Inhibit Matrix Metalloproteinases Research Articles

Retinol and Hydroxyasiaticoside Synergistically Relieve Histamine-Induced Atopic Dermatitis Activity by Repressing TRPV1, L1R1, and CD130 Targets

Background: Retinol, an important bioactive substance with multiple physiological functions such as promoting collagen synthesis, inhibiting matrix metalloproteinase activity, alleviating oxidative stress, regulating gene expression, and promoting epidermal cell proliferation, has a significant effect on skin damage recovery. Hydroxyasiaticoside, a triterpenoid saponin derived from Centella asiatica (L.) Urb., is closely related to the secretion of collagen types I and III, and possesses multiple biological activities, including moisturizing, antioxidants, anti-apoptosis, neuroprotection, anti-inflammation, and the promotion of wound healing. It plays a particularly prominent role in reducing oxidative stress in wounds and inducing vasodilatation. Objective: The aim of this study was to investigate the therapeutic efficacy of retinol combined with hydroxyasiaticoside in histamine-induced atopic dermatitis. Materials and Methods: The experiment was carried out using three different concentrations of a retinol and hydroxyasiaticoside mixed solution: low, medium, and high concentrations. After inducing atopic dermatitis in mice through histamine administration, these solutions were applied to the skin surface of the mice, and a comparative analysis was conducted with both the control group and the model group. The effect of combination therapy on atopic dermatitis was evaluated through histopathology, immunohistochemistry, and transcriptomic analysis. Results: The combination of retinol and hydroxyasiaticoside significantly attenuated histamine-induced scratching behaviors, alleviated the phenomenon of epidermal hyperplasia, and effectively reduced the proliferation, infiltration, and degranulation of mast cells. In addition, the combination inhibited the expression of relevant pro-inflammatory cytokines. Quantitative RNA-seq analysis revealed that the gene expression patterns were similar in different concentration groups. However, the medium dose group may be able to regulate skin inflammation by regulating upstream genes to inhibit autophagy-related pathways. Further GO analysis revealed that the low-dose group mainly affected metabolism-related genes, the medium-dose group affected more genes related to body systems, and the high-dose group was dominated by genes related to human diseases.

The Mechanism and Inflammatory Markers Involved in the Potential Use of N-acetylcysteine in Chronic Pain Management.

N-acetylcysteine (NAC) has established use as an antidote for acetaminophen overdose and treatment for pulmonary conditions and nephropathy. It plays a role in regulating oxidative stress and interacting with various cytokines including IL-1β, TNFα, IL-8, IL-6, IL-10, and NF-κB p65. The overexpression of reactive oxygen species (ROS) is believed to contribute to chronic pain states by inducing inflammation and accelerating disease progression, favoring pain persistence in neuropathic and musculoskeletal pain conditions. Through a comprehensive review, we aim to explore the mechanisms and inflammatory pathways through which NAC may manage neuropathic and musculoskeletal pain. Evidence suggests NAC can attenuate neuropathic and musculoskeletal pain through mechanisms such as inhibiting matrix metalloproteinases (MMPs), reducing reactive oxygen species (ROS), and enhancing glutamate transport. Additionally, NAC may synergize with opioids and other pain medications, potentially reducing opioid consumption and enhancing overall pain management. Further research is needed to fully elucidate its therapeutic potential and optimize its use in pain management. As an adjuvant therapy, NAC shows potential for chronic pain management, offering significant benefits for public health.

Simple theranostics nanoagent for precision suppression of tumor growth and metastasis: A traditional fermented product having a novel functional breakthrough

Biomass-based nanoagents constitute a focal point in the clinical development of tumor nanotheranostics, characterized by their high biocompatibility, biodegradability, controllability, and sustainability. However, achieving satisfactory nanoagents with biological safety and high theranostic efficacy for clinical translation remains a significant challenge. Herein, based on the design concept of medicine food homology, we developed a simple, mass-produced theranostics nanoagent (HSAVMn@CM NA) using Shanxi aged vinegar (SAV) as the raw material, enabling second near-infrared fluorescence/photoacoustic (NIR-II FL/PA) imaging-guided photo/catalytic/chemodynamic synergistic tumor therapy. A novel strategy involving the hydrolysis of SAV (HSAV) via the hydrolysis-acidification method has been developed to enhance NIR-II FL imaging performance. The HSAVMn@CM NAs have improved tumor-targeted efficiency through biomimetic modification of tumor membranes. Guided by NIR-II FL/PA dual-modal imaging, the HSAVMn@CM NAs achieve targeted photothermal/photodynamic synergistic phototherapy. Notably, the employment of a single laser source for simultaneous photothermal/photodynamic therapy has led to an enhancement in the efficacy of phototherapy. Moreover, the HSAVMn@CM NAs effectively chelated Zn2+ ions within the tumor microenvironment, to inhibit matrix metalloproteinase 2/9 (MMP 2/9) activity, thereby synergistically suppressing primary tumor growth and metastasis. Taken together, this research provides a novel design strategy for biomass-based nanoagents with potential clinical translation in precise tumor theranostics.

Balancing Relief and Pain: Effects of COX-2 Inhibitor Valdecoxib

Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, was initially acclaimed for its gastrointestinal safety and effectiveness in managing chronic inflammatory conditions and pain. It reduced gastrointestinal complications compared to other anti-inflammatory drugs, benefiting patients with complex medication regimens. The injectable form, parecoxib, was seen as promising for acute post-surgery pain management. However, clinical trials in high-risk cardiovascular patients, particularly those undergoing coronary artery bypass grafting, revealed increased risks when using higher doses of parecoxib. These findings led to the re-evaluation of valdecoxib’s safety profile and its subsequent market withdrawal due to cardiovascular concerns and reports of serious skin reactions. Despite its withdrawal, valdecoxib has garnered interest for repurposing in other conditions. Its pharmacodynamic and pharmacokinetic properties suggest potential in qualifying palmitate-induced insulin resistance in type 2 diabetes and inhibiting matrix metalloproteinases for wound healing. Its efficacy against SARS-CoV-2 highlights drug repurposing strategies for health crises like COVID-19. Valdecoxib's established success in arthritis, dysmenorrhea, and postoperative pain, along with its potential in treating glaucoma, underscores the value of repurposing existing drugs for new therapeutic purposes. In conclusion, valdecoxib exemplifies the balance between drug safety, clinical utility, and innovative repurposing. The aim of this study is to fully harness drug potential in medical science through a concerted effort made by the scientific community, regulatory bodies, and industry stakeholders to navigate the technological and regulatory hurdles.

Fibulin-3 Regulates Tissue Inhibitor of Metalloproteinases 3 to Inhibit Senescence in Intervertebral Disc Nucleus Pulposus Cells

To investigate the effect of fibulin-3 on the senescence of intervertebral disc nucleus pulposus cells (NPCs) through the regulation of tissue inhibitor of metalloproteinases 3 (TIMP-3) expression and to elucidate the molecular mechanisms involved. 1). The nucleus pulposus tissues and imaging data of 37 patients who had undergone intervertebral disc surgery were collected. The degree of degeneration of the intervertebral discs were classified according to the Pfirrmann grading system. The senescence degree of NPCs was determined using senescence-associated β-galactosidase (SA-β-gal) staining. Fibulin-3 expression levels were determined using Western blot and ELISA. The relationship between fibulin-3 and disc degeneration and NPCs senescence was investigated. 2). Human intervertebral disc NPCs were cultured in vitro. The proliferation and senescence of NPC across continuous passage were observed via CCK-8 assay and SA-β-gal staining, respectively. Fibulin-3 expression levels and the expression of inflammatory cytokines and matrix metalloproteinases were assessed. Exogenous fibulin-3 was added to verify its effect on the proliferation and senescence of NPCs. 3). The effect of fibulin-3 on the apoptosis and proliferation of NPCs was verified through gene overexpression, which was used in combination with an apoptosis inhibitor for bidirectional verification. 4). Bioinformatics analysis was performed to explore the relationship between fibulin-3 and the TIMP family. Experiments overexpressing fibulin-3 and silencing the TIMP-3 gene were performed to verify their role in NPCs senescence. 1). The intervertebral disc degeneration samples from 37 patients were classified according to the Pfirrmann grading system. The higher the degeneration grade, the lower fibulin-3 expression. Spearman correlation analysis showed that the disc grade was negatively correlated with the NPC senescence grade (r=－0.87, P<0.001) and fibulin-3 expression (r=－0.79, P<0.001). 2). As the passage number of NPCs increased, fibulin-3 expression gradually decreased, cell proliferation ability weakened, and the expression of inflammatory cytokines and matrix metalloproteinases increased. After exogenous fibulin-3 was added, cell morphology and growth status were maintained, cell senescence was significantly inhibited, and the expression of inflammatory cytokines and matrix metalloproteinases was markedly reduced. 3). Gene overexpression experiments showed that fibulin-3 reduced NPC apoptosis and promoted cell proliferation, thereby inhibiting NPC senescence. 4). Bioinformatics analysis revealed a significant association between fibulin-3 and TIMP-3 of the TIMP family. Further experiments confirmed that overexpressing fibulin-3 enhanced TIMP-3 expression, while silencing the TIMP-3 gene significantly weakened the inhibitory effect of fibulin-3 on NPCs senescence. This indicates that, through regulating TIMP-3, fibulin-3 inhibits the activity of matrix metalloproteinases, affects the synthesis and degradation of the extracellular matrix, and ultimately inhibits NPCs senescence. This study demonstrates that fibulin-3 plays a crucial role in inhibiting the senescence of intervertebral disc NPCs by regulating TIMP-3. The specific mechanisms involved are as follows, fibulin-3 upregulates TIMP-3 expression, inhibits matrix metalloproteinase activity, and reduces extracellular matrix degradation, thereby promoting extracellular matrix synthesis. Additionally, fibulin-3 inhibits NPCs senescence by reducing apoptosis and promoting cell proliferation. Therefore, fibulin-3 and TIMP-3 have potential therapeutic significance in maintaining intervertebral disc health and delaying degeneration.

The Effect of Green Tea Extract on Pulmonary Inflammation in Nanoparticles-Exposed Mice.

Titanium dioxide nanoparticles (TiO2 NPs) are air pollutants that exacerbate chronic respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD) However, little is known about the mechanism underlying the antipollutant effects of green tea extract (GTE). This study evaluates the efficacy and mechanism of GTE on lung inflammation and fibrosis in mice exposed to TiO2 NPs. The TiO2 NPs model is induced by having mice inhale TiO2 NPs, while controls receive an equivalent volume of saline. Treatment with oral GTE is initiated after TiO2 NPs inhalation and is given once daily for 4 weeks. Airway resistance and pulmonary inflammation are increased in mice exposed to TiO2 NPs. GTE treatment reduces the airway inflammation and airway resistance, and attenuates the pathological changes including lung fibrosis compared to the mice exposed to TiO2 NPs. With GTE, there are no significant increases in cytokines and immunoglobulin E (IgE) in mice exposed to TiO2 NPs. GTE inhibits matrix metalloproteinases (MMPs) and apoptotic factors induced by TiO2 NPs exposure, and these protective effects of GTE are closely related to the mitogen-activated protein kinase (MAPK) signaling pathway. GTE modulates pulmonary inflammation in mice exposed to air pollutants, suggesting that GTE may be beneficial in respiratory diseases exacerbated by such pollutants.

Cobalt-phenolic nanoparticles-driven self-assembly of hyaluronic acid hydrogels providing a multifactorial approach for chronic wound management

Chronic wounds are persistent non-healing lesions whose complex management is due to the interplay of multiple factors promoting chronicity, such as oxidative stress, overexpressed enzyme activities impeding the tissue repair and bacterial contamination. Currently marketed chronic wound dressings are designed mainly to absorb wound exudate, and at most to release antimicrobial agents, usually ionic silver. However, an effective wound repair requires addressing the multifactorial nature of the wound in a holistic approach. This study explores the potential of metal phenolic network (MPN) nanoparticles (NPs), comprised of epigallocatechin gallate (EGCG) and cobalt, as active agents and structural elements in wound dressings. The MPN NPs were able to generate reactive oxygen species (ROS), disturb bacterial membrane, and inhibit the biofilm of both gram-positive Staphylococcus aureus and gram-negative Pseudomonas aeruginosa. Owing to the high interfacial activity of their phenolic shells, the NPs drove the self-assembly of thiolated hyaluronic acid (THA) hydrogels featuring injectability, self-healing, stimuli-responsive NPs delivery in wound microenvironment, and control over deleterious enzyme activities, oxidative stress and bacterial colonisation. Specifically, the hydrogels inhibited matrix metalloproteinases (MMPs) and myeloperoxidase (MPO) by 60 and 80 %, respectively, and achieved 4-log reduction of S. aureus and 2-log reduction of P. aeruginosa concentrations. Finally, the hydrogels were in-vivo validated in a mouse animal model, showing lack of toxicity and similar wound healing efficiency as an antibiotic-containing commercial product.

Effects of Minocycline as a Neuroprotective Agent for Stroke on Mmp-9 Levels, Functional Outcome, and Mortality

Highlights:1. As minocycline plays an important role in stroke microglia activation and iron chelation, it is important to further analyze its effects on stroke treatment.2. This meta-analysis revealed a significant effect of minocycline therapy, as evidenced by improved functional outcomes and inhibited matrix metalloproteinase-9 (MMP-9) activity. Abstract Stroke is the most common and devastating cerebrovascular disease. Many neuroprotective medications, such as scale and minocycline, have been developed to help the nervous system recover or regenerate after a stroke. However, it remains unclear whether minocycline provides a beneficial effect on stroke. We conducted this systematic review and meta-analysis to synthesize the effects of minocycline in stroke treatment. The systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO), with registration number CRD42023485168. The quality of the eligible studies was assessed using the Jadad scale. This systematic review included three ischemic stroke trials, seven intracerebral hemorrhage trials, and one study on acute stroke. There was a significant association between minocycline intervention and stroke severity according to the National Institute of Health Stroke Scale (NIHSS), with a pooled mean difference (MD) of -1.92, a 95% confidence interval (CI) of -3.39 to -0.45, and a value of p=0.01. In the subgroup of ischemic stroke, the modified Rankin Scale (mRS) was significantly lower in the minocycline treatment group compared to the control group (MD=-0.89, 95% CI=-1.54 to -0.25, p=0.007). Additionally, matrix metalloproteinase-9 (MMP-9) levels for the intracerebral hemorrhage subgroup were significantly lower in the minocycline treatment group compared to the control group (MD=-19.93, 95% CI=-36.9 to -2.96, p=0.02). The analysis revealed that minocycline intervention was not significantly associated with hematoma volume, mortality, or stroke recurrence. Our findings indicate that minocycline supplementation is a potential intervention strategy for treating ischemic stroke and intracerebral hemorrhage.

Peroxynitrite-Triggered Carbon Monoxide Donor Improves Ischemic Stroke Outcome by Inhibiting Neuronal Apoptosis and Ferroptosis.

Cerebral ischemia-reperfusion injury produces excessive reactive oxygen and nitrogen species, including superoxide, nitric oxide, and peroxynitrite (ONOO-). We recently developed a new ONOO--triggered metal-free carbon monoxide donor (PCOD585), exhibiting a notable neuroprotective outcome on the rat middle cerebral artery occlusion model and rendering an exciting intervention opportunity toward ischemia-induced brain injuries. However, its therapeutic mechanism still needs to be addressed. In the pharmacological study, we found PCOD585 inhibited neuronal Bcl2/Bax/caspase-3 apoptosis pathway in the peri-infarcted area of stroke by scavenging ONOO-. ONOO- scavenging further led to decreased Acyl-CoA synthetase long-chain family member 4 and increased glutathione peroxidase 4, to minimize lipoperoxidation. Additionally, the carbon monoxide release upon the ONOO- reaction with PCOD585 further inhibited the neuronal Iron-dependent ferroptosis associated with ischemia-reperfusion. Such a synergistic neuroprotective mechanism of PCOD585 yields as potent a neuroprotective effect as Edaravone. Additionally, PCOD585 penetrates the blood-brain barrier and reduces the degradation of zonula occludens-1 by inhibiting matrix metalloproteinase-9, thereby protecting the integrity of the blood-brain barrier. Our study provides a new perspective for developing multi-functional compounds to treat ischemic stroke.

Marine-derived antimicrobial peptide piscidin-1 triggers extrinsic and intrinsic apoptosis in oral squamous cell carcinoma through reactive oxygen species production and inhibits angiogenesis

Cancer of the head and neck encompasses a wide range of cancers, including oral and oropharyngeal cancers. Oral cancer is often diagnosed at advanced stages and has a dismal prognosis. Piscidin-1, a marine antimicrobial peptide (AMP) containing approximately 22 amino acids, also exhibits significant anticancer properties. We investigated the possible anti-oral cancer effects of piscidin-1 and clarified the mechanisms underlying these effects. We treated the oral squamous cell carcinoma cell lines OC2 and SCC4 with piscidin-1. Cell viability and the expression of different hallmark apoptotic molecules, including reactive oxygen species (ROS), were tested using the appropriate MTT assay, flow cytometry and western blotting assays, and human umbilical vein endothelial cell (HUVEC) wound healing, migration, and tube formation (angiogenesis) assays. Piscidin-1 increases cleaved caspase 3 levels to induce apoptosis. Piscidin-1 also increases ROS levels and intensifies oxidative stress in the endoplasmic reticulum and mitochondria, causing mitochondrial dysfunction. Additionally, it decreases the oxygen consumption rates and activity of mitochondrial complexes I–V. As expected, the antioxidants MitoTEMPOL and N-acetylcysteine reduce piscidin-1–induced ROS generation and intracellular calcium accumulation. Piscidin-1 also inhibits matrix metalloproteinase (MMP)-2/-9 expression in HUVECs, affecting migration and tube formation angiogenesis. We demonstrated that piscidin-1 can promote apoptosis via both intrinsic and extrinsic apoptotic pathways and findings indicate that piscidin-1 has anti-proliferative and anti-angiogenic properties in oral cancer treatment. Our study on piscidin-1 thus provides a basis for future translational anti-oral cancer drug research and a new theoretical approach for anti-oral cancer clinical research.

Inhibition of Metalloproteinases Extends Longevity and Function of In Vitro Human iPSC-Derived Skeletal Muscle.

In vitro culture longevity has long been a concern for disease modeling and drug testing when using contractable cells. The dynamic nature of certain cells, such as skeletal muscle, contributes to cell surface release, which limits the system's ability to conduct long-term studies. This study hypothesized that regulating the extracellular matrix (ECM) dynamics should be able to prolong cell attachment on a culture surface. Human induced pluripotent stem cell (iPSC)-derived skeletal muscle (SKM) culture was utilized to test this hypothesis due to its forceful contractions in mature muscle culture, which can cause cell detachment. By specifically inhibiting matrix metalloproteinases (MMPs) that work to digest components of the ECM, it was shown that the SKM culture remained adhered for longer periods of time, up to 80 days. Functional testing of myofibers indicated that cells treated with the MMP inhibitors, tempol, and doxycycline, displayed a significantly reduced fatigue index, although the fidelity was not affected, while those treated with the MMP inducer, PMA, indicated a premature detachment and increased fatigue index. The MMP-modulating activity by the inhibitors and inducer was further validated by gel zymography analysis, where the MMP inhibitor showed minimally active MMPs, while the inducer-treated cells indicated high MMP activity. These data support the hypotheses that regulating the ECM dynamics can help maximize in vitro myotube longevity. This proof-of-principle strategy would benefit the modeling of diseases that require a long time to develop and the evaluation of chronic effects of potential therapeutics.

Inhibition of MAGL attenuates Intervertebral Disc Degeneration by Delaying nucleus pulposus senescence through STING

Intervertebral disc degeneration (IVDD) stands as the primary cause of low back pain (LBP). A significant contributor to IVDD is nucleus pulposus cell (NPC) senescence. However, the precise mechanisms underlying NPC senescence remain unclear. Monoacylglycerol lipase (MAGL) serves as the primary enzyme responsible for the hydrolysis of 2-arachidonoylglycerol (2-AG), breaking down monoglycerides into glycerol and fatty acids. It plays a crucial role in various pathological processes, including pain, inflammation, and oxidative stress. In this study, we utilized a lipopolysaccharide (LPS)-induced NPC senescence model and a rat acupuncture-induced IVDD model to investigate the role of MAGL in IVDD both in vitro and in vivo. Initially, our results showed that MAGL expression was increased 2.41-fold and 1.52-fold within NP tissues from IVDD patients and rats induced with acupuncture, respectively. This increase in MAGL expression was accompanied by elevated expression of p16INK4α. Following this, it was noted that the suppression of MAGL resulted in a notable decrease in the quantity of SA-β-gal-positive cells and hindered the manifestation of p16INK4α and the inflammatory factor IL-1β in NPCs. MAGL inhibition promotes type II collagen (Col-2) expression and inhibits matrix metalloproteinase 13 (MMP13), thereby restoring the balance of extracellular matrix (ECM) metabolism both in vitro and in vivo. A significant role for STING has also been demonstrated in the regulation of NPC senescence by MAGL. The expression of the STING protein was reduced by 57% upon the inhibition of MAGL. STING activation can replicate the effects of MAGL and substantially increase LPS-induced inflammation while accelerating the senescence of NPCs. These results strongly indicate that the inhibition of MAGL can significantly suppress nucleus pulposus senescence via its interaction with STING, consequently restoring the balance of ECM metabolism. This insight provides new perspectives for potential treatments for IVDD.

Ginkgolide B can alleviate spinal cord glymphatic system dysfunction and provide neuroprotection in painful diabetic neuropathy rats by inhibiting matrix metalloproteinase-9

The glymphatic system plays a crucial role in maintaining optimal central nervous system (CNS) function by facilitating the removal of metabolic wastes. Aquaporin-4 (AQP4) protein, predominantly located on astrocyte end-feet, is a key pathway for metabolic waste excretion. β-Dystroglycan (β-DG) can anchor AQP4 protein to the end-feet membrane of astrocytes and can be cleaved by matrix metalloproteinase (MMP)-9 protein. Studies have demonstrated that hyperglycemia upregulates MMP-9 expression in the nervous system, leading to neuropathic pain. Ginkgolide B (GB) exerts an inhibitory effect on the MMP-9 protein. In this study, we investigated whether inhibition of MMP-9-mediated β-DG cleavage by GB is involved in the regulation of AQP4 polarity within the glymphatic system in painful diabetic neuropathy (PDN) and exerts neuroprotective effects. The PDN model was established by injecting streptozotocin (STZ). Functional changes in the glymphatic system were observed using magnetic resonance imaging (MRI). The paw withdrawal threshold (PWT) was measured to assess mechanical allodynia. The protein expressions of MMP-9, β-DG, and AQP4 were detected by Western blotting and immunofluorescence. Our findings revealed significant decreases in the efficiency of contrast agent clearance within the spinal glymphatic system of the rats, accompanied by decreased PWT, increased MMP-9 protein expression, decreased β-DG protein expression, and loss of AQP4 polarity. Notably, GB treatment demonstrated the capacity to ameliorate spinal cord glymphatic function by modulating AQP4 polarity through MMP-9 inhibition, offering a promising therapeutic avenue for PDN.

Exosome-like nanovesicles derived from Momordica charantia ameliorate delayed t-PA thrombolysis-induced hemorrhagic transformation by inhibiting the ONOO−/HMGB1/MMP-9 pathway

Hemorrhagic transformation (HT) and restrictive therapeutic time window are significant limitations of delayed t-PA (tissue-type plasminogen activator) thrombolytic therapy in ischemic stroke patients. Plant Momordica charantia-derived exosome-like nanovesicles (MC-ELNs) can protect the blood–brain barrier (BBB) and inhibit neuronal apoptosis in stroke rats by inhibiting matrix metalloproteinase 9(MMP-9) expression. This study explored the therapeutic function and underlying mechanisms of MC-ELNs in treating HT. In delayed t-PA-treated ischemia-reperfusion rats, MC-ELNs significantly reduced mortality, HT, and cell apoptosis; MC-ELNs improved neurological function and BBB's integrity. MC-ELNs reduced ONOO− and MMP-9 expression and inhibited the release of HMGB1 from intracellular to extracellular in vivo and in vitro. ONOO− donor SIN-1 directly induced extracellular secretion of HMGB1, MC-ELNs and FeTmPyP (ONOO− decomposition catalyst, PDC) significantly reduced the expression of HMGB1 and inhibited MMP-9 activation in vitro. These findings indicate that MC-ELNs could protect BBB integrity and improve t-PA-induced HT by inhibiting the ONOO−/HMGB1/MMP-9 pathway.

Dietary Isoeugenol Supplementation Attenuates Chronic UVB-Induced Skin Photoaging and Modulates Gut Microbiota in Mice.

Photoaging, the primary cause of skin aging damage, results from chronic ultraviolet (UV) exposure, leading to dryness and wrinkle formation. Nutritional intervention has emerged as a practical approach for preventing and addressing the effect of skin photoaging. The primary aromatic compound isolated from clove oil, isoeugenol (IE), has antibacterial, anti-inflammatory, and antioxidant qualities that work to effectively restrict skin cancer cell proliferation. This investigation delved into the advantages of IE in alleviating skin photoaging using UVB-irradiated skin fibroblasts and female SKH-1 hairless mouse models. IE alleviated UVB-induced photodamage in Hs68 dermal fibroblasts by inhibiting matrix metalloproteinase secretion and promoting extracellular matrix synthesis. In photoaged mice, dietary IE reduced wrinkles, relieved skin dryness, inhibited epidermal thickening, and prevented collagen loss. Additionally, the intestinal dysbiosis caused by prolonged UVB exposure was reduced with an IE intervention. The results of Spearman's analysis showed a strong correlation between skin photoaging and gut microbiota. Given the almost unavoidable UVB exposure in contemporary living, this research demonstrated the efficacy of dietary IE in reversing skin photoaging, presenting a promising approach to tackle concerns related to extrinsic skin aging.

Placenta-derived mesenchymal stem cells attenuate secondary brain injury after controlled cortical impact in rats by inhibiting matrix metalloproteinases

Placenta-derived mesenchymal stem cells attenuate secondary brain injury after controlled cortical impact in rats by inhibiting matrix metalloproteinases

TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization.

Blood-brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting MMP activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular hyperpermeability. Here, we investigate the ability of TIMP2 to ameliorate BBB disruption in TBI and the underlying molecular mechanisms. Both TIMP2 and AlaTIMP2, a TIMP2 mutant without MMP-inhibiting activity, attenuated neurological deficits and BBB leakage in TBI mice; they also inhibited junctional protein degradation and translocation to reduce paracellular permeability in human brain microvascular endothelial cells (ECs) exposed to hypoxic plus inflammatory insult. Mechanistic studies revealed that TIMP2 interacted with α3β1 integrin on ECs, inhibiting Src activation-dependent VE-cadherin phosphorylation, VE-cadherin/catenin complex destabilization, and subsequent VE-cadherin internalization. Notably, localization of VE-cadherin on the membrane was critical for TIMP2-mediated EC barrier integrity. Furthermore, TIMP2-mediated increased membrane localization of VE-cadherin enhanced the level of active Rac1, thereby inhibiting stress fiber formation. All together, our studies have identified an MMP-independent mechanism by which TIMP2 regulates EC barrier integrity after TBI. TIMP2 may be a therapeutic agent for TBI and other neurological disorders involving BBB breakdown.

Enhanced Bonding to Caries-Affected Dentin Using an Isocyanate-Based Primer

Dental caries is the most common oral disease and the most common cause of resin restorations. In minimally invasive dentistry, the principle behind cavity preparation is to remove external caries-infected dentin (CID) and preserve internal caries-affected dentin (CAD) and sound dentin (SD). The cavity floor is mainly composed of CAD, but the poor bonding performance of CAD has become a widespread concern. This study evaluated the performance of a new collagen-reactive monomer (ITCM) used as a primer to improve the bonding performance of CAD. The experimental specimens were grouped as follows: SD, CAD, and ITCM-pretreated CAD (CAD-ITCM). Dentin slices were obtained for attenuated total reflectance–Fourier transform infrared (ATR-FTIR) analysis. The bonded samples were subjected to microtensile bond strength analysis after 24 h of water storage or aging by thermocycling, and the bonding interface quality was evaluated by nanoleakage assessment, interfacial nanoindentation testing, and in situ zymography. Cytotoxicity experiments with ITCM were performed. ATR-FTIR showed that the isocyanate groups in ITCM can covalently bind and form hydrogen bonds with the collagen in CAD to mediate chemical bonding. ITCM pretreatment significantly improved the bond strength of CAD (P < 0.05), reduced interfacial nanoleakage, improved the sealing of the bonding interface, enhanced the homogeneity of the hybrid layer, and inhibited matrix metalloproteinase activity. In addition, ITCM presented acceptable biocompatibility for dental restorative application. Taken together, this study reported the application of ITCM to induce collagen-based chemical bonding in the CAD bonding system, which fills the gap in strategies to improve the bonding performance of CAD immediately and after aging and has important clinical application prospects.

CAR-T cells inhibit vascular smooth muscle phenotypic switching and reduce intimal hyperplasia in vein grafts

Abstract Background Intimal hyperplasia (IH) is a prevalent cause of vein graft stenosis after coronary artery bypass grafting (CABG) in the middle and long term. Vascular smooth muscle cell (VSMC) phenotypic switching from a contractile phenotype to a synthetic phenotype is a hallmark of this process, along with the degradation of extracellular matrix (ECM) and smooth muscle migration. Chimeric antigen receptor (CAR)-T cell therapy is a targeted cellular immunotherapy that uses genetically engineered T cells to specifically eliminate the antigen-bearing cells. There is a potential to apply CAR-T therapy to cardiovascular diseases. Purpose In this study, we aim to design a novel CAR-T cell therapy to eliminate synthetic vascular smooth muscle cells in intimal hyperplasia, inhibit phenotypic switching, in order to reduce vein graft stenosis. Methods and results Using bulk RNA-seq dataset from the GEO database, we have identified human organic cation transporter (OCT1) as a key marker for synthetic vascular smooth muscle cell in vein grafts (Fig.1A, B). We then engineered switchable fourth-generation CAR-T cells incorporating CD28 and CD3 ζ costimulatory domains (Fig.1C, E). In addition, these CAR-T cells secrete tissue inhibitor of metalloproteinase-3 (TIMP3), a protein that had been shown to inhibit matrix metalloproteinases (MMPs) activity and the ERK1/2 pathway (Fig. 1F). Targeting FITC instead of OCT1 itself allows a controllable and switchable working process for the CAR-T cells, as they only start to identify synthetic VSMCs in combination with a FITC-conjugated OCT1 antibody (Fig.1D). Immunostaining of PDGF-induced synthetic VSMCs co-cultured with CAR-T cells and FITC-conjugated OCT1 antibody revealed increased expression of contractile markers, and reduced expression of synthetic markers (Fig1.G), along with decreased mitochondrial membrane potentials, which could be reverted after pre-treatment with a pan caspase inhibitor (Fig.1H),. In vivo studies using mice vein graft model showed reduced intimal thickness, increased intimal/medial ratio in cross-sections, in addition to increased peak velocity and inner wall diameter on ultrasound after CAR-T cell therapy (Fig.2). Conclusion Switchable CAR-T cell therapy targeting synthetic vascular smooth muscle cells might be a promising approach to alleviate intimal hyperplasia in vein graft stenosis.

MicroRNA-93 promotes the pathogenesis of glaucoma by inhibiting matrix metalloproteinases as well as up-regulating extracellular matrix and Rho/ROCK signaling pathways

ObjectiveTo investigate the effect and potential molecular mechanism of microRNA-93 (miR-93) on retinal ganglion cells (RGCs) apoptosis as well as retinal damage in acute glaucoma mice. MethodsRGCs apoptosis were induced by oxygen-glucose deprivation and reperfusion (OGD/R). The pro-apoptotic effect of miR-93 was evaluated by transfecting miR-93 mimics or miR-93 inhibitor into OGD/R-induced RGCs. The viability and apoptosis of RGCs were determined by MTT assay and flow cytometry. Mouse model of acute glaucoma were successfully induced via high intraocular pressure (IOP), and then these model animals were randomly divided into vehicle group, miR-93 mimics group or miR-93 inhibitor group (n = 10), using healthy mice as normal control. Histopathologic changes of retinal tissue were evaluated by Hematoxylin and Eosin (H&E) staining method. Moreover, cell counts of retinal ganglion cell layer and mean thickness of different layers were also determined. Quantitative real-time PCR (qPCR) and western blotting analysis were used to detect the mRNA and protein expression levels of extracellular matrix (ECM), matrix metalloproteinases (MMPs) and Rho/ROCK signaling pathway. ResultsmiR-93 mimics significantly decreased or promoted the viability and apoptosis of OGD/R-induced RGCs, respectively. In addition, miR-93 mimics significantly exacerbated the degree of retinal tissue damage in mice with acute glaucoma, which was accompanied by a decrease in the number of ganglion cell layer (GCL) cells and the thickness of different tissue layers. Moreover, miR-93 mimics significantly increased IOP in mice with acute glaucoma. Significantly, miR-93 inhibitors significantly reversed the above changes. In addition, results of Western blot analysis showed that miR-93 mimics increased and decreased the expression of ECM-associated and MMP-associated proteins, respectively, by activating the Rho/ROCK signaling pathway. In contrast, miR-93 significantly decreased and increased the expression of ECM-associated and MMP-associated proteins, and suppressed the expression of Rho/ROCK signaling pathway-related proteins. ConclusionmiR-93 can promote the development of glaucoma by activating Rho/ROCK signaling pathway to mediate the accumulation of ECM-related proteins as well as the down-regulation of MMP-related proteins.