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Bipolar disorders (BD) are chronic, debilitating disorders. The blood-brain barrier (BBB) has been increasingly investigated in BD. This systematic review aimed to assess the available evidence on the relationship between BD and markers of BBB dysfunction. A systematic search in PubMed, Embase, PsycINFO, CINAHL and Web of Science was run where the primary outcomes were BBB markers such as S100B, albumin ratio, matrix metalloproteinase (MMP), cell adhesion molecule (CAM), and tight junction proteins. Techniques included blood, cerebrospinal fluid (CSF), post-mortem, genetic and imaging methods in BD compared to healthy controls. 55 studies were identified, 38 of which found an association between BD and markers of BBB dysfunction. 16/29 studies found increased blood/CSF albumin ratio, S100B, CAMs or MMP levels in BD participants compared to controls. 5/19 post-mortem studies found increased levels of chondroitin sulphate proteoglycans, intercellular CAM, neurexin or claudin-5 mRNA in distinct locations throughout the brain in BD compared to controls. One imaging study identified extensive BBB leakage in 30 % of BD participants, compared to 0 % in controls. The diversity in methodologies used in the included studies makes direct comparison of results challenging. Furthermore, imaging methods are the gold standard, but only one study used them. Other markers are only indicative of BBB permeability. This review suggests an association between BD and BBB dysfunction. Further research is needed to provide definite answers considering the existing literature's limitations, and to clarify whether this association provides a pathogenic mechanism, or is an epiphenomenon of BD. • Blood brain barrier (BBB) dysfunction has been related to psychiatric disorders. • This review analysed the evidence for BBB dysfunction in bipolar disorders (BD). • MMP9, ICAM, Claudin-5, and S100B were associated with BD and its progression. • BBB leakage was associated with longer and more severe episodes in BD. • BBB dysfunction appears to be implicated in BD, but the mechanisms remain unknown. [ABSTRACT FROM AUTHOR]

Background: Migraine is a highly prevalent and complex neurovascular disease. However, the currently available therapeutic drugs often fall to adequately meet clinical needs due to limited effectiveness and numerous undesirable side effects. This study aims to identify putative novel targets for migraine treatment through proteome-wide Mendelian randomization (MR). Methods: We utilized MR to estimate the causal effects of plasma proteins on migraine and its two subtypes, migraine with aura (MA) and without aura (MO). This analysis integrated plasma protein quantitative trait loci (pQTL) data with genome-wide association studies (GWAS) findings for these migraine phenotypes. Moreover, we conducted a phenome-wide MR assessment, enrichment analysis, protein–protein interaction networks construction, and mediation MR analysis to further validate the pharmaceutical potential of the identified protein targets. Results: We identified 35 protein targets for migraine and its subtypes (p < 8.04 × 10–6), with prioritized targets showing minimal side effects. Phenome-wide MR identified novel protein targets—FCAR, UBE2L6, LATS1, PDCD1LG2, and MMP3—that have no major disease side effects and interacted with current acute migraine medication targets. Additionally, MMP3, PDCD1LG2, and HBQ1 interacted with current preventive migraine medication targets. The causal effects of plasma protein on migraine were partly mediated by plasma metabolites (proportion of mediation from 3.8% to 21.0%). Conclusions: A set of potential protein targets for migraine and its subtypes were identified. These proteins showed rare side effects and were responsible for biological mechanisms involved in migraine pathogenesis, indicating priority for the development of migraine treatments. [ABSTRACT FROM AUTHOR]

Combining phytochemicals and nanotechnology to improve the unfavorable innate properties of phytochemicals and develop them into potent nanomedicines to enhance antitumor efficacy has become a novel strategy for cancer chemoprevention. Melanoma is the most aggressive, metastatic, and deadly disease of the primary cutaneous neoplasms. In this study, we fabricated phytoconstituent-derived zingerone nanoparticles (NPs) and validated their effects on cell adhesion and motility in melanoma B16F10 cells. Our data indicated that zingerone NPs significantly induced cytotoxicity and anti-colony formation and inhibited cell migration and invasion. Moreover, zingerone NPs dramatically interfered with the cytoskeletal reorganization and markedly delayed the period of cell adhesion. Our results also revealed that zingerone NPs-mediated downregulation of MMPs (matrix metalloproteinases) activity is associated with inhibiting cell adhesion and motility. We further evaluated the effects of zingerone NPs on Src/FAK /Paxillin signaling, our data showed that zingerone NPs significantly inhibited the protein activities of Src, FAK, and Paxillin, indicating that they play important roles in zingerone NP-mediated anti-motility and anti-invasion in melanoma cells. Accordingly, the phytoconstituent-zingerone NPs can strengthen the inhibition of tumor growth, invasion, and metastasis in malignant melanoma. Altogether, these multi-pharmacological benefits of zingerone NPs will effectively achieve the purpose of melanoma prevention and invasion inhibition. [Display omitted] • Nanosizing ginger phytoconstituent zingerone possesses superior anti-tumorigenesis. • Zingerone NPs promoted cytotoxicity and anti-cell adhesion in melanoma cells. • Zingerone NPs-mediated downregulation of cell invasion and MMPs activity. • Src/FAK/Paxillin signaling is involved in zingerone NP-mediated anti-cell motility. [ABSTRACT FROM AUTHOR]

Ultraviolet-B (UVB) radiation-induced photoaging of the skin is characterized by amplified expression of matrix metalloproteinase-1 (MMP-1) and reduced collagen fibers, both of which contribute to skin wrinkle formation. Edible natural products can protect against skin photoaging. Here, we investigate the protective effect of Dolichos lablab Linne (DLL) water extract against UVB radiation-prompted skin damage and attempt to uncover its fundamental mechanisms in human keratinocytes (HaCaT) and HR-1 hairless mouse. We found DLL extract rescued the reduction in cell viability associated with UVB exposure without any associated cytotoxic effects. It also protected against skin photoaging by inhibiting mitogen-activating protein kinase (MAPK) signaling, thereby preventing the UVB-associated increase in MMP-1 and -9 expression. DLL extract also increased the expression of both superoxide dismutase 1 (SOD1) and catalase (CAT). We identified chikusetsusaponin IVa, soyasaponin Bb, and sandosaponin A as bioactive components of DLL. Although we have not yet identified the mechanisms by which these compounds reduce the effects of photoaging, we have demonstrated that chikusetsusaponin IVa, soyasaponin Bb, and sandosaponin A reduce MMP-1, MMP-9, p–c-Fos, and p–c-Jun expression, while also avoiding any cytotoxicity. We found oral administration of DLL extract effectively alleviated dorsal epidermal thickening and skin dehydration in HR-1 hairless mouse visible to UVB. DLL extract also prevents UVB-induced activation of the MAPK/AP-1 signaling pathway, thereby reducing the expression of MMPs in dorsal mouse skin. Our results indicate that chikusetsusaponin IVa, soyasaponin Bb, and sandosaponin A are bioavailable components of DLL extract that can reduce UVB-induced skin damage via MMPs by deactivating the MAPK/AP-1 signaling pathway. These findings suggest DLL extract can be used as a skin anti-photoaging agent. [ABSTRACT FROM AUTHOR]

Intracranial aneurysms (IAs) may afflict up to 5% of the general population, or up to 15 million individuals in the US. The two forms of IAs that can be recognized by their shape are saccular and nonsaccular IAs, with uncommon aneurysm types, fusiform and dissecting aneurysms, comprising 13% of nonsaccular IAs. Conceivably, among the various risk factors for IA development, vessel wall inflammation represents a major cause. Accordingly, IAs may not necessarily be the result of passive widening of vessel wall structures, but may also be the result of inflammation and tissue degeneration. Thus, flow‐induced vascular remodeling during IA pathogenesis may reflect immune cell infiltration and consequent release of proinflammatory cytokine, chemokine, and matrix metalloproteinase that contribute to vessel wall degeneration and weakening. Thus, infiltrating neutrophils, macrophages, T‐lymphocytes and complement factors, and the resulting immune microenvironment may be pertinent in IA pathogenesis. [ABSTRACT FROM AUTHOR]

Dental implant restoration shows an effective method for the rehabilitation of missing teeth. The failure rate of periodontal implants in patients with chronic periodontitis is associated with periodontal flora, inflammation, and long-term periodontal bone resorption caused by chronic periodontitis. However, the therapeutic effects of dental implant restoration on inflammation in patients with chronic periodontitis have not addressed. The purpose of this study is to evaluate the risk indicators for inflammation, bone loss and implant failure in patients with chronic periodontitis. A total of 284 patients with dental implant restoration were recruited and divided into periodontally healthy patients (n = 128) and chronic periodontitis patients (n = 156). Periodontal indices including probing depth (PD), sulcus bleeding index (SBI), plaque index (PLI), gingival bleeding (GIL) and bleeding on probing (BOP) were compared in two groups. Inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 (IL-1), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) levels at baseline, 6 and 12 months after surgery, and the implant survival rate at 12 months after surgery, as well as the risk factors associated with failure of dental implant were also assessed. Outcomes demonstrated that patients in the chronic periodontitis group had higher values of periodontal indices than those in the periodontally healthy group. All inflammatory parameters in the chronic periodontitis group were higher than those in the periodontally healthy group and negatively associated with the chronic periodontal index (CPI) in chronic periodontitis patients. Chronic periodontitis patients had higher the prevalence of mucositis and peri-implantitis than patients with healthy periodontium. Implant diameter, length and design was associated with the risk of implant failure for chronic periodontitis patients receiving dental implant. The cumulative implant failure rate and incidence of implant fractures for chronic periodontitis patients at 12 months after surgery were 12.10% and 7.23% (p < 0.05), respectively, while were lower in the heathy periodontitis patients. Location, diameter, implant design, immediate loading and bone defect were risk indicators for bone loss for dental implant patients. The risk factors associated with failure of dental implant was higher in chronic periodontitis patients than patients in the periodontally healthy group (14.25% vs. 4.92%, p < 0.05). In conclusion, data in the current study indicate that inflammation is a risk indicator bone loss, implant fracture and implant failure in patients with chronic periodontitis. [ABSTRACT FROM AUTHOR]

Dermal fibroblasts deposit type I collagen, the dominant extracellular matrix molecule found in skin, during early postnatal development. Coincident with this biosynthetic program, fibroblasts proteolytically remodel pericellular collagen fibrils by mobilizing the membrane-anchored matrix metalloproteinase, Mmp14. Unexpectedly, dermal fibroblasts in Mmp14-/- mice commit to a large-scale apoptotic program that leaves skin tissues replete with dying cells. A requirement for Mmp14 in dermal fibroblast survival is recapitulated in vitro when cells are embedded within, but not cultured atop, three-dimensional hydrogels of crosslinked type I collagen. In the absence of Mmp14-dependent pericellular proteolysis, dermal fibroblasts fail to trigger β1 integrin activation and instead actuate a TGF-β1/phospho-JNK stress response that leads to apoptotic cell death in vitro as well as in vivo. Taken together, these studies identify Mmp14 as a requisite cell survival factor that maintains dermal fibroblast viability in postnatal dermal tissues. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Objective Methods Results Conclusion Skin aging is characterized by an imbalance between the generation and degradation of extracellular matrix molecules (ECM). Matrix metalloproteinases (MMPs) are the primary enzymes responsible for ECM breakdown. Intrinsic and extrinsic stimuli can induce different MMPs. However, there is limited literature especially on the summary of skin MMPs and potential inhibitors.We aim to focus on the upregulation of MMP expression or activity in skin cells following exposure to UV radiation. We also would like to offer valuable insights into potential clinical applications of MMP inhibitors for mitigating skin aging.This article presents the summary of prior research, which involved an extensive literature search across diverse academic databases including Web of Science and PubMed.Our findings offer a comprehensive insight into the effects of MMPs on skin aging after UV irradiation, including their substrate preferences and distinct roles in this process. Additionally, a comprehensive list of natural plant and animal extracts, proteins, polypeptides, amino acids, as well as natural and synthetic compounds that serve as inhibitors for MMPs is compiled.Skin aging is a complex process influenced by environmental factors and MMPs. Research focuses on UV‐induced skin damage and the formation of Advanced Glycosylation End Products (AGEs), leading to wrinkles and impaired functionality. Inhibiting MMPs is crucial for maintaining youthful skin. Natural sources of MMP inhibitor substances, such as extracts from plants and animals, offer a safer approach to obtain inhibitors through dietary supplements. Studying isolated active ingredients can contribute to developing targeted MMP inhibitors. [ABSTRACT FROM AUTHOR]

Fucosterols have been widely studied for their antioxidant, anticancer, and anti-inflammatory properties. However, they have not yet been studied in the field of dentistry. This study aimed to determine whether pretreatment of dentin with fucosterol before resin restoration enhances bond stability in resin-dentin hybrid layers. After applying 0.1, 0.5, and 1.0 wt% fucosterol to demineralized dentin, microtensile bond strength (MTBS) and nanoleakage tests were performed before and after collagenase aging, and the surface was observed using scanning electron microscope (SEM). The fucosterol-treated group showed better bond strength and less nanoleakage both before and after collagenase aging, and the corresponding structures were confirmed using SEM. MMP zymography confirmed that the activity of MMPs was relatively low along the concentration gradient of fucosterol, and the FTIR analysis confirmed the production of collagen crosslinks. In addition, fucosterol exhibits cytotoxicity against Streptococcus mutans, the main cause of dental decay. The results of this study suggest that fucosterol pretreatment improves bond strength and reduces nanoleakage at the resin-dentin interface, possibly through a mechanism involving collagen cross-link formation via the inhibition of endogenous and exogenous MMP activity. This study demonstrates the potential of fucosterol as an MMP inhibitor in dentin, which contributes to long-term resin-dentin bond stability and can be used as a restorative material. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is one of the most common causes of death worldwide. Today, this disease does not have an effective treatment, leading to the exploration of novel pharmacological molecules. In this paper, we design and synthesize with a new synthetic route the lipophilic cation derived from gallic acid (TPP+C10) and gentisic acid (GA-TPP+C10), both able to reach mitochondria and uncouple the electron transport chain. Our results show that combining 5-fluorouracil with GA-TPP+C10 has a synergistic cytotoxic effect on CRC cells. Both compounds show antimigratory effects, decreasing signaling pathways and biomarkers. Our results show that mitochondrial agents could be an alternative to standard CRC drugs against this disease. Colorectal cancer (CRC) is the third leading cause of cancer deaths in the world. Standard drugs currently used for the treatment of advanced CRC—such as 5-fluorouracil (5FU)—remain unsatisfactory in their results due to their high toxicity, high resistance, and adverse effects. In recent years, mitochondria have become an attractive target for cancer therapy due to higher transmembrane mitochondrial potential. We synthesized gallic acid derivatives linked to a ten-carbon aliphatic chain associated with triphenylphosphonium (TPP+C10), a lipophilic cationic molecule that induces the uncoupling of the electron transport chain (ETC). Other derivatives, such as gentisic acid (GA-TPP+C10), have the same effects on colorectal cancer cells. Although part of our group had previously reported preparing these structures by a convergent synthesis route, including their application via flow chemistry, there was no precedent for a new methodology for preparing these compounds. In this scenario, this study aims to develop a new linear synthesis strategy involving an essential step of Steglich esterification under mild conditions (open flask) and a high degree of reproducibility. Moreover, the study seeks to associate GA-TPP+C10 with 5FU to evaluate synergistic antineoplastic effects. In addition, we assess the antimigratory effect of GA-TPP+C10 and TPP+C10 using human and mouse metastatic CRC cell lines. The results show a new and efficient synthesis route of these compounds, having synergistic effects in combination with 5FU, increasing apoptosis and enhancing cytotoxic properties. Additionally, the results show a robust antimigratory effect of GATPP+C10 and TPP+C10, reducing the activation pathways linked to tumor progression and reducing the expression of VEGF and MMP-2 and MMP-9, common biomarkers of advanced CRC. Moreover, TPP+C10 and GA-TPP+C10 increase the activity of metabolic signaling pathways through AMPK activation. The data allow us to conclude that these compounds can be used for in vivo evaluations and are a promising alternative associated with conventional therapies for advanced colorectal cancer. Additionally, the reported intermediates of the new synthesis route could give rise to analog compounds with improved therapeutic activity. [ABSTRACT FROM AUTHOR]

Background: Periodontal tissue damage is mainly caused by the active form of collagenolytic matrix metalloproteinase-8, aMMP-8, the concentration of which in the mouth rinse can be measured with a mouth rinse chairside-test. The mouth rinse chair side test can be used to identify adolescents with a risk of periodontitis. Methods: The data were collected at the Kotka Health Centre (2004–2005, N = 501 and 2014–2015, N = 47) and at the Hämeenlinna Health Centre (2017–2018, N = 125) consisting of adolescents aged 14–17. They underwent a complete periodontal examination, and some were subjected to the aMMP-8-test. Results: We identified bacterial plaques in combination with increased bleeding on probing (BOP), elevated aMMP-8 concentration, smoking and male sex as the main risk factors for initial periodontitis. Approximately 10% of adolescents had subclinical periodontitis, they were not periodontally healthy, but also not sick. They may not develop periodontitis, but they are at the risk. The aMMP-8 test positivity had a stronger association with initial periodontitis than BOP. Conclusions: In addition to identifying risk factors, these adolescents need individual prevention and, if necessary, early treatment. For the periodontal health biomarker aMMP-8, test negativity ([-], ≤20 ng/mL) should be sought. [ABSTRACT FROM AUTHOR]

There are multiple methods to prepare lipoaspirate for autologous fat transfer; however, graft retention remains unpredictable. The purpose of this study was to compare the cellular and protein composition of adipose grafts and the stromal vascular fraction (SVF) resulting from three common techniques to prepare adipose grafts. Adipose grafts were harvested from healthy donors and processed via three techniques: centrifugation (C), a single-filter (SF) device, and a double-filtration (DF) system. Part of each graft was analyzed or further processed to isolate the SVF. Cell viability, surface markers, cytokine, and growth factors were compared between the graft and SVF as well as adipose-derived stem cells (ASCs). Overall, we found variations across the three processing techniques and among the graft components (ASCs, SVF, and fat). Cell viability within the grafts was similar (94.6%, 92.3%, and 93.6%; P = 0.93). The trend was a greater percentage of ASCs from SF versus DF or centrifugation (6.95%, 4.63%, and 1.93%, respectively, P = 0.06). Adipogenic markers (adiponectin and leptin) were similar among all three grafts (P = 0.45). Markers of tissue remodeling were greatest in the SVF compared with fat and ASCs, regardless of processing technique. There was higher relative expression of MMP-9 (2×), Extracellular matrix metalloproteinase inducer (EMMPRIN) (2.5×), endoglin (5×), and IL-8 (1.5×) in the SVF (P < 0.005). Our study identified differences in cytokine expression in adipose grafts and the SVF, particularly in cytokines important in inflammation and wound healing. These secretomes may impact graft retention and fat necrosis and have the potential implications in cell-assisted lipotransfer. There were no significant differences between the final products of any of the processing techniques. [ABSTRACT FROM AUTHOR]

Prostaglandin E2 (PGE2) has recently gained attention in the field of regenerative medicine because of the beneficial effects of this molecule on stem cell proliferation and migration. Furthermore, PGE2 has the ability to mitigate immune rejection and fibrosis. In the colon and kidney, PGE2 induces YAP1, a transcription factor critical for cardiac regeneration. Establishing a similar connection in stem cells that can be transplanted in the heart could lead to the development of more effective therapeutics. In this report, we identify the effects of PGE2 on neonatal Islet-1+ stem cells. These stem cells synthesize PGE2, which functions by stimulating the transcription of the extracellular matrix protein Agrin. Agrin upregulates YAP1. Consequently, both YAP1 and Agrin are induced by PGE2 treatment. Our study shows that PGE2 upregulated the expression of both YAP1 and Agrin in Islet-1+ stem cells through the EP4 receptor and stimulated proliferation using the same mechanisms. PGE2 administration further elevated the expression of stemness markers and the matrix metalloproteinase MMP9, a key regulator of remodeling in the extracellular matrix post-injury. The expression of PGE2 in neonatal Islet-1+ cells is a factor which contributes to improving the functional efficacy of these cells for cardiac repair. [ABSTRACT FROM AUTHOR]

Objectives: The current study assesses the utility of matrix metalloprotease-3 (MMP-3) as a biomarker for joint damage in patients with rheumatoid arthritis receiving peficitinib. Methods: Rheumatoid arthritis patients with inadequate response to methotrexate were randomised to peficitinib 100 mg, peficitinib 150 mg, or placebo, combined with methotrexate, for 52 weeks; patients receiving placebo switched to peficitinib 100/150 mg at Week (W)12/28. This post hoc analysis investigated association between MMP-3 above/below upper limit of normal (ULN) at W12/28 and radiographic progression [modified total Sharp score (mTSS), joint space narrowing score, or erosion score >0.5] at W52 or swollen joint count 66 at W28, stratified by baseline glucocorticoid use and renal function. Results: MMP-3 levels decreased in both peficitinib-treated groups but more slowly in patients with baseline glucocorticoids and those with radiographic progression at W52. There was no clear correlation between MMP-3 change from baseline (CFB) at W12, CFB in mTSS, joint space narrowing score, or erosion score at W52, or CFB in swollen joint count 66 at W28. More patients with MMP-3 ≤ULN versus >ULN at W12 had radiographic non-progression at W52. MMP-3 normalisation at W12 was significantly associated with mTSS non-progression at W52. Conclusions: Normalisation of MMP-3 at W12 may be a predictor for subsequent non-progression of joint damage at W52. [ABSTRACT FROM AUTHOR]

Conventional topical psoriasis treatments suffer from limited delivery to affected areas and skin irritation due to high local drug concentration. This study aims to prepare hypericin (HYP) loaded nanostructured lipid carriers (NLCs) and their application in psoriasis treatment through intradermal administration using hollow microneedles assisted by photodynamic therapy. The colloidal characteristics of NLCs, entrapment efficiency and morphology were evaluated. An ex-vivo skin distribution study was conducted along with testing the in vivo antipsoriatic activity in mice with the imiquimod-induced psoriasis model. The particle size and zeta potential of HYP-NLCs were 167.70 nm and −18.1, respectively. The ex-vivo skin distribution study demonstrated the superior distribution of HYP-NLCs to a depth of 1480 µm within the skin layers relative to only 750 µm for free HYP. In vivo studies revealed that the levels of NF-KB, IL 6, MMP1, GSH, and catalase in the group treated with HYP-NLCs in the presence of light were comparable to the negative control. The histopathological inspection of dissected skin samples reflected the superiority of HYP-NLCs over HYP ointment. This could be ascribed to the effect of nanoencapsulation on improving HYP properties besides the ability of hollow microneedles to ensure effective HYP delivery to the affected psoriatic area. [ABSTRACT FROM AUTHOR]

Tendinopathy is a leading cause of mobility issues. Currently, the cell–matrix interactions involved in the development of tendinopathy are not fully understood. In vitro tendon models provide a unique tool for addressing this knowledge gap as they permit fine control over biochemical, micromechanical, and structural aspects of the local environment to explore cell–matrix interactions. In this study, direct-write, near-field electrospinning of gelatin solution was implemented to fabricate micron-scale fibrous scaffolds that mimic native collagen fiber size and orientation. The stiffness of these fibrous scaffolds was found to be controllable between 1 MPa and 8 MPa using different crosslinking methods (EDC, DHT, DHT+EDC) or through altering the duration of crosslinking with EDC (1 h to 24 h). EDC crosslinking provided the greatest fiber stability, surviving up to 3 weeks in vitro. Differences in stiffness resulted in phenotypic changes for equine tenocytes with low stiffness fibers (∼1 MPa) promoting an elongated nuclear aspect ratio while those on high stiffness fibers (∼8 MPa) were rounded. High stiffness fibers resulted in the upregulation of matrix metalloproteinase (MMPs) and proteoglycans (possible indicators for tendinopathy) relative to low stiffness fibers. These results demonstrate the feasibility of direct-written gelatin scaffolds as tendon in vitro models and provide evidence that matrix mechanical properties may be crucial factors in cell–matrix interactions during tendinopathy formation. [ABSTRACT FROM AUTHOR]

Due to an unexpected activation of different zinc (Zn) transporters in a recent prospective clinical study, we have revisited the role of Zn homeostasis and the activation of matrix metalloproteinases (MMPs) in skeletal muscle exposed to the intensive care unit (ICU) condition (immobilization and mechanical ventilation). ICU patients exposed to 12 days ICU condition were followed longitudinally with six repeated muscle biopsies while they showed a progressive preferential myosin loss, i.e., the hallmark of Critical Illness Myopathy (CIM), in parallel with the activation of Zn-transporters. In this study, we have revisited the expression of Zn-transporters and the activation of MMPs in clinical as well as in experimental studies using an established ICU model. MMPs are a group Zn-dependent endopeptidases which do not only target and cleave extracellular proteins but also intracellular proteins including multiple sarcomeric proteins. MMP-9 is of specific interest since the hallmark of CIM, the preferential myosin loss, has also been reported in dilated cardiomyopathy and coupled to MMP-9 activation. Transcriptional activation of Zn-transporters was observed in both clinical and experimental studies as well as the activation of MMPs, in particular MMP-9, in various limb and respiratory muscles in response to long-term exposure to the ICU condition. The activation of Zn-transporters was paralleled by increased Zn levels in skeletal muscle which in turn showed a negative linear correlation with the preferential myosin loss associated with CIM, offering a potential intervention strategy. Thus, activation of Zn-transporters, increased intramuscular Zn levels, and activation of the Zn-dependent MMPs are forwarded as a probable mechanism involved in CIM pathophysiology. These effects were confirmed in different rat strains subjected to a model of CIM and exacerbated by old age. This is of specific interest since old age and muscle wasting are the two factors most strongly associated with ICU mortality. [Display omitted] • An upregulation of Zn transporters in limb, respiratory and postural muscles in response to the ICU condition and an increased intramuscular Zn content. • An upregulation of the Zn-dependent matrix metalloproteinases (MMPs) in response to the ICU condition. • MMP-9 was upregulated in both rats and patients exposed to the ICU condition offering a potential mechanism underlying the preferential myosin loss associated with Critical Illness Myopathy (CIM) and supported by a negative linear correlation between the preferential myosin loss and intramuscular Zn levels. • Seven common genes involved in Zn ion homeostasis and activation of metalloproteinases were activated similarly in ICU patients and two different rat strains in response to immobilization and mechanical ventilation suggesting their pivotal role in CIM pathophysiology. • A robust downregulation of Pax7 in clinical and experimental studies in response to the ICU condition suggests an early impairment of myogenesis. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to evaluate the association of serum biomarkers with baseline psoriatic arthritis (PsA) disease activity, pharmacodynamic effects of deucravacitinib on biomarker levels, and the relationship between biomarkers and clinical responses to deucravacitinib. Methods: The phase 2 trial (ClinicalTrials.gov identifier: NCT03881059) randomly assigned 203 patients with PsA 1:1:1 to placebo, deucravacitinib at 6 mg once daily (QD), or deucravacitinib at 12 mg QD. Serum biomarkers associated with the interleukin 23 (IL‐23) pathway (IL‐17A, β‐defensin [BD‐2], and IL‐19), type I interferon pathway, inflammation, and collagen matrix turnover were measured by immunoassay. Clinical responses (≥75% improvement from baseline in the Psoriasis Area and Severity Index [PASI75] and ≥20% improvement from baseline in American College of Rheumatology criteria [ACR20] responses) were measured at week 16. Hematologic variables were also assessed. Results: IL‐17A, BD‐2, and IL‐19 had a modest association with PASI scores (r = 0.4, r = 0.56, and r = 0.5, respectively) at baseline. In deucravacitinib groups, IL‐17A, BD‐2, IL‐19, C‐X‐C motif ligand 9 (CXCL9), CXCL10, C‐reactive protein, matrix metalloproteinase 3, and collagen type 4 degradation marker levels were significantly reduced at week 16 versus baseline (P < 0.01); higher levels of IL‐23 pathway–associated biomarkers predicted higher PASI75 and ACR20 response rates in deucravacitinib‐treated patients. Significantly higher PASI75 response rates were seen in patients with high baseline IL‐17A (odds ratio 15.76) and BD‐2 levels (odds ratio 15.41) versus low baseline IL‐17A and BD‐2 levels. Changes in hematologic variables that are characteristic of JAK inhibition were not observed with deucravacitinib. Conclusion: Deucravacitinib significantly impacted biomarkers associated with Tyk2 signaling pathways of key inflammatory cytokines, including IL‐23 and type I interferon, and those related to collagen matrix turnover. These biomarkers may predict treatment responses to deucravacitinib. [ABSTRACT FROM AUTHOR]

Ankle osteoarthritis is a relatively understudied condition and the molecular mechanisms involved in its development are not well understood. This investigation aimed to explore the role and underlying molecular mechanisms of Yes-associated protein (YAP) in rat ankle osteoarthritis. The results demonstrated that YAP expression levels were abnormally increased in the ankle osteoarthritis cartilage model. In addition, knockdown of YAP expression was shown to hinder the imbalance in ECM metabolism induced by IL-1β in chondrocytes, as demonstrated by the regulation of matrix metalloproteinase (MMP)-3, MMP-9, and MMP-13, a disintegrin, metalloprotease with thrombospondin motifs, aggrecan, and collagen II expression. Additional studies revealed that downregulation of YAP expression markedly inhibited the overexpression of β-catenin stimulated by IL-1β. Furthermore, inhibition of the Wnt/β-catenin signaling pathway reversed the ECM metabolism imbalance caused by YAP overexpression in chondrocytes. It is important to note that the YAP-specific inhibitor verteporfin (VP) significantly delayed the progression of ankle osteoarthritis. In conclusion, the findings highlighted the crucial role of YAP as a regulator in modulating the progression of ankle osteoarthritis via the Wnt/β-catenin signaling pathway. These findings suggest that pharmacological inhibition of YAP can be an effective and critical therapeutic target for alleviating ankle osteoarthritis. [ABSTRACT FROM AUTHOR]

Objective(s): 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 highdose groups regarding the immunohistochemical reactivity of αVβ3 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, αVβ3 integrin, and VEGF. Treatment that modulates these molecules can lead to enhanced and quicker recovery of damaged skin in coffee lovers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• A variety of matrix metalloproteinases play an important role in the migration and invasion of prostate cancer. • Epigenetic modification plays an important role in prostate cancer. • Interaction between epigenetic modification and matrix metalloproteinases. • New strategies for prostate cancer diagnosis and treatment. Prostate cancer (PCa) is one of the most common tumors affecting men all over the world. PCa has brought a huge health burden to men around the world, especially for elderly men, but its pathogenesis is unclear. In prostate cancer, epigenetic inheritance plays an important role in the development, progression, and metastasis of the disease. An important role in cancer invasion and metastasis is played by matrix metalloproteinases (MMPs), zinc-dependent proteases that break down extracellular matrix. We review two important forms of epigenetic modification and the role of matrix metalloproteinases in tumor regulation, both of which may be of significant value as novel biomarkers for early diagnosis and prognosis monitoring. The author considers that both mechanisms have promising therapeutic applications for therapeutic agent research in prostate cancer, but that efforts should be made to mitigate or eliminate the side effects of drug therapy in order to maximize quality of life of patients. The understanding of epigenetic modification, MMPs, and their inhibitors in the functional regulation of prostate cancer is gradually advancing, it will provide a new technical means for the prevention of prostate cancer, early diagnosis, androgen-independent prostate cancer treatment, and drug research. [ABSTRACT FROM AUTHOR]

To investigate the effects of resveratrol (Res) on human fetal scleral fibroblasts (HFSFs) and its potential mechanism. HFSFs were randomly divided into the Res-treated group and the control group. Following, HFSFs were treated with or without a concentration of 10 μM Res for 48 h. To detect the expression of related genes, reverse transcription quantitative PCR (RT-qPCR) and western blotting were used. The apoptosis rate of different groups was determined using flow cytometry. The mRNA expression of matrix metalloproteinase 2 (MMP-2), Collagen, Type I, Alpha 1 (COL1A1), Janus Kinase 2 (JAK2), and Signal Transducer and Activator of Transcription 3 (STAT3)" was downregulated in the Res-treatment group compared to the control group, according to RT-qPCR. Western blotting revealed that Res therapy reduced the expression of MMP-2, JAK2, P-JAK2, STAT3, P-STAT3, and Bcl-2 associated protein X (Bax) while increasing the expression of COL1A1 and B-cell lymphoma-2 (Bcl-2). Flow cytometry showed that the cell apoptosis rate was significantly lower in HFSFs treated with Res. In conclusion, these findings suggest that Res increases COL1A1 expression while inhibiting MMP-2 and cell apoptosis in HFSFs, possibly through modulation of the JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]

10-methacryloyloxidecyl dihydrogen phosphate monomer (10-MDP) is commonly used as a bonding monomer in universal adhesives. Adhesives that contain this monomer can directly contact the surrounding periodontium due to the chemical binding of 10-MDP with hydroxyapatite in hard tissue to form calcium salts. However, the effect of these calcium salts on the periodontium in the case of subgingival fillings remains poorly understood. The objective of this study was to investigate effects of 10-MDP calcium salts on osteoblasts and fibroblasts in the periodontal tissues. This study investigated the effects of different concentrations of 10-MDP calcium salts on the migration, proliferation, and differentiation of osteoblasts (MC3T3-E1) and fibroblasts (L929); additionally, the effect on apoptosis and matrix metalloproteinases (MMPs) expression in these cells was evaluated. Cell proliferation assay, alkaline phosphatase (ALP) activity assay, Western blotting, and quantitative real-time polymerase chain reaction were performed to determine the effects. The 10-MDP calcium salts (within a concentration of 0.5 mg/mL) showed no cytotoxicity and did not seem to influence the apoptosis, mitochondrial membrane potential, and reactive oxygen species (ROS) levels in the cells. However, they had an inhibitory effect on the secretion of MMP2 and MMP9 in the osteoblasts and fibroblasts. The ALP activity assay and Alizarin Red staining did not reveal any significant effects of the 10-MDP calcium salts on osteoblast differentiation. These results suggest that applying 10-MDP-containing adhesives to subgingival fillings may be safe and beneficial for the periodontal tissues. [Display omitted] • 10-MDP calcium salts directed contact the periodontium in the case of subgingival resin filling. • 10-MDP calcium salts have inhibitory effect on the secretion of MMP2 and MMP9 in the osteoblasts and fibroblasts. • 10-MDP calcium salts showed no cytotoxicity and influences on the mitochondria in osteoblasts and fibroblasts. [ABSTRACT FROM AUTHOR]

Thoracic aortic dissection (TAD) is a highly lethal disease occurring inside the aortic wall and is characterized by matrix degradation. Matrix metalloproteinases (MMPs) are members of a large endopeptidase family that function in the degradation of the extracellular matrix (ECM) proteins, the maintenance of the ECM, and the regulation of signaling in the aorta. MMPs are found in tissue with their natural inhibitors. Tissue inhibitors of metalloproteinases (TIMPs) are actively involved in both the activation and inhibition of MMPs. The present study was designed to determine the mRNA level gene expression differences of MMP2, MMP9, TIMP2 and TIMP3, which are considered to have an essential role in TAD, in aortic tissue and circulating monocyte cells. For the purpose of the present study, aortic vascular tissue and peripheral blood-derived monocyte cells were obtained from 10 patients with TAD and 10 control individuals. The gene expression levels of targeted genes (MMP2, MMP9, TIMP2 and TIMP3) were examined by droplet digital PCR. In research results, decreased expression of MMP9, TIMP2 and TIMP3 genes (P=0.043, P=0.009 and P=0.028, respectively) and increased ratio of MMP2/TIMP3 (P=0.012) were obtained in the aortic tissue. No changes were observed in terms of gene expression in monocyte cells. When the results obtained were evaluated within the framework of TAD pathogenesis, it was concluded that expression changes in MMP9, TIMP2 and TIMP3 genes may provide a sensitive environment in aortic tissue and may be associated with TAD formation. In addition, since the expression ratios of MMPs and TIMPs may reflect disease development, it was considered that the evaluation of MMPs along with TIMPs may be an appropriate and informative approach for future studies. [ABSTRACT FROM AUTHOR]

Background: Regular physical exercise is an essential part of a healthy lifestyle, maintaining and strengthening public health. Recently, a steady increase in the number of recurrent musculoskeletal injuries occurring during physical exercise is being diagnosed. A serious risk factor for such damage is initial connective tissue pathology. Pathognomonic dysplastic phenotypes, indicating a particular susceptibility to injuries, were established. The decisive role in increasing connective tissue disorders severity is attributed in part to magnesium deficiency that is one of the most common deficient human conditions. Objective: To present the magnesium role in connective tissue homeostasis for pathogenetic substantiation of magnesium correction in persons with predisposition to musculoskeletal injuries. Methods: An analytical review of recent data published between January 2004 and December 2023 in the electronic resources such as Global Health, ScienceDirect, Elsevier, Medline, Embase, PubMed-NCBI, RSCI Scopus, Cochrane Library, e-Library, Google Academy, and CyberLeninka was conducted. Data analysis was performed from January 2023 to December 2023. Results: The analysis of the obtained data allowed to identify the main pathogenetic mechanisms of magnesium deficiency effect on connective tissues, including RNA cell destabilization, inactivation of hyaluronan synthetases, modulation of hyaluronidase activity, stimulation of matrix metalloproteinases, deactivation of elastase, realization of autoimmune reaction, lysyl oxidase, and transglutaminase activation. These processes result in increased degradation of collagen, elastin, and hyaluronan polysaccharide chains; reduction of cross-linking of fibrous structure; and intensification of inflammatory processes. This leads to defective connective tissue formation and increases sensitivity to physical stress and the risk of injury. Active magnesium participates in almost all biochemical reactions of connective tissue metabolism, and the impossibility of its synthesis in the body requires sufficient intake of this element with food and water. In the case of moderate-to-severe magnesium deficiency, it is pathogenetically reasonable to prescribe magnesium supplementation, which should take into account comorbidities, severity of deficiency, and age. Conclusion: Regular therapy with magnesium preparations helps to improve the mechanical properties of connective tissues, prevent the progression of dysplastic disorders, reduce the risk of injury, and maintain health during physical exercise. [ABSTRACT FROM AUTHOR]

Background Psoriasis is a T cell-mediated chronic inflammatory skin condition characterized by the interaction of T cells with various cell types, forming an inflammatory microenvironment that sustains psoriatic inflammation. Homeostasis of these tissue-resident T cells is supported by fibroblasts, the primary structural cells in the dermis. In psoriasis, there is increased expression of matrix metalloproteinase 2 (MMP2), mediating structural alterations in skin tissues and modulating inflammation. Additionally, the CD100–plexin-B2 (PLXNB2) axis is known to enhance psoriasis inflammation via keratinocytes, and CD103 levels are associated with the severity of psoriasis upon relapse. Objectives To elucidate the role of fibroblasts and the MMP2–CD100 axis in modulating psoriasis inflammation. Methods CD100 expression and function in psoriasis were assessed using immunofluorescence, enzyme-linked immunosorbent assay, single-cell transcriptome sequencing, cellular interaction analyses and quantitative reverse transcriptase polymerase chain reaction. CD8+ T cells from people with psoriasis were isolated using magnetic beads, to investigate the regulatory effect of MMP2 on CD100 expression on their membranes. Single-cell transcriptome sequencing, spatial transcriptome sequencing, mimetic timing analysis, immunofluorescence and flow cytometry were used to determine the origin of MMP2 and its impact on CD103+ CD8+ T cells. The hypotheses were further validated in vivo using MMP2 and CD100 inhibitors. Results Soluble CD100 (sCD100) was significantly upregulated in both psoriatic lesions and peripheral blood, amplifying psoriasis inflammation by promoting the production of inflammatory cytokines by keratinocytes, fibroblasts and endothelial cells via the sCD100–PLXNB2 axis. Fibroblasts that highly expressed MMP2 (MMP2hi) exacerbated psoriasis symptoms by facilitating CD100 shedding from CD8+ T-cell membranes. Additionally, it was shown that fibroblasts enhance the upregulation of the CD8+ T-cell residency factor CD103 in co-cultures with CD8+ T cells. Inhibitors targeting MMP2 and CD100 were effective in reducing inflammation in an imiquimod-induced psoriasis model. Conclusions Our findings underscore the pivotal role of MMP2hi fibroblasts in the amplification and recurrence of inflammatory responses in psoriasis. These fibroblasts augment psoriasis inflammation through the CD100–PLXNB2 axis by facilitating CD100 shedding on CD8+ T-cell membranes and by upregulating CD103, thereby enhancing CD8+ T-cell residency. [ABSTRACT FROM AUTHOR]

Scientific evidence has linked diabetes to a higher incidence and increased aggressiveness of breast cancer; however, mechanistic studies of the numerous regulators involved in this process are insufficiently thorough. Advanced glycation end products (AGEs) play an important role in the chronic complications of diabetes, but the mechanisms of AGEs in breast cancer are largely unexplored. In this study, we first demonstrate that high AGE levels in breast cancer tissues are associated with the diabetic state and poor patient outcomes. Furthermore, AGEs interact with the receptor for AGEs (RAGE) to promote breast cancer cell migration and invasion. Mechanistically, based on RNA sequencing (RNA-seq) analysis, we reveal that growth arrest and DNA damage gene 45α (GADD45α) is a vital protein upregulated by AGEs through a P53-dependent pathway. Next, GADD45α recruits thymine DNA glycosylase for base excision repair to form the demethylation complex at the promoter region of MMP-9 and enhance MMP-9 transactivation through DNA demethylation. Overall, our results indicate a critical regulatory role of AGEs in patients with breast cancer and diabetes and reveal a novel mechanism of epigenetic modification in promoting breast cancer metastasis. [ABSTRACT FROM AUTHOR]

Alternatively activated macrophage (M2) polarization can result in one of four subtypes based on cytokines and signaling pathways associated with macrophage activation: M2a, M2b, M2c, and M2d macrophages. The majority of M2 subtypes are anti-inflammatory and pro-angiogenic, secreting growth factors (VEGF, PDGF) and matrix metalloproteinases (MMP2, MMP9) which boost tumor growth, metastasis, and invasion. M2-polarized macrophages are associated with immune suppressor cells harboring Myeloid derived suppressor cells, Regulatory T cells (Tregs), Regulatory B cells as well as alternatively activated (N2) neutrophils. Treg cells selectively support the metabolic stability, mitochondrial integrity, and survival rate of M2-like TAMs in an indirect environment. Also, the contribution of Breg cells influences macrophage polarization towards the M2 direction. TAM is activated when TAN levels in the tumor microenvironment are insufficient or vice versa, suggesting that macrophage and its polarization are fine-tuned. Understanding the functions of immune suppressive cells, mediators, and signaling pathways involved with M2 polarization will allow us to identify potential strategies for targeting the TAM repolarization phenotype for innovative immunotherapy approaches. In this review, we have highlighted the critical factors for M2 macrophage polarization, differential cytokine/chemokine profiles of M1 and M2 macrophage subtypes, and other immune cells' impact on the polarization within the immunosuppressive niche. Highlights: M2 macrophages are targetable immune cells for immunotherapy strategies. M2 type macrophages are more heterogeneous populations than M1 macrophages. M2 polarization is influenced by Tregs, Bregs, MDSCs, and N2 neutrophils. [ABSTRACT FROM AUTHOR]

Astrocytes in Alzheimer's disease (AD) exert a pivotal role in the maintenance of blood-brain barrier (BBB) integrity essentially through structural support and release of soluble factors. This study provides new insights into the vascular remodeling processes occurring in AD, and reveals, in vivo , a pathological profile of astrocytic secretion involving Vascular Endothelial Growth Factor (VEGF), Matrix Metalloproteinases (MMP)-9, MMP-2 and Endothelin-1 (ET-1). Cerebrospinal fluid (CSF) levels of VEGF, MMP-2/-9 were lower in patients belonging to the AD continuum, compared to aged-matched controls. CSF levels of VEGF and ET-1 positively correlated with MMP-9 but negatively with MMP-2, suggesting a complex vascular remodeling process occurring in AD. Only MMP-2 levels were significantly associated with CSF AD biomarkers. Conversely, higher MMP-2 (β = 0.411, p < 0.001), ET-1 levels (β = 0.344, p < 0.001) and VEGF (β = 0.221, p = 0.022), were associated with higher BBB permeability. Astrocytic-derived vascular remodeling factors are altered in AD, disclosing the failure of important protective mechanisms which proceed independently alongside AD pathology. • Astrocytic-derived vascular remodeling factors can be measured in AD patients' CSF. • Astrocytic-derived VEGF, MMP-2 and MMP-9 CSF levels are reduced in AD patients. • MMP-2 CSF levels associate with AD core biomarkers. • MMP-2, ET-1 and VEGF CSF levels contribute to BBB regulation in AD. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most frequent bone malignancy in humans. Previous evidence suggest that circ_0032463 is an oncogenic circular RNA (circRNA) in various cancers, including OS. However, the molecular mechanism of circ_0032463 involved in OS is still unclear. Circ_0032463, microRNA‐145‐5p (miR‐145‐5p), GDNF receptor alpha 1 (GFRA1), and Wilms tumor 1‐associated protein (WTAP) levels were determined using real‐time quantitative polymerase chain reaction (RT‐qPCR). Cell proliferation, apoptosis, migration, invasion, and angiogenesis were analyzed using 5‐ethynyl‐2′‐deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays. Western blot analysis was performed to measure matrix metalloproteinase 2 (MMP2), MMP9, GFRA1, and WTAP protein levels. Binding between miR‐145‐5p and circ_0032463 or GFRA1 was confirmed using a dual‐luciferase reporter and pull‐down assay. The biological role of circ_0032463 on OS cell growth was also analyzed using a xenograft tumor model in vivo. Methylated RNA immunoprecipitation assay validated the interaction between WTAP and circ_0032463. Circ_0032463, GFRA1, and WTAP levels were increased, and miR‐145‐5p was decreased in OS tissues and cells. Circ_0032463 deficiency might hinder OS cell proliferation, migration, invasion, angiogenesis, and promote apoptosis in vitro. Mechanically, circ_0032463 worked as a miR‐145‐5p sponge to increase GFRA1 expression. Repression of circ_0032463 knockdown on tumor cell growth was proved in vivo. Besides, N6‐methyladenosine (m6A) modification facilitates the biogenesis of circ_0032463. Taken together, m6A‐mediated biogenesis of circ_0032463 facilitates OS cell malignant biological behavior partly via regulating the miR‐145‐5p/GFRA1 axis, suggesting a promising molecular marker for OS treatment. [ABSTRACT FROM AUTHOR]

To further understand the regulatory network and molecular mechanisms of gene expression after skin burns, we performed bioinformatics analysis of gene expression profiles of skin burn samples and identified key genes associated with skin burns. The GSE8056 and GSE139028 datasets were downloaded from the Gene Expression Omnibus database for analysis and validation. The limma package was used to screen for differentially expressed genes (DEGs). Gene ontology and pathway enrichment analyses (KEGG) were then performed. Subsequently, LASSO regression analysis was performed on DEGs and a regulatory network map of skin burn-related genes was constructed. Finally, the infiltration of immune cells was calculated and coexpression network maps of immune-related key genes and skin regeneration genes were constructed. Analysis of the GSE8056 dataset showed that 432 genes were upregulated and 351 genes were downregulated. The DEGs were mainly focused on immune response and skin regeneration. Meanwhile, these two groups of pivotal genes were significantly associated with abnormal infiltration of nine immune cells. GSE139028 validation revealed that three hub genes associated with skin burn immunity were differentially expressed, except for S100A8, while only the DPT gene was differentially expressed among the seven hub genes associated with skin regeneration. In short, the effect of skin burn on patients is to regulate the expression of immune-related genes UPP1, MMP1, MMP3, and skin regeneration-related gene DPT, which may be the key target for the treatment of skin burn. [ABSTRACT FROM AUTHOR]

The basement membrane zone is the interface between the epidermis and dermis, and it is disrupted in several skin conditions. Here, we report the results of a comprehensive investigation into the structural and molecular factors of the basement membrane zone in vitiligo, a dermatological disorder characterised by depigmented patches on the skin. Using electron microscopy and immunofluorescence staining, we confirmed abnormal basement membrane zone morphology and disrupted basement membrane zone architecture in human vitiliginous skin. Furthermore, we identified elevated expression of matrix metalloproteinase 2 (MMP2) in human dermal fibroblasts as a key factor responsible for basement membrane zone matrix degradation. In our in vitro and ex vivo models, overexpression of MMP2 in fibroblasts led to basement membrane zone disruption and melanocyte disappearance. Importantly, we reveal that the loss of melanocytes in vitiligo is primarily linked to their weakened adhesion to the basement membrane, mediated by binding between integrin β1 and laminin and discoidin domain receptor 1 and collagen IV. Finally, inhibition of matrix metalloproteinase 2 expression reversed depigmentation in a mouse model of vitiligo. In conclusion, our research shows the importance of basement membrane zone integrity in melanocyte residence and offers new avenues for therapeutic interventions to address this challenging skin condition. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

To address the limitations of conventional nanotechnology-based drug delivery systems, this work developed enzyme and reduction dual-responsive polymeric micelles. These micelles were synthesized with copolymers composed of TPGS3350-PVGLIG-DOX (TPD) and FA-SS-DOX (FSD), which endow them with tumor-targeted drug delivery capabilities. TPGS3350 contributes to extending the circulation of micelles in body, augmenting their accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect. Upon localized the tumor site, matrix metalloproteinase 2 (MMP2) cleaves the PVGLIG peptide moiety within the micelles, thereby releasing TPGS3350 and exposing the targeting ligand of folate. This approach enables the subsequent internalization of the micelles by tumor cells through folate receptor-mediated endocytosis. After internalization, the high intracellular concentration of glutathione (GSH) triggers the reduction of the disulfide bond within the FA-SS-DOX, leading to the release of the anticancer-drug doxorubicin (DOX), which promotes apoptosis in the tumor cells and enhances the efficacy of chemotherapy. [ABSTRACT FROM AUTHOR]

Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Methods Results Conclusion Ameloblastoma is a locally destructive benign odontogenic tumor. While the neoplastic cells of conventional ameloblastoma can infiltrate the connective tissue and bone, in unicystic ameloblastoma the epithelium is encapsulated. The mechanisms driving ameloblastoma's bone resorption remains unclear.RNA sequencing (RNA‐seq) was performed in a discovery cohort of conventional ameloblastoma, and pathway enrichment analysis was carried out. mRNA levels of MMP13, a gene associated with bone resorption, were assessed using RT‐qPCR in a larger cohort of conventional ameloblastoma and in unicystic ameloblastoma. Zymogram gels and the immunoexpression profile of collagenase 3 (encoded by MMP13 gene) were evaluated as well.Enriched pathways related to bone mineralization and upregulation of MMP13 were observed in ameloblastomas. Collagenolytic activity of collagenase 3 was detected in the tumor lysates. Collagenase 3 immunopositivity was observed in ameloblastomatous epithelium infiltrating the fibrous capsule of unicystic ameloblastoma. At the tumor–bone interface, collagenase 3 expression was detected in stromal cells, osteoblasts, and osteocytes.The results indicate a potential involvement of MMP13 in ameloblastoma‐related bone resorption and progression. [ABSTRACT FROM AUTHOR]

Introduction: Matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) are critical components of the extracellular matrix (ECM) in colorectal cancer (CRC). We aimed to evaluate the prognostic value of MMP-2 and MMP-9 in patients with CRC. Methods: We performed a meta-analysis of cohort studies with available data on the effect of MMP-2 and MMP-9 expression on both disease-free survival (DFS) and overall survival (OS) by the risk ratios (RRs) with their 95% confidence intervals (CIs). Studies were subgrouped based on the different tissue types, including cancer tissue and normal tissue, and the subgroup effect of MMP expression in different tissues was analyzed through meta-regression. To ensure the quality and reduce the risk of bias, the Newcastle‒Ottawa Scale (NOS) was used to assess the included studies. A sensitivity analysis was randomly performed to assess the potential impact of each study on our results. Results: Eighteen trials were selected (Table 1) and included a total of 3944 patients. According to our primary meta-analysis, the expression of MMP-2 was significantly associated with a decrease in OS (RR = 1.75, 95% CI = 1.34 to 2.29, P < 0.001) and DFS (RR = 2.62, 95% CI = 1.25 to 5.49, P < 0.001), and the expression of MMP-9 was not significantly associated with a decrease in OS (RR = 1.48, 95% CI = 0.97 to 2.24, P = 0.069) or DFS (RR = 1.60, 95% CI = 0.87 to 2.94, P = 0.133). According to the subgroup analysis of MMPs in different tissues, high MMP-2 expression in cancer tissue (RR = 1.90, 95% CI = 1.29 to 2.79) and normal tissue (RR = 1.59, 95% CI = 1.17 to 2.17) were significant indicators of poor OS. High MMP-2 expression in cancer tissue was significant indicator of poor DFS (RR = 2.12, 95% CI = 1.09 to 4.11). MMP-9 expression was also associated with poor OS (RR = 1.40, 95% CI = 0.85 to 2.29), but the difference in OS between the high and low expression groups was not statistically significant. Conclusions: High MMP-2 expression, especially in cancer tissue, is significantly associated with both poor DFS and poor OS in patients with CRC. High MMP-9 expression tended to indicate a poor prognosis of CRC but the correlation was not significant. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusion Impaired left ventricular–arterial coupling (VAC) has been shown to correlate with worse prognosis in cardiac diseases and heart failure (HF). The extent of the relationship between VAC and circulating biomarkers associated with HF has been scarcely documented. We aimed to explore associations of VAC with proteins involved in HF pathophysiology within a large population‐based cohort of middle‐aged individuals.In the forth visit of the STANISLAS family cohort, involving 1309 participants (mean age 48 ± 14 years; 48% male) from parent and children generations, we analysed the association of 32 HF‐related proteins with non‐invasively assessed VAC using pulse wave velocity (PWV)/global longitudinal strain (GLS) and arterial elastance (Ea)/ventricular end‐systolic elastance (Ees). Among the 32 tested proteins, fatty acid‐binding protein adipocyte 4, interleukin‐6, growth differentiation factor 15, matrix metalloproteinase (MMP)‐1, and MMP‐9 and adrenomedullin were positively associated with PWV/GLS whereas transforming growth factor beta receptor type 3, MMP‐2 and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were negatively associated. In multivariable models, only MMP‐2 and NT‐proBNP were significantly and inversely associated with PWV/GLS in the whole population and in the parent generation. Higher levels of NT‐proBNP were also negatively associated with Ea/Ees in the whole cohort but this association did not persist in the parent subgroup.Elevated MMP‐2 and NT‐proBNP levels correlate with better VAC (lower PWV/GLS), possibly indicating a compensatory cardiovascular response to regulate left ventricular pressure amidst cardiac remodelling and overload. [ABSTRACT FROM AUTHOR]

Background: Matrix metalloproteinases (MMPs) are critical enzymes involved in the remodeling and defense mechanisms of dental pulp tissue. While their role in permanent teeth has been extensively studied, research focusing on MMPs in primary teeth remains limited. This gap highlights the need for further investigations to understand the specific contributions of MMPs to pulpal defense in primary teeth. Moreover, the clinical efficacy of Biodentine as a pulpotomy material in primary teeth warrants further exploration through well-designed studies to establish its success and long-term outcomes in pediatric dentistry. Aim: This study aims to compare the expression levels of MMP-2, MMP-8, and MMP-9 in cases of reversible and irreversible pulpitis. Additionally, it seeks to evaluate the clinical success of Mineral Trioxide Aggregate (MTA) and Biodentine when used as pulpotomy agents in primary molars. By analyzing the differential expression of these MMPs, the study will contribute to a better understanding of their role in pulpal inflammation and the potential therapeutic outcomes of MTA and Biodentine in primary molars. Design: In this parallel randomized controlled trial, 63 mandibular primary second molars were assigned to two main groups: Group 1, consisting of 42 teeth diagnosed with reversible pulpitis, and Group 2, consisting of 21 teeth diagnosed with irreversible pulpitis. Group 1 was further divided into two randomized subgroups, each containing 21 teeth. The expression levels of MMP-2, MMP-8, and MMP-9 were evaluated in all samples. Pulpotomy treatments were performed using MTA and Biodentine in Group 1. Clinical and radiographic evaluations were conducted over an 18-month follow-up period. Statistical analyses were carried out using The Kolmogorov-Smirnov test, t-test and Fisher's exact test (p < 0.05). Results: The study revealed that MMP-2 and MMP-9 expression levels were significantly elevated in specimens with irreversible pulpitis (p = 0.01), indicating a potential correlation between these matrix metalloproteinases and the severity of pulpal inflammation. However, no significant difference was observed in the clinical success rates of pulpotomies performed with MTA and Biodentine, suggesting that both materials are equally effective in the treatment of primary molars with reversible pulpitis. Conclusions: The expression of MMP-2 and MMP-9 in pulpal blood presents a promising biomarker for assessing the degree of pulpal inflammation in primary teeth, offering a potentially valuable diagnostic tool. Additionally, the clinical success of Biodentine in pulpotomy procedures supports its viability as an effective alternative to MTA, providing a reliable option. Clinical Trial Registration ID: The study protocol has been registered with an ID: NCT05145686. Registration Date: 9th November 2021. [ABSTRACT FROM AUTHOR]

Background: Considering the complex pathological mechanisms behind spinal cord injury (SCI) and the adverse effects of present non-approved drugs against SCI, new studies are needed to introduce novel multi-target active ingredients with higher efficacy and lower side effects. Polydatin (PLD) is a naturally occurring stilbenoid glucoside recognized for its antioxidative and anti-inflammatory properties. This study aimed to assess the effects of PLD on sensory-motor function following SCI in rats. Methods: Following laminectomy and clip compression injury at the thoracic 8 (T8)-T9 level of the spinal cord, rats were randomly assigned to five groups: Sham, SCI, and three groups receiving different doses of PLD treatment (1, 2, and 3 mg/kg). Over 4 weeks, behavioral tests were done such as von Frey, acetone drop, hot plate, Basso-Beattie-Bresnahan, and inclined plane test. At the end of the study, changes in catalase and glutathione activity, nitrite level, activity of matrix metalloproteinase 2 (MMP2) and MMP9 as well as spinal tissue remyelination/neurogenesis, were evaluated. Results: The results revealed that PLD treatment significantly improved the behavioral performance of the animals starting from the first week after SCI. Additionally, PLD increased catalase, and glutathione levels, and MMP2 activity while reduced serum nitrite levels and MMP9. These positive effects were accompanied by a reduction in the size of the lesion and preservation of neuronal count. Conclusion: In conclusion, PLD showed neuroprotective effects in SCI rats by employing anti-inflammatory and antioxidant effects, through which improve sensory and motor function. [ABSTRACT FROM AUTHOR]

Tendinopathy is a common age-related disease which causes significant morbidity for both human athletes and performance horses. In the latter, the superficial digital flexor tendon is an excellent model for human tendinopathies because it is a functional homologue of the human Achilles tendon and a primary site of injuries with strong similarities to the human disease. Corticosteroids have been previously used clinically to treat tendinopathic inflammation, but they upregulate the p53-p21 axis with concomitant reductions in cell proliferation and collagen synthesis in human tenocytes. This phenotype is consistent with the induction of cellular senescence in vitro and in vivo and probably represents an important clinical barrier to their effective use. Because of the many differences in senescence mechanisms between species, this study aimed to evaluate these mechanisms after corticosteroid treatment in equine tenocytes. Exposure to clinically reflective levels of dexamethasone for 48 hours drove equine tenocytes into steroid induced senescence (SIS). This was characterised by permanent growth arrest and upregulation of p53, the cyclin dependent kinase inhibitors p21waf and p16ink4a as well as the matrix degrading enzymes MMP1, MMP2 and MMP13. SIS also induced a distinctive equine senescence associated secretory phenotype (eSASP) characterised by enhanced secretion of IL-8 and MCP-1. Preincubation with resveratrol or the potent SIRT1 activator SRT1720 prevented SIS in equine tenocytes, while treatment with the non-SIRT1 activating resveratrol analogue V29 was equally protective against SIS, consistent with a novel, as yet uncharacterised SIRT1-indendent mechanism which has relevance for the development of future preventative and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: Osteoarthritis (OA) is a chronic inflammatory disease where pro-inflammatory cytokines, damage-associated molecular patterns and macrophages play a crucial role. However, the interaction of these mediators, the exact cause, and the treatment of knee osteoarthritis (KOA) are still unclear. Moreover, the interaction of interleukin (IL)-33, platelet-derived growth factor-BB (PDGF-BB), and matrix metalloproteinase-9 (MMP-9) with other factors in the pathogenesis of KOA has not been elaborately explored. Method: Therefore, in this study, we analyzed the expression of IL-33, PDGF-BB, and MMP-9 in the knee cartilage tissue of model mice, murine KOA was induced by using the destabilization of the medial meniscus (DMM) model. Results: Compared with the sham operation control group, the expression levels of PDGF-BB, IL-33, and MMP-9 were increased significantly, and the pathological sections showed obvious cartilage damage. Additionally, we assessed the levels of IL-33 and MMP-9 expression in the knee joint of KOA model mice following intervention with PDGF-BB antibody, and we found that the expression level of MMP-9 was reduced following intervention with IL-33 antibody. When the effects of the three antibodies were compared in a mouse disease model, it was discovered that the IL-33 antibody could dramatically lower the relative expression level of MMP-9, resulting in the least amount of cartilage damage and improved protection. In conclusion, inhibiting IL-33 can significantly lower inflammatory factor levels in the knee joint, including IL-33 and MMP-9, and it can improve cartilage breakdown in osteoarthritis of the knee. Conclusion: Overall, the results indicate that IL-33 has a therapeutic function in the treatment of knee osteoarthritis and may be a novel target for treatment of the underlying causes of KOA. Additionally, PDGF-BB might be an upstream pathway of IL-33, and KOA's MMP-9 is an downstream pathway of IL-33. [ABSTRACT FROM AUTHOR]

Intracranial aneurysm (IA) can cause subarachnoid hemorrhage or some other hemorrhagic stroke after rupture. Because of the poor outcome in spite of the intensive medical care after the onset of hemorrhage, the development of a novel therapeutic strategy like medical therapy to prevent the progression of the disease becomes a social need. As the reduction of arterial stiffness due to the degeneration of the extracellular matrix via Matrix Metalloproteinases (MMPs) becomes one of the central machineries leading to the progression of IAs through a series of studies, factors regulating the expression or the activity of MMPs could be a therapeutic target. In the present study, specimens from human IA lesions and the animal model of IAs were used to examine the expression of c-Jun N-terminal kinase (JNK) which might exacerbate expressions of MMPs in the lesions to weaken arterial walls resulting in the progression of the disease. In some human IA lesions examined, the expression of p-JNK, the activated form of JNK, could be detected mostly in the medial smooth muscle cells. In IA lesions induced in rats, the activation of JNK was induced during the progression of the disease and accompanied with the activation of downstream transcriptional factor c-Jun and importantly with the expression of MMP-2 or -9. The genetic deletion of Jnk2, not Jnk1, in mice significantly prevented the incidence of IAs with the suppression of the expression of MMP-2 or MMP-9. These results combined together have suggested the crucial role of JNK in the progression of IAs through regulating the expression of MMPs. The results from the present study provides the novel insights about the pathogenesis of IA progression and also about the therapeutic target. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase (MMP)‐12 has been reported to have diverse functions, including regulation of immune reactions and anti‐inflammatory effects, but the potential roles of MMP‐12 in kidney injury have not been fully elucidated. This study aimed to determine whether MMP‐12 contributes to tubulointerstitial injury in a unilateral ureteric obstruction (UUO) model. MMP‐12‐deficient (MMP‐12−/−) mice and C57BL/6J mice as controls (MMP‐12+/+) were subjected to UUO and analysed 7 days after UUO. To analyse the functions of MMP‐12 on monocytes/macrophages, we generated MMP‐12‐deficient, irradiated, chimeric mice (BM‐MMP‐12−/−) and performed UUO. Bone marrow‐derived macrophages (BMDMs) were isolated from both groups of mice and used for investigations. MMP‐12−/− mice showed exacerbation of macrophage accumulation and interstitial fibrosis in the UUO‐kidney compared with control mice. BM‐MMP‐12−/− mice also showed exacerbation of kidney injury. UUO induced accumulation of Ly6C+ macrophages in MMP‐12−/− mice compared with control mice. Increases in inflammatory cytokine (tumour necrosis factor α, interleukin [IL]‐1β, IL‐6) levels from BMDMs after lipopolysaccharide stimulation were higher in MMP‐12−/− mice than in MMP‐12+/+ mice. MMP‐12 may play protective roles against kidney injury by UUO in mice, decreasing inflammatory cytokines from BMDMs and macrophage accumulation. [ABSTRACT FROM AUTHOR]

Purpose: To verify the effect and mechanism of baicalein in the treatment of periodontitis through network pharmacology, molecular docking and in vitro experiments. Methods: Firstly, multiple databases were used to predict targets of baicalein and periodontitis. And the screened key target genes of baicalein for treating periodontitis were subjected to GO and KEGG analysis; then these targets were analyzed by molecular docking techniques. In vitro experiments including CCK-8, RT-qPCR, ELISA and Immunofluorescence were conducted to validate the efficacy of baicalein in treating periodontitis. Results: Seventeen key targets were screened from the databases, GO and KEGG analysis of these targets revealed that baicalein may exert therapeutic effects through regulating TNF, PI3K-Akt, HIF-1 and other signaling pathways. Molecular docking analysis showed that baicalein has good binding potential to several targets. In vitro cellular assays showed that baicalein inhibited the expression of TNF-α, MMP-9, IL-6 and MCP1 in P.g-LPS-induced macrophages at both the mRNA and protein level. And the immunofluorescence intensity of iNOS, a marker of M1 type macrophages, which mainly secretes inflammatory factors, was significantly reduced. Conclusion: Baicalein has the characteristics and advantages of "multicomponent, multitarget, and multipathway" in the treatment of periodontitis. In vitro cellular assays further confirmed the inhibitory effect of baicalein on the secretion of inflammatory factors of macrophages in periodontitis models, providing a theoretical basis for further study of the material basis and molecular mechanism of baicalein in the treatment of periodontal diseases. [ABSTRACT FROM AUTHOR]

Objective: In this study, we employed a bioinformatics approach to identify diagnostic biomarkers for tongue squamous cell carcinoma (TSCC) and investigate the infiltration of immune cells in TSCC, as well as the relationship between biomarkers and immune cells. Methods: We obtained the TSCC expression dataset from a database and conducted differential gene expression analysis between TSCC and adjacent normal tissues using R software. Enrichment analysis of the differentially expressed genes (DEGs) was performed using the DAVID website. Protein interaction networks for the DEGs were constructed, and hub genes were identified using tools such as STRING and Cytoscape. Survival analysis was conducted to identify diagnostic biomarkers and the infiltration of immune cells in TSCC was analyzed using the inverse convolution algorithm with Cibersort software. Finally, the expression of the discovered molecules was verified through clinical pathological sections. Results: We identified 24 DEGs in TSCC, primarily associated with signal transduction, substance metabolism, innate immune response, and other related signaling pathways. Among the 24 hub genes screened through the construction of a protein–protein interaction (PPI) network, seven (MMP13, POSTN, MMP9, MMP10, MMP3, SPP1, MMP1) exhibited prognostic value. Survival analysis indicated that SPP1 demonstrated diagnostic potential. The expression level of the SPP1 gene showed a correlation with TSCC as well as several immune cell types, including macrophage M0, M1, M2, CD8+ T cell, activated NK cell, and monocyte (p < 0.05). Histological results confirmed higher expression of SPP1 in TSCC tissues compared to adjacent non-cancerous tissues, particularly in CD68-expressing macrophages. Conclusion: Our findings suggest that SPP1 serves as a diagnostic biomarker for TSCC and is involved in immune cell infiltration within TSCC tissues. The correlation between SPP1 and macrophages may offer new insights for targeted therapeutic research on TSCC. [ABSTRACT FROM AUTHOR]

Integrin β4 (ITGB4) is a transmembrane protein that functions as a mechanosensor, mediating the bidirectional exchange of information between the intracellular and extracellular matrices. ITGB4 plays a critical role in cell adhesion, migration, and signaling. Numerous studies have implicated ITGB4 as a key facilitator of tumor migration and invasion. This review provides a foundational description of the mechanisms by which ITGB4 regulates tumor migration and invasion through pathways involving focal adhesion kinase (FAK), protein kinase B (AKT), and matrix metalloproteinases (MMPs). These mechanisms encompass epithelial-mesenchymal transition (EMT), phosphorylation, and methylation of associated molecules. Additionally, this review explores the role of ITGB4 in the migration and invasion of prevalent clinical tumors, including those of the digestive system, breast, and prostate. [ABSTRACT FROM AUTHOR]

Introduction: Inflammation-induced remodelling of gestational tissues that underpins spontaneous preterm birth (sPTB, delivery < 37 weeks' gestation) may vary by race and context. To explore relationships between markers of these pathological processes, we (a) characterised the cervicovaginal fluid (CVF) cytokine profiles of pregnant South African women at risk of PTB; (b) determined CVF matrix-metalloproteinase-9 (MMP-9) and its regulator tissue inhibitor of metalloproteinase-1 (TIMP-1); and (c) explored the predictive potential of these markers for sPTB. Method of study: The concentrations of 10 inflammatory cytokines and MMP-9 and TIMP-1 were determined by ELISA in CVF samples from 47 non-labouring women at high risk of PTB. We studied CVF sampled at three gestational time points (GTPs): GTP1 (20-22 weeks, n = 37), GTP2 (26-28 weeks, n = 40), and GTP3 (34-36 weeks, n = 29) and analysed for changes in protein concentrations and predictive capacities (area under the ROC curve (AUC) and 95% confidence interval (CI)) for sPTB. Results: There were 11 (GTP1), 13 (GTP2), and 6 (GTP3) women who delivered preterm within 85.3 ± 25.9, 51.3 ± 15.3, and 11.8 ± 7.5 (mean ± SD) days after assessment, respectively. At GTP1, IL-8 was higher (4-fold, p = 0.02), whereas GM-CSF was lower (~1.4-fold, p = 0.03) in the preterm compared with term women with an average AUC = 0.73. At GTP2, IL-1β (18-fold, p < 0.0001), IL-8 (4-fold, p = 0.03), MMP-9 (17-fold, p = 0.0007), MMP-9/TIMP-1 ratio (9-fold, p = 0.004), and MMP-9/GM-CSF ratio (87-fold, p = 0.005) were higher in preterm compared with term women with an average AUC = 0.80. By contrast, IL-10 was associated with term delivery with an AUC (95% CI) = 0.75 (0.55-0.90). At GTP3, IL-1β (58-fold, p = 0.0003), IL-8 (12-fold, p = 0.002), MMP-9 (296-fold, p = 0.03), and TIMP-1 (35-fold, p = 0.01) were higher in preterm compared with term women with an average AUC = 0.85. Elevated IL-1β was associated with delivery within 14 days of assessment with AUC = 0.85 (0.67-0.96). Overall, elevated MMP-9 at GTP3 had the highest (13.3) positive likelihood ratio for distinguishing women at risk of sPTB. Lastly, a positive correlation between MMP-9 and TIMP-1 at all GTPs (r = 0.61, p < 0.01) for women delivering at term was only observed at GTP1 for those who delivered preterm (r = 0.70, p < 0.03). Conclusions: In this cohort, sPTB is associated with gestation-dependent increase in pro-inflammatory cytokines, decreased IL-10 and GM-CSF, and dysregulated MMP-9-TIMP-1 interaction. Levels of cytokine (especially IL-1β) and ECM remodelling proteins rise significantly in the final 2 weeks before the onset of labour when sPTB is imminent. The signalling mechanisms for these ECM remodelling observations remain to be elucidated. [ABSTRACT FROM AUTHOR]

Background: Group B Streptococcus (GBS) is the leading cause of neonatal meningitis responsible for a substantial cause of death and disability worldwide. The vast majority of GBS neonatal meningitis cases are due to the CC17 hypervirulent clone. However, the cellular and molecular pathways involved in brain invasion by GBS CC17 isolates remain largely elusive. Here, we studied the specific interaction of the CC17 clone with the choroid plexus, the main component of the blood-cerebrospinal fluid (CSF) barrier. Methods: The interaction of GBS CC17 or non-CC17 strains with choroid plexus cells was studied using an in vivo mouse model of meningitis and in vitro models of primary and transformed rodent choroid plexus epithelial cells (CPEC and Z310). In vivo interaction of GBS with the choroid plexus was assessed by microscopy. Bacterial invasion and cell barrier penetration were examined in vitro, as well as chemokines and cytokines in response to infection. Results: GBS CC17 was found associated with the choroid plexus of the lateral, 3rd and 4th ventricles. Infection of choroid plexus epithelial cells revealed an efficient internalization of the bacteria into the cells with GBS CC17 displaying a greater ability to invade these cells than a non-CC17 strain. Internalization of the GBS CC17 strain involved the CC17-specific HvgA adhesin and occurred via a clathrin-dependent mechanism leading to transcellular transcytosis across the choroid plexus epithelial monolayer. CPEC infection resulted in the secretion of several chemokines, including CCL2, CCL3, CCL20, CX3CL1, and the matrix metalloproteinase MMP3, as well as immune cell infiltration. Conclusion: Our findings reveal a GBS strain-specific ability to infect the blood-CSF barrier, which appears to be an important site of bacterial entry and an active site of immune cell trafficking in response to infection. [ABSTRACT FROM AUTHOR]