tea extract (GTE) has been confirmed in asthmatic mice, however, the pharmacological mechanism is not fully elucidated. Methods: To investigate the therapeutic efficacy of GTE in asthma and identify specific pathways, murine model of allergic asthma was established by ovalbumin (OVA) sensitization and the challenge for 4 weeks, with oral treatment using GTE and dexamethasone (DEX). Inflammatory cell counts, cytokines, OVA-specific IgE, airway hyperreactivity, and antioxidant markers in the lung were evaluated. Also, pulmonary histopathological analysis and western blotting were performed. In vitro, we established the model by stimulating the human airway epithelial cell line NCI-H292 using lipopolysaccharide, and treating with GTE and mitogen-activated protein kinases (MAPKs) inhibitors. Results: The GTE100 and GTE400 groups showed a decrease in airway hyperresponsiveness and the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) compared to the OVA group. GTE treatment also reduced interleukin (IL)-13, IL-5, and IL-4 levels in the BALF, and OVA-specific immunoglobulin E levels in the serum compared to those in the OVA group. GTE treatment decreased OVA-induced mucus secretion and airway inflammation. In addition, GTE suppressed the oxidative stress, and phosphorylation of MAPKs, which generally occurs after exposure to OVA. GTE administration also reduced matrix metalloproteinase-9 activity and protein levels. Conclusion: GTE effectively inhibited asthmatic respiratory inflammation and mucus hyperproduction induced by OVA inhalation. These results suggest that GTE has the potential to be used for the treatment of asthma.

Proteolysis of the pericellular matrix: Pinpointing the role and involvement of matrix metalloproteinases in early osteoarthritic remodeling.

The pericellular matrix (PCM) serves a critical role in signal transduction and mechanoprotection in chondrocytes. Osteoarthritis (OA) leads to a gradual deterioration of the cartilage, marked by a shift in the spatial arrangement of chondrocytes from initially isolated strands to large cell clusters in end-stage degeneration. These changes coincide with progressive enzymatic breakdown of the PCM. This study aims to assess the role and involvement of specific matrix metalloproteinases (MMPs) in PCM degradation during OA. We selected cartilage samples from 148 OA patients based on the predominant spatial chondrocyte patterns. The presence of various MMPs (-1,-2,-3,-7,-8,-9,-10,-12,-13) was identified by multiplexed immunoassays. For each pattern and identified MMP, the levels and activation states (pro-form vs. active form) were measured by zymograms and western blots. The localization of these MMPs was determined using immunohistochemical labeling. To verify these results, healthy cartilage was exposed to purified MMPs, and the consecutive structural integrity of the PCM was analyzed through immunolabeling and proximity ligation assay. Screening showed elevated levels of MMP-1,-2,-3,-7, and -13, with their expression profile showing a clear dependency of the degeneration stage. MMP-2 and -7 were localized in the PCM, whereas MMP-1,-7, and -13 were predominantly intracellular. We found that MMP-2 and -3 directly disrupt collagen type VI, and MMP-3 and -7 destroy perlecan. MMP-2, -3, and -7 emerge as central players in early PCM degradation in OA. With the disease's initial stages already displaying elevated peaks in MMP expression, this insight may guide early targeted therapies to halt abnormal PCM remodeling. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) causes a gradual deterioration of the articular cartilage, accompanied by a progressive breakdown of the pericellular matrix (PCM). The PCM's crucial function in protecting and transmitting signals within chondrocytes is impaired in OA. By studying 148 OA-patient cartilage samples, the involvement of matrix metalloproteinases (MMPs) in PCM breakdown was explored. Findings highlighted elevated levels of certain MMPs linked to different stages of degeneration. Notably, MMP-2, -3, and -7 were identified as potent contributors to early PCM degradation, disrupting key components like collagen type VI and perlecan. Understanding these MMPs' roles in initiating OA progression, especially in its early stages, provides insights into potential targets for interventions to preserve PCM integrity and potentially impeding OA advancement.

Early vascular embolization improves neurological function in patients with intracranial aneurysm.

OBJECTIVES: To investigate the effect of early vascular embolization for intracranial aneurysms and the effect of matrix metalloproteinase-9 (MMP-9) and nuclear factor-kappa B (NF-κB) on nerve function. METHODS: This is a retrospective analysis study. A total of 90 patients with intracranial aneurysms admitted to our hospital from January 2017 to December 2021 were selected as research subjects. The patients were divided into a control group (n=47) and an observation group (n=43) according to different embolization timing. Both groups were treated with vascular embolization, the observation group received vascular embolization within 72 h after onset, while the control group received vascular embolization after 72 h. In addition, both groups were given clopidogrel bisulfate tablets and enteric-coated aspirin tablets from the day after operation for 3 months. The embolization at 3 months after operation, the occurrence of complications, the daily activities and neurological function before and 3 months after operation, serum levels of MMP-9 and NF-κB, the protein expression of MMP-9 and NF-κB, and the prognosis at 3 months after operation were compared between the two groups. RESULTS: The complete embolization rate (90.70%) in observation group was higher than that of the control group (72.34%) at 3 months after operation (P<0.05). The postoperative complications in the observation group (9.30%) were lower than those of the control group (27.66%) (P<0.05). The improvement in Modified Barthel index score, as well as serum levels of MMP-9 and NF-κB were better in the observation group than those of the control group 3 months after operation (P<0.05). The prognosis of patients in the observation group was better than those of the control group 3 months after operation (P<0.05). CONCLUSION: Early vascular embolization is an effective approach for intracranial aneurysm. It helps improve patients' neurological function, and reduce their serum and protein levels of both MMP-9 and NF-κB, thereby leading to favorable prognosis.

Treatment of cholangiocarcinoma by pGCsiRNA-vascular endothelial growth factor in vivo.

Background: The early diagnosis and treatment of cholangiocarcinoma may benefit from specific tumor markers to be used in clinical practice. Objectives: To investigate whether the pGCsiRNA-vascular endothelial growth factor (VEGF) can affect the onset and progression of cholangiocarcinoma and its possible mechanism using the targeted therapy of nude mouse model of cholangiocarcinoma with attenuated Salmonella carrying the plasmid pGCsiRNA-VEGF. Methods: The nude mouse model of cholangiocarcinoma was established by tail vein injection of QBC939 cells and given attenuated Salmonella carrying the plasmid pGCsiRNA-VEGF. One month later, the tumor volume of nude mice was observed, and the tumor growth curve was plotted. The harvested tumors were weighed and detected for tissue structural changes and cell death status by hematoxylin-eosin staining. The protein and mRNA expressions of VEGF, matrix metalloproteinase 2 (MMP2), and MMP9 were detected by Western blotting and PCR, respectively. Results: The tumor volume and weight of the pGCsiRNA-VEGF group were significantly smaller than those of the mock and the si-scramble groups (P < 0.05). The expressions of VEGF, MMP2, and MMP9 at the transcriptional and translational levels were inhibited by pGCsiRNA-VEGF. PGCsiRNA-VEGF promoted tissue apoptosis and destroyed the tissue structure. Conclusions: In vivo silencing of VEGF can affect cell survival and inhibit cell migration, invasion, and development, probably by enhancing apoptosis and inhibiting the expressions of MMP2 and MMP9.

Hydroxylated polychlorinated biphenyls may affect the thyroid hormone-induced brain development during metamorphosis of Xenopus laevis by disturbing the expression of matrix metalloproteinases.

BACKGROUND: Thyroid hormones are primarily responsible for the brain development in perinatal mammals. However, this process can be inhibited by external factors such as environmental chemicals. Perinatal mammals are viviparous, which makes direct fetal examination difficult. METHODS: We used metamorphic amphibians, which exhibit many similarities to perinatal mammals, as an experimental system. Therefore, using metamorphic amphibians, we characterized the gene expression of matrix metalloproteinases, which play an important role in brain development. RESULTS: The expression of many matrix metalloproteinases (mmps) was characteristically induced during metamorphosis. We also found that the expression of many mmps was induced by T3 and markedly inhibited by hydroxylated polychlorinated biphenyls (PCBs). CONCLUSION: Overall, our findings suggest that hydroxylated PCBs disrupt normal brain development by disturbing the gene expression of mmps.

[The Miao medicine Sidaxue alleviates rheumatoid arthritis in rats possibly by downregulating matrix metalloproteinases].

OBJECTIVE: To explore the inhibitory effect of Sidaxue, a traditional Miao herbal medicine formula, on articular bone and cartilage destruction and synovial neovascularization in rats with collagen-induced arthritis (CIA). METHODS: In a SD rat model of CIA, we tested the effects of daily gavage of Sidaxue at low, moderate and high doses (10, 20, and 40 g/kg, respectively) for 21 days, with Tripterygium glycosides (GTW) as the positive control, on swelling in the hind limb plantar regions by arthritis index scoring. Pathologies in joint synovial membrane of the rats were observed with HE staining, and serum TNF-α and IL-1ß levels were detected with ELISA. The expressions of NF-κB p65, matrix metalloproteinase 1 (MMP1), MMP2 and MMP9 at the mRNA and protein levels in the synovial tissues were detected using real-time PCR and Western blotting. Network pharmacology analysis was conducted to identify the important target proteins in the pathways correlated with the therapeutic effects of topical Sidaxue treatment for RA, and the core target proteins were screened by topological analysis. RESULTS: Treatment with GTW and Sidaxue at the 3 doses all significantly alleviated plantar swelling, lowered arthritis index scores, improved cartilage and bone damage and reduced neovascularization in CIA rats (P<0.05), and the effects of Sidaxue showed a dose dependence. Both GTW and Sidaxue treatments significantly lowered TNF-α, IL-1ß, NF-κB p65, MMP1, MMP2, and MMP9 mRNA and protein expressions in the synovial tissues of CIA rats (P<0.05). Network pharmacological analysis identified MMPs as the core proteins associated with topical Sidaxue treatment of RA. CONCLUSION: Sidaxue alleviates articular bone and cartilage damages and reduces synovial neovascularization in CIA rats possibly by downregulating MMPs via the TNF-α/IL-1ß/NF-κB-MMP1, 2, 9 signaling pathway, and MMPs probably plays a key role in mediating the effect of Sidaxue though the therapeutic pathways other than oral administration.

Epi-revolution in rheumatology: the potential of histone deacetylase inhibitors for targeted rheumatoid arthritis intervention.

Autoimmune diseases hold significant importance in the realm of medical research, prompting a thorough exploration of potential therapeutic interventions. One crucial aspect of this exploration involves understanding the intricate processes of histone acetylation and deacetylation. Histone acetylation, facilitated by histone acetyl transferases (HATs), is instrumental in rendering DNA transcriptionally active. Conversely, histone deacetylases (HDACs) are responsible for the removal of acetyl groups, influencing gene expression regulation. The upregulation of HDACs, observed in various cancers, has steered attention towards histone deacetylase inhibitors (HDACi) as promising anti-cancer agents. Beyond cancer, HDACi has demonstrated anti-inflammatory properties, prompting interest in their potential therapeutic applications for inflammatory diseases such as rheumatoid arthritis (RA). RA, characterized by the immune system erroneously attacking healthy cells, leads to joint inflammation. Recent studies suggest that HDACi could offer a viable therapeutic strategy for RA, with potential mechanisms including the inhibition of synovial tissue growth and suppression of pro-inflammatory cytokines. Furthermore, HDACi may exert protective effects on bone and cartilage, common targets in RA pathology. In-depth investigations through in vivo and histopathology studies contribute to the ongoing discourse on the therapeutic benefits of HDACis in the context of RA treatment.

Correlation of serum matrix metalloproteinase 3 with osteoporosis in patients of postmenopausal rheumatoid arthritis.

Osteoporosis (OP) is a common complication of postmenopausal women with rheumatoid arthritis (RA). Herein, the objective of our study was to explore the correlation between serum matrix metalloproteinase 3 (MMP3) and OP among postmenopausal women with RA to foster better diagnosis and treatment. A total of 208 elderly postmenopausal women with RA were included in this study, with 83 patients diagnosed with OP after RA diagnosis and 125 patients without OP. Serum MMP3 levels and bone mineral density (BMD) were measured and compared. The predictive value of serum MMP3 for OP in this population was also analyzed using receiver operating curve (ROC) analysis. Postmenopausal women with RA and OP diagnosis had markedly higher serum MMP3 levels, compared to those without OP. ROC analysis showed that serum MMP3 had predictive value for OP. Additionally, a negative correlation was observed between serum MMP3 levels and BMD. High serum MMP3 levels were also found to be associated with high abnormal bone metabolism. We found that serum MMP3 levels are strongly correlated with OP in postmenopausal women with RA and that elevated levels of serum MMP3 are linked to low BMD and high abnormal bone metabolism. Serum MMP3 may be a useful biomarker for predicting OP in this population, and could potentially aid in the development of targeted prevention and treatment strategies.

A study of inflammatory biomarkers in crystalline silica exposed rock drillers.

BACKGROUND: Crystalline silica (CS) exposure can cause serious lung disease in humans, but mechanisms of pulmonary toxicity have not been completely elucidated. AIMS: To assess pro-inflammatory and anti-inflammatory biomarkers and biomarkers related to the development of chronic obstructive pulmonary disease and fibrosis in serum of rock drillers exposed to CS. METHODS: Rock drillers (N = 123) exposed to CS and non-specified particulate matter (PM) were compared to 48 referents without current or past exposure to PM in a cross-sectional study. RESULTS: The rock drillers had been exposed to CS for 10.7 years on average. Geometric mean (GM) current exposure was estimated to 36 µg/m3. Their GM concentration of matrix metalloproteinase 12 (MMP-12) was significantly higher (16 vs. 13 ng/L; p = 0.04), while interleukin (IL) 6 and IL-8 were significantly lower compared to the referents. Also pentraxin 3 was significantly lower (3558 vs. 4592 ng/L; p = 0.01) in the rock drillers. A dose-response relationship was observed between cumulative exposure to CS and MMP-12, the highest exposed subgroup having significantly higher MMP-12 concentrations than the referents. CONCLUSION: Exposure to CS may increase circulating MMP-12 concentrations in a dose-response related fashion. The results may also suggest a down-regulation of pro-inflammatory pathways.

Unraveling the Mechanisms Involved in the Beneficial Effects of Magnesium Treatment on Skin Wound Healing.

The skin wound healing process consists of hemostatic, inflammatory, proliferative, and maturation phases, with a complex cellular response by multiple cell types in the epidermis, dermis, and immune system. Magnesium is a mineral essential for life, and although magnesium treatment promotes cutaneous wound healing, the molecular mechanism and timing of action of the healing process are unknown. This study, using human epidermal-derived HaCaT cells and human normal epidermal keratinocyte cells, was performed to investigate the mechanism involved in the effect of magnesium on wound healing. The expression levels of epidermal differentiation-promoting factors were reduced by MgCl2, suggesting an inhibitory effect on epidermal differentiation in the remodeling stage of the late wound healing process. On the other hand, MgCl2 treatment increased the expression of matrix metalloproteinase-7 (MMP7), a cell migration-promoting factor, and enhanced cell migration via the MEK/ERK pathway activation. The enhancement of cell migration by MgCl2 was inhibited by MMP7 knockdown, suggesting that MgCl2 enhances cell migration which is mediated by increased MMP7 expression. Our results revealed that MgCl2 inhibits epidermal differentiation but promotes cell migration, suggesting that applying magnesium to the early wound healing process could be beneficial.

miR-200b-3p accelerates progression of pituitary adenomas by negatively regulating expression of RECK.

MicroRNA (miR)-200b-3p has been associated with many tumors, but its involvement in pituitary adenoma is unclear. This study investigated the molecular mechanism underlying miR-200b-3p regulation in pituitary adenomas to provide a theoretical basis for treatment. Bioinformatics was used to analyze pituitary adenoma-related genes and screen new targets related to RECK and miRNA. As well, the relationship between miR-200b-3p and RECK protein was verified using a double-luciferase reporter gene assay. The expression of miR-200b-3p in clinical samples was analyzed by in situ hybridization. Transfection of the miR-200b-3p inhibitor and small interfering-RECK (si-RECK) was verified by qPCR. GH3 cell viability and proliferation were detected using CCK8 and EdU assays. Apoptosis was detected by flow cytometry and western blotting. Wound healing and Transwell assays were used to detect cell migration and invasion. The effects of miR-200b-3p and RECK on GH3 cells were verified using salvage experiments. miR-200b-3p was highly expressed in pituitary tumor tissue. Inhibitors of miR-200b-3p inhibited cell proliferation promoted cell apoptosis, inhibited invasion and migration, and inhibited the expression of matrix metalloproteinases. Interestingly, miR-200b-3p negatively regulated RECK. The expression of RECK in pituitary adenoma tissues was lower than that in neighboring tissues. Si-RECK rescued the function of miR-200b-3p inhibitors in the above cellular behaviors, and miR-200b-3p accelerated the development of pituitary adenoma by negatively regulating RECK expression. In summary, this study investigated the molecular mechanism by which miR-200b-3p regulates the progression of pituitary adenoma through the negative regulation of RECK. The findings provide a new target for the treatment of pituitary adenoma.

The Effects of Chronic Immunosuppressive Treatment on Morphological Changes in Cardiac Tissue and the Balance between Matrix Metalloproteinases (MMP-2 and MMP-9) and Their Inhibitors in the Rat Heart.

Using different three-drug immunosuppressive treatment regimens in a rat model, we aimed to determine the effects of long-term therapy on metalloproteinase-2 and metalloproteinase-9 activity and the expression of their inhibitors, as well as to assess the morphology of the animals' cardiac tissue. Our results suggest that chronic use of immunosuppressive drugs disrupts the balance between the activity of MMPs and TIMPs. Depending on the type of drug regimen used, this leads to abnormalities in the cardiac structure, collagen fiber accumulation, or cardiomyocyte hypertrophy. The information obtained in the present study allows us to conclude that the chronic treatment of rats with the most common clinical immunosuppressive regimens may contribute to abnormalities in the myocardial structure and function. The results presented in this study may serve as a prelude to more in-depth analyses and additional research into the optimal selection of an immunosuppressive treatment with the lowest possible risk of cardiovascular complications for patients receiving organ transplants.

Assessing Sarcocornia as a Salt Substitute: Effects on Lipid Profile and Gelatinase Activity.

Sodium, although essential for life, is a key factor in changes in vascular function and cardiovascular disease when consumed in excess. Sarcocornia spp., a halophyte plant with many nutritional benefits, presents itself as a promising substitute for the consumption of purified salt. Matrix metalloproteinases (MMPs) 2 and 9 are widely studied due to their action in physiological processes and as biomarkers at the diagnostic level due to their increased expression in inflammatory processes. This study aimed to evaluate whether replacing salt with Sarcocornia perennis (S. perennis) powder in healthy young people leads to an improvement in biochemical profiles and the attenuation of MMP-2 and MMP-9 activity. In the present study, 30 participants were randomized into a control group that consumed salt and an intervention group that replaced salt with powdered S. perennis. The evaluation of the biochemical parameters was carried out by the spectrophotometry method, and the evaluation of MMP activity was carried out by zymography. A significant decrease was observed in the intervention group in total cholesterol, high-density lipoprotein cholesterol (HDL-c), and creatinine (p-value ≤ 0.05), along with lower but not significantly different mean values of triglycerides. Regarding MMP activity after the intervention, a lower mean value was observed for MMP-9 activity, with there being higher mean values for MMP-2 activity, both with p-values ≥ 0.05. The results confirmed that the consumption of S. perennis is a beneficial choice for health regarding the lipid profile. The evaluation of MMP activity indicated the potential of S. perennis in the regulation of MMP-9 activity in healthy individuals, along with the need for the further study of these proteases in individuals with pathologies.

Sivelestat (Neutrophil Elastase Inhibitor) as an Anti-inflammatory and Anti-viral Agent: An In Silico Study.

Background Sivelestat is a potent and specific neutrophil elastase inhibitor. It is clinically used in treating lung injury and respiratory distress syndrome. This engaged us to undertake the present study in which sivelestat was studied as an anti-inflammatory and anti-viral agent. Methodology The docking study of sivelestat on matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), chikungunya virus nonstructural protein-2 (CVnsP2) protease, and influenza A (H1N9) virus neuraminidase was assessed using the Chemistry at Harvard Macromolecular Mechanics (CHARMM) Dock (CDOCK) method. Furthermore, molecular physicochemical; bioactivity; absorption, distribution, metabolism, and excretion (ADME); toxicity; and Search Tool for Interacting Chemicals (STITCH) analyses were performed by using the Molinspiration (Molinspiration Cheminformatics, Slovensky Grob, Slovak Republic), SwissADME SwissADME (Swiss Institute of Bioinformatics, Quartier Sorge - Bâtiment Amphipôle, Switzerland), pkCSM (University of Melbourne, Melbourne, Australia), and STITCH-free online tools. Results The molecular physicochemical assessment of the ligand (sivelestat) showed no (zero) violation and agreed with the thumb rule of five, otherwise known as Lipinski's rule of five. ADME prediction of the ligand (sivelestat) is shown to possess a low gastrointestinal absorption (GIA) property. Similarly, toxicity analysis of the ligand (sivelestat) is predicted to have a hepatotoxicity effect. STITCH analysis reveals that the ligand (sivelestat) has exhibited interactions with the three human proteins. Conclusions The present molecular docking studies showed that the ligand (sivelestat) has successfully docked with all four enzymes of interest. Hence, the current finding has provided a good understanding of sivelestat as an effective suppressor activity against all four enzymes: MMP-2, MMP-9, CVnsP2 protease, and influenza neuraminidase.

Long noncoding RNAs HAND2-AS1 ultrasound microbubbles suppress hepatocellular carcinoma progression by regulating the miR-873-5p/tissue inhibitor of matrix metalloproteinase-2 axis.

BACKGROUND: Increasing data indicated that long noncoding RNAs (lncRNAs) were directly or indirectly involved in the occurrence and development of tumors, including hepatocellular carcinoma (HCC). Recent studies had found that the expression of lncRNA HAND2-AS1 was downregulated in HCC tissues, but its role in HCC progression is unclear. Ultrasound targeted microbubble destruction mediated gene transfection is a new method to overexpress genes. AIM: To study the role of ultrasound microbubbles (UTMBs) mediated HAND2-AS1 in the progression of HCC, in order to provide a new reference for the treatment of HCC. METHODS: In vitro, we transfected HAND2-AS1 siRNA into HepG2 cells by UTMBs, and detected cell proliferation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) by cell counting kit-8 assay, flow cytometry, Transwell invasion assay and Western blotting, respectively. In addition, we transfected miR-837-5p mimic into UTMBs treated cells and observed the changes of cell behavior. Next, the UTMBs treated HepG2 cells were transfected together with miR-837-5p mimic and tissue inhibitor of matrix metalloproteinase-2 (TIMP2) overexpression vector, and we detected cell proliferation, apoptosis, invasion and EMT. In vivo, we established a mouse model of subcutaneous transplantation of HepG2 cells and observed the effect of HAND2-AS1 silencing on tumor formation ability. RESULTS: We found that UTMBs carrying HAND2-AS1 restricted cell proliferation, invasion, and EMT, encouraged apoptosis, and HAND2-AS1 silencing eliminated the effect of UTMBs. Additionally, miR-873-5p targets the gene HAND2-AS1, which also targets the 3'UTR of TIMP2. And miR-873-5p mimic counteracted the impact of HAND2-AS1. Further, miR-873-5p mimic solely or in combination with pcDNA-TIMP2 had been transformed into HepG2 cells exposed to UTMBs. We discovered that TIMP2 reversed the effect of miR-873-5p mimic caused by the blocked signalling cascade for matrix metalloproteinase (MMP) 2/MMP9. In vivo results showed that HAND2-AS1 silencing significantly inhibited tumor formation in mice. CONCLUSION: LncRNA HAND2-AS1 promotes TIMP2 expression by targeting miR-873-5p to inhibit HepG2 cell growth and delay HCC progression.

Matrix Metalloproteinase-7 Promoter Site Single Nucleotide Polymorphism (-181A>G) in Epithelial Ovarian Cancer in the Eastern Indian Population.

BACKGROUND: Matrix metalloproteinase-7 (MMP7) plays multiple roles in different stages of tumor development. Elevated MMP7 activity has been reported in ovarian cancer. Single nucleotide polymorphism (SNP) of promoter sites of the MMP7 gene has been shown to cause alteration in gene expression, hence resulting in changes in susceptibility to various diseases and tumor development. METHODS: The current study evaluated the association of epithelial ovarian cancer risk with MMP7 promoter site -181A>G polymorphism in the population of eastern India. The present case-control study included 64 histopathologically confirmed cases of epithelial ovarian cancer and 100 control subjects. The MMP7 -181A/G polymorphism was identified using polymerase chain reaction-restriction fragment length polymorphism. The association between genotypes and epithelial ovarian cancer risk was analyzed by odds ratio (OR) with a 95% confidence interval. RESULTS: The frequencies of AA, AG, and GG genotypes in ovarian cancer cases were 37.5%, 46.9%, and 15.6%, respectively, while that of control subjects were 56%, 36%, and 8%, respectively, in the study population. By taking the wild-type AA genotype as a reference, it was found that genotype GG was associated with a significant risk for epithelial ovarian cancer (OR: 2.92). Frequency distribution of genotypes did not show any significant association with tumor characteristics like the International Federation of Gynecology and Obstetrics (FIGO) stage, histology, lymph node status, and distant metastasis. CONCLUSION: The present study demonstrated the association of MMP7 promoter site -181 GG genotype and the G allele with increased risk for epithelial ovarian cancer in the eastern Indian population.

Renal Fibrosis and Oxidative Stress Induced by Silica Nanoparticles in Male Rats and Its Molecular Mechanisms.

Background: The utilization of amorphous silica nanoparticles (SiNPs) is gaining popularity in various applications, but it poses a potential risk to human and environmental health. However, the underlying causes and mechanisms of SiNPs-induced kidney damage are still largely unknown. Objectives: This study aimed to investigate the SiNPs-induced damage in the kidney and further explore the possible mechanisms of SiNPs-induced nephrotoxicity. Methods: Thirty adult male rats were divided into 3 different groups. Rats in groups 2 and 3 were administered SiNPs at 2 dosage levels (25 and 100 mg/kg of body weight), while the rats in the control group received no treatment for 28 days. Reactive oxygen species (ROS), antioxidant enzyme activities (glutathione peroxidase [GPx], superoxide dismutase [SOD], and catalase [CAT]), glutathione (GSH) levels, and oxidation markers (such as lipid peroxidation [malondialdehyde (MDA)] and protein oxidation [protein carbonyl (PCO)]) were analyzed in the kidney tissue. Additionally, renal fibrogenesis was studied through histopathological examination and the expression levels of fibrotic biomarkers. Results: The findings revealed that in vivo treatment with SiNPs significantly triggered oxidative stress in kidney tissues in a dose-dependent manner. This was characterized by increased production of ROS, elevated levels of MDA, PCO, and nitric oxide (NO), along with a significant decline in the activities of SOD, CAT, GPx, and reduced GSH. These changes were consistent with the histopathological analysis, which indicated interstitial fibrosis with mononuclear inflammatory cell aggregation, tubular degeneration, glomerulonephritis, and glomerular atrophy. The fibrosis index was confirmed using Masson's trichrome staining. Additionally, there was a significant upregulation of fibrosis-related genes, including transforming growth factor-beta 1 (TGF-ß1), matrix metalloproteinases 2 and 9 (MMP-2/9), whereas the expression of tissue inhibitor of metalloproteinase 2 (TIMP2) was downregulated. Conclusions: This study provided a new research clue for the role of ROS and deregulated TGF-ß signaling pathway in SiNPs nephrotoxicity.