Triptolide attenuates pulmonary fibrosis by inhibiting fibrotic extracellular matrix remodeling mediated by MMPs/LOX/integrin.

BACKGROUND: Fibrotic extracellular matrix (ECM) remodeling characterized different types of pulmonary fibrosis, and its regulation could be a potential shared treatment strategy for pulmonary fibrosis. PURPOSE: We aimed to investigate the effect of triptolide on pulmonary fibrosis through the inhibition of several important aspects of fibrotic ECM remodeling. METHODS: Bleomycin-induced pulmonary fibrosis mice and TGF-ß1-induced primary lung fibroblasts were used. The effect of triptolide on pulmonary fibrosis was detected using histopathology, immunostaining, RT-qPCR, western blotting, ELISA, and protein activity assay. RESULTS: Triptolide significantly alleviated bleomycin-induced pulmonary fibrosis in mice. It inhibited the expression of fibrotic genes α-SMA, collagen I, fibronectin, and vimentin and blocked the TGF-ß-SMAD signaling pathway both in vivo and in vitro. In addition, triptolide regulated the expression and activity of MMPs during fibrosis. Interestingly, it suppressed the expression of lysyl oxidase, which was responsible for matrix cross-linking and elevated ECM stiffness. Furthermore, triptolide blocked the biomechanical stress transduction pathway integrin-ß1-FAK-YAP signaling and attenuated the pro-fibrotic feedback of fibrotic ECM on fibroblasts via integrin inhibition. CONCLUSION: These findings show that triptolide prevents the key linkages of fibrotic ECM remodeling, including deposition, degradation, cross-linking, and pro-fibrotic feedback and, therefore, has potential therapeutic value for pulmonary fibrosis.

Metalloproteinases and their inhibitors in neurological disease.

Matrix metalloproteinases (MMPs) are a group of endopeptidases that degrade the extracellular matrix and are responsible for many physiological and pathological processes. We aim to review the MMP inhibition from a clinical perspective and its possible therapeutic use in the future. MMPs play a role in various neurodegenerative and cerebrovascular diseases such as large artery atherosclerosis and ischemic stroke; for example, MMPs increase blood-brain barrier permeability favoring neuroinflammation. Synthetic MMPs inhibitors have been tested mostly in oncological trials and failed to demonstrate efficacy; some of them were discontinued because of the severe adverse reactions. Tetracyclines, in submicrobial doses, act as an MMP inhibitor, although tetracyclines have not yet been proven effective in several neurological conditions in which they were tested against placebo; it is uncertain whether there may be a use for tetracyclines in cerebrovascular disease, as a neuroprotective agent or in dolichoectasia.

Cannabidiol Decreases Metalloproteinase Activity and Normalizes Angiogenesis Factor Expression in UVB-Irradiated Keratinocytes from Psoriatic Patients.

The development of psoriasis is associated with the consequences of oxidative stress and inflammation leading to metabolic changes locally, in the skin cells, and systemically, in the blood. Therefore, the aim of this study was to analyze the effect of psoriasis vulgaris (PsV) and psoriatic arthritis (PsA) on the basal plasma/keratinocyte levels of matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), and angiogenesis factors, as well as to evaluate the effect of CBD on these parameters in keratinocytes isolated from psoriatic/healthy individuals with and without in vitro irradiation by UVB. A quantitative chemiluminescent method of detection based on an ELISA protocol and zymography technique was used during analysis. It was shown that activity levels of MMP-9 and TIMP-2 in PsA plasma were higher than in PsV. Changes in the proteolytic activity were accompanied by an increase in markers of angiogenesis (angiopoietin-2, HGF, VEGF, TNFα, PDGF, FGF), where in the specific case of angiopoietin-2 and TNFα, the overexpression in PsV was significantly stronger than in PsA. CBD application to keratinocytes partially restored levels of MMP-1/2/3/7 and TIMP-1/2 (in an effect which was particularly enhanced by UVB irradiation), as well as levels of the examined angiogenic factors except TNFα (levels of which were increased in psoriatic keratinocytes and decreased in healthy keratinocytes). Presented results indicate that CBD may be suggested as an antiangiogenic factor that reduces the proinflammatory action of UVB in psoriatic keratinocytes and partially has a protective effect for healthy keratinocytes.

Avenanthramide C as a novel candidate to alleviate osteoarthritic pathogenesis.

Osteoarthritis (OA) is a degenerative disorder that can result in the loss of articular cartilage. No effective treatment against OA is currently available. Thus, interest in natural health products to relieve OA symptoms is increasing. However, their qualities such as efficacy, toxicity, and mechanism are poorly understood. In this study, we determined the efficacy of avenanthramide (Avn)-C extracted from oats as a promising candidate to prevent OA progression and its mechanism of action to prevent the expression of matrix-metalloproteinases (MMPs) in OA pathogenesis. Interleukin-1 beta (IL-1ß), a proinflammatory cytokine as a main causing factor of cartilage destruction, was used to induce OAlike condition of chondrocytes in vitro. Avn-C restrained IL-1ß- mediated expression and activity of MMPs, such as MMP-3, -12, and -13 in mouse articular chondrocytes. Moreover, Avn-C alleviated cartilage destruction in experimental OA mouse model induced by destabilization of the medial meniscus (DMM) surgery. However, Avn-C did not affect the expression of inflammatory mediators (Ptgs2 and Nos) or anabolic factors (Col2a1, Aggrecan, and Sox9), although expression levels of these genes were upregulated or downregulated by IL-1ß, respectively. The inhibition of MMP expression by Avn-C in articular chondrocytes was mediated by p38 kinase and c-Jun N-terminal kinase (JNK) signaling, but not by ERK or NF-κB. Interestingly, Avn-C added with SB203580 and SP600125 as specific inhibitors of p38 kinase and JNK, respectively, enhanced its inhibitory effect on the expression of MMPs in IL-1ß treated chondrocytes. Taken together, these results suggest that Avn-C is an effective candidate to prevent OA progression and a natural health product to relieve OA pathogenesis. [BMB Reports 2021; 54(10): 528-533].

Danhong injection enhances the therapeutic effect of mannitol on hemispheric ischemic stroke by ameliorating blood-brain barrier disruption.

Mannitol, a representative of hyperosmolar therapy, is indispensable for the treatment of malignant cerebral infarction, but its therapeutic effect is limited by its exacerbation of blood-brain barrier (BBB) disruption. This study was to explore whether Danhong injection (DHI), a standardized product extracted from Salvia miltiorrhiza Bunge and Carthamus tinctorius L., inhibits the destructive effect of mannitol on BBB and thus enhancing the treatment of hemispheric ischemic stroke. SD rats were subjected to pMCAO followed by intravenous bolus injections of mannitol with/without DHI intervention. Neurological deficit score, brain edema, infarct volume at 24 h after MCAO and histopathology, microvascular ultrastructure, immunohistochemistry and immunofluorescence staining of endothelial cell junctions, energy metabolism in the ischemic penumbra were assessed. Intravenous mannitol after MCAO resulted in a decrease in 24 h mortality and cerebral edema, whereas no significant benefit on neurological deficits, infarct volume and microvascular ultrastructure. Moreover, mannitol led to the loss of endothelial integrity, manifested by the decreased expression of occludin, junctional adhesion molecule-1 (JAM-1) and zonula occluden-1 (ZO-1) and the discontinuity of occludin staining around the periphery of endothelial cells. Meanwhile, after mannitol treatment, energy-dependent vimentin and F-actin, ATP content, and ATP5D expression were down-regulated, while MMP2 and MMP9 expression increased in the ischemic penumbra. All the insults after mannitol treatment were attenuated by addition of intravenous DHI. The results suggest DHI as a potential remedy to attenuate mannitol-related BBB disruption, and the potential of DHI to upregulate energy metabolism and inhibit the activity of MMPs is likely attributable to its effects observed.

Selective toxicity of antibacterial agents-still a valid concept or do we miss chances and ignore risks?

BACKGROUND: Selective toxicity antibacteribiotics is considered to be due to interactions with targets either being unique to bacteria or being characterized by a dichotomy between pro- and eukaryotic pathways with high affinities of agents to bacterial- rather than eukaryotic targets. However, the theory of selective toxicity oversimplifies the complex modes of action of antibiotics in pro- and eukaryotes. METHODS AND OBJECTIVE: This review summarizes data describing multiple modes of action of antibiotics in eukaryotes. RESULTS: Aminoglycosides, macrolides, oxazolidinones, chloramphenicol, clindamycin, tetracyclines, glycylcyclines, fluoroquinolones, rifampicin, bedaquillin, ß-lactams inhibited mitochondrial translation either due to binding to mitosomes, inhibition of mitochondrial RNA-polymerase-, topoisomerase 2ß-, ATP-synthesis, transporter activities. Oxazolidinones, tetracyclines, vancomycin, ß-lactams, bacitracin, isoniazid, nitroxoline inhibited matrix-metalloproteinases (MMP) due to chelation with zinc and calcium, whereas fluoroquinols fluoroquinolones and chloramphenicol chelated with these cations, too, but increased MMP activities. MMP-inhibition supported clinical efficacies of ß-lactams and daptomycin in skin-infections, and of macrolides, tetracyclines in respiratory-diseases. Chelation may have contributed to neuroprotection by ß-lactams and fluoroquinolones. Aminoglycosides, macrolides, chloramphenicol, oxazolidins oxazolidinones, tetracyclines caused read-through of premature stop codons. Several additional targets for antibiotics in human cells have been identified like interaction of fluoroquinolones with DNA damage repair in eukaryotes, or inhibition of mucin overproduction by oxazolidinones. CONCLUSION: The effects of antibiotics on eukaryotes are due to identical mechanisms as their antibacterial activities because of structural and functional homologies of pro- and eukaryotic targets, so that the effects of antibiotics on mammals are integral parts of their overall mechanisms of action.

Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis.

Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial-mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment, the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose-dependent or time-dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function through the downregulation of MMPs and EMT in NSCLC metastasis.

Challenges with matrix metalloproteinase inhibition and future drug discovery avenues.

INTRODUCTION: Matrix metalloproteinases have been in the scope of pharmaceutical drug discovery for decades as promising targets for drug development. Until present, no modulator of the enzyme class survived clinical trials, all failing for various reasons. Nevertheless, the target family did not lose its attractiveness and there is ever more evidence that MMP modulators are likely to overcome the hurdles and result in successful clinical therapies. AREAS COVERED: This review provides an overview of past efforts that were taken in the development of MMP inhibitors and insight into promising strategies that might enable drug discovery in the field in the future. Small molecule inhibitors as well as biomolecules are reviewed. EXPERT OPINION: Despite the lack of successful clinical trials in the past, there is ongoing research in the field of MMP modulation, proving the target class has not lost its appeal to pharmaceutical research. With ever-growing insights from different scientific fields that shed light on previously unknown correlations, it is now time to use synergies deriving from biological knowledge, chemical structure generation, and clinical application to reach the ultimate goal of bringing MMP derived drugs on a broad front for the benefit of patients into therapeutic use.

Sulforaphane suppresses polyinosinic­polycytidylic acid­stimulated release of cytokines, chemokines and MMPs by human corneal fibroblasts.

Viral corneal infection is a common cause of visual impairment and blindness. Polyinosinic­polycytidylic acid, or poly(I:C), is similar to viral double­stranded RNA in structure and has been implicated in the release of a variety of cytokines, chemokines and matrix metalloproteinases (MMPs) by corneal fibroblasts. Sulforaphane (SFN) is an isothiocyanate compound found in cruciferous vegetables. The present study investigated the potential effect of SFN on the poly(I:C)­stimulated release of cytokines, chemokines and MMPs in human corneal fibroblasts (HCFs). ELISA showed that SFN was associated with a time­ and dose­dependent reduction in poly(I:C)­stimulated production of interleukin (IL)­8, chemoattractant protein­1, IL­6, MMP­1 and MMP­3 by HCFs. Western blot analysis indicated that SFN suppressed the function of poly(I:C) by modulating mitogen­activated protein kinases (MAPKs), including p38 and extracellular signal­regulated kinase (ERK), activator protein­1 (AP­1) component c­Jun and the kinase, Akt, and the phosphorylation and degradation of the nuclear factor (NF)­κB inhibitor IκB­α. Immunofluorescence analysis revealed that SFN attenuated the production of poly(I:C)­induced nuclear translocation of the NF­κB p65 subunit. Reverse transcription­quantitative PCR analysis revealed that SFN prevented the poly(I:C)­induced upregulation of Toll­like receptor 3 (TLR3) mRNA expression in HCFs. No significant cytotoxic effect of SFN on HCFs was observed. In summary, SFN attenuated the poly(I:C)­induced production of proinflammatory chemokines, cytokines and MMPs by HCFs, by inhibiting TLR3, MAPK (p38 and ERK), AP­1, Akt and NF­κB signaling. SFN may therefore be a potential novel treatment for viral corneal infection by limiting immune cell infiltration.

Dieckol, an algae-derived phenolic compound, suppresses airborne particulate matter-induced skin aging by inhibiting the expressions of pro-inflammatory cytokines and matrix metalloproteinases through regulating NF-κB, AP-1, and MAPKs signaling pathways.

Exposure to particulate matter causes skin aging. In the present study, we investigated the effect of an algae-derived phenolic compound, dieckol (DK), against Chinese particulate matter (CPM)-stimulated aging in vitro in human dermal fibroblasts (HDF cells) and in vivo in zebrafish. DK effectively protected HDF cells against CPM-induced oxidative stress by scavenging intracellular reactive oxygen species. Moreover, DK significantly improved collagen synthesis and inhibited intracellular collagenase activity in CPM-stimulated HDF cells. In addition, DK remarkably reduced the expression of pro-inflammatory cytokines and matrix metalloproteinases via regulating the nuclear factor kappa B, activator protein 1, and mitogen-activated protein kinases signaling pathways in CPM-stimulated HDF cells. Furthermore, the in vivo test results demonstrated that DK effectively improved the survival rate of CPM-stimulated zebrafish via suppressing oxidative stress and inflammatory response. In conclusion, this study suggests that DK is a potential anti-aging compound that can be used as a therapeutic agent to improve CPM-induced skin aging, or as an ingredient to develop a cosmetic or medicine in the cosmeceutical and pharmaceutical industries.

The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier.

As researchers across the globe have focused their attention on understanding SARS-CoV-2, the picture that is emerging is that of a virus that has serious effects on the vasculature in multiple organ systems including the cerebral vasculature. Observed effects on the central nervous system include neurological symptoms (headache, nausea, dizziness), fatal microclot formation and in rare cases encephalitis. However, our understanding of how the virus causes these mild to severe neurological symptoms and how the cerebral vasculature is impacted remains unclear. Thus, the results presented in this report explored whether deleterious outcomes from the SARS-CoV-2 viral spike protein on primary human brain microvascular endothelial cells (hBMVECs) could be observed. The spike protein, which plays a key role in receptor recognition, is formed by the S1 subunit containing a receptor binding domain (RBD) and the S2 subunit. First, using postmortem brain tissue, we show that the angiotensin converting enzyme 2 or ACE2 (a known binding target for the SARS-CoV-2 spike protein), is ubiquitously expressed throughout various vessel calibers in the frontal cortex. Moreover, ACE2 expression was upregulated in cases of hypertension and dementia. ACE2 was also detectable in primary hBMVECs maintained under cell culture conditions. Analysis of cell viability revealed that neither the S1, S2 or a truncated form of the S1 containing only the RBD had minimal effects on hBMVEC viability within a 48 h exposure window. Introduction of spike proteins to invitro models of the blood-brain barrier (BBB) showed significant changes to barrier properties. Key to our findings is the demonstration that S1 promotes loss of barrier integrity in an advanced 3D microfluidic model of the human BBB, a platform that more closely resembles the physiological conditions at this CNS interface. Evidence provided suggests that the SARS-CoV-2 spike proteins trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function. Together, these results are the first to show the direct impact that the SARS-CoV-2 spike protein could have on brain endothelial cells; thereby offering a plausible explanation for the neurological consequences seen in COVID-19 patients.

A Network Pharmacology Analysis of the Active Components of the Traditional Chinese Medicine Zuojinwan in Patients with Gastric Cancer.

BACKGROUND Zuojinwan (ZJW) is a traditional Chinese prescription normally used for gastritis. Several studies indicated that it could fight against gastric cancer. This study was designed to determine the potential pharmacological mechanism of ZJW in the treatment of gastric cancer. MATERIAL AND METHODS Bioactive compounds and potential targets of ZJW and related genes of gastric cancer were retrieved from public databases. Pharmacological mechanisms including crucial ingredients, potential targets, and signaling pathways were determined using protein-protein interaction (PPI) and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Virtual docking was performed to validate the findings. RESULTS Network analysis identified 47 active ZJW compounds, and 48 potential ZJW target genes linked to gastric cancer. Quercetin, beta-sitosterol, isorhamnetin, wogonin, and baicalein were identified as potential candidate agents. Our PPI analysis results combined with previously published results indicated that matrix metalloproteinases family members MMP9, MMP1, and MMP3 may play key roles in the anti-gastric cancer effect of ZJW. Molecular docking analysis showed that these crucial targets had good affinity for the representative components in ZJW. GO and KEGG enrichment analysis showed that ZJW target genes functioned in multiple pathways for treating gastric cancer, including interleukin-17 signaling and platinum drug resistance. CONCLUSIONS Our results illuminate the active ingredients, associated targets, biological processes, and signaling pathways of ZJW in the treatment of gastric cancer. This study enhances our understanding of the potential effects of ZJW in gastric cancer and demonstrates a feasible method for discovering potential drugs from Chinese medicinal formulas.

Modulation of the acute defence reaction by eplerenone prevents cardiac disease progression in viral myocarditis.

AIMS: Left ventricular (LV) dysfunction in viral myocarditis is attributed to myocardial inflammation and fibrosis, inducing acute and long-time cardiac damage. Interventions are not established. On the basis of the link between inflammation, fibrosis, aldosterone, and extracellular matrix regulation, we aimed to investigate the effect of an early intervention with the mineralocorticoid receptor antagonist (MRA) eplerenone on cardiac remodelling in a murine model of persistent coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS: SWR/J mice were infected with 5 × 104 plaque-forming units of CVB3 (Nancy strain) and daily treated either with eplerenone (200 mg/kg body weight) or with placebo starting from Day 1. At Day 8 or 28 post infection, mice were haemodynamically characterized and subsequently sacrificed for immunohistological and molecular biology analyses. Eplerenone did not influence CVB3 load. Already at Day 8, 1.8-fold (P < 0.05), 1.4-fold (P < 0.05), 3.2-fold (P < 0.01), and 2.1-fold (P < 0.001) reduction in LV intercellular adhesion molecule 1 expression, presence of monocytes/macrophages, oxidative stress, and apoptosis, respectively, was observed in eplerenone-treated vs. untreated CVB3-infected mice. In vitro, eplerenone led to 1.4-fold (P < 0.01) and 1.2-fold (P < 0.01) less CVB3-induced cardiomyocyte oxidative stress and apoptosis. Furthermore, collagen production was 1.1-fold (P < 0.05) decreased in cardiac fibroblasts cultured with medium of eplerenone-treated vs. untreated CVB3-infected HL-1 cardiomyocytes. These ameliorations were in vivo translated into prevention of cardiac fibrosis, as shown by 1.4-fold (P < 0.01) and 2.1-fold (P < 0.001) lower collagen content in the LV of eplerenone-treated vs. untreated CVB3-infected mice at Days 8 and 28, respectively. This resulted in an early and long-lasting improvement of LV dimension and function, as indicated by reduced LV end-systolic volume and end-diastolic volume, and an increase in LV contractility (dP/dtmax ) and LV relaxation (dP/dtmin ), respectively (P < 0.05). CONCLUSIONS: Early intervention with the MRA eplerenone modulates the acute host and defence reaction and prevents cardiac disease progression in experimental CVB3-induced myocarditis without aggravation of viral load. The findings advocate for an initiation of therapy of viral myocarditis as early as possible, even before the onset of inflammation-induced myocardial dysfunction. This may also have implications for coronavirus disease-19 therapy.

Effect of Chitosan as a Cross-Linker on Matrix Metalloproteinase Activity and Bond Stability with Different Adhesive Systems.

The aim of the present study was to evaluate the effect of 0.1% chitosan (Ch) solution as an additional primer on the mechanical durability and enzymatic activity on dentine using an etch-and-rinse (E&R) adhesive and a universal self-etch (SE) adhesive. Microtensile bond strength and interfacial nanoleakage expression of the bonded interfaces for all adhesives (with or without pretreatment with 0.1% Ch solution for 1 min and air-dried for 5 seconds) were analyzed immediately and after 10,000 thermocycles. Zymograms of protein extracts from human dentine powder incubated with Optibond FL and Scotchbond Universal on untreated or Ch-treated dentine were obtained to examine dentine matrix metalloproteinase (MMP) activities. The use of 0.1% Ch solution as an additional primer in conjunction with the E&R or SE adhesive did not appear to have influenced the immediate bond strength (T0) or bond strength after thermocycling (T1). Zymography showed a reduction in MMP activities only for mineralized and demineralized dentine powder after the application of Ch. Application of 0.1% Ch solution does not increase the longevity of resin-dentine bonds. Nonetheless, the procedure appears to be proficient in reducing dentine MMP activities within groups without adhesive treatments. Further studies are required to comprehend the cross-linking of Ch with dentine collagen.

Matrix Metalloproteinases as New Targets in Alzheimer's Disease: Opportunities and Challenges.

Although matrix metalloproteinases (MMPs) are implicated in the regulation of numerous physiological processes, evidence of their pathological roles have also been obtained in the last decades, making MMPs attractive therapeutic targets for several diseases. Recent discoveries of their involvement in central nervous system (CNS) disorders, and in particular in Alzheimer's disease (AD), have paved the way to consider MMP modulators as promising therapeutic strategies. Over the past few decades, diverse approaches have been undertaken in the design of therapeutic agents targeting MMPs for various purposes, leading, more recently, to encouraging developments. In this article, we will present recent examples of inhibitors ranging from small molecules and peptidomimetics to biologics. We will also discuss the scientific knowledge that has led to the development of emerging tools and techniques to overcome the challenges of selective MMP inhibition.

Matrix Metalloproteinases and Glaucoma Treatment.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from in vivo and in vitro studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect.

Inhibition of matrix metalloproteinase expression and cellular invasion by NF-κB inhibitors of microbial origin.

Matrix metalloproteinases (MMPs) are zinc-dependent extracellular matrix remodeling endopeptidases. MMPs cleave various matrix proteins such as collagen, elastin, gelatin and casein. MMPs are often implicated in pathological processes, such as cancer progression including metastasis. Meanwhile, microorganisms produce various secondary metabolites having unique structures. We designed and synthesized dehydroxymethylepoxyquinomicin (DHMEQ) based on the structure of epoxyquinomicin C derived from Amycolatopsis as an inhibitor of NF-κB. This compound inhibited cancer cell migration and invasion. Since DHMEQ is comparatively unstable in the body, we designed and synthesized a stable DHMEQ analog, SEMBL. SEMBL also inhibited cancer cell migration and invasion. We also looked for inhibitors of cancer cell migration and invasion from microbial culture filtrates. As a result, we isolated a known compound, ketomycin, from Actinomycetes. DHMEQ, SEMBL, and ketomycin are all NF-κB inhibitors, and inhibited the expression of MMPs in the inhibition of cellular migration and invasion. These are all compounds with comparatively low toxicity, and may be useful for the development of anti-metastasis agents.

Antimetastatic Properties of Tea Polyphenols.

Metastasis of cells from primary site to distant organs involves a series of sequential steps, and molecules responsible for all these events are understandably considered as potential targets for metastasis management. Tea polyphenols, the secondary metabolites of the tea leaf Camellia sinensis, are increasingly being studied for their antimetastatic properties. In this article, effects of green tea polyphenols (GTP) and black tea polyphenols (BTP) on the molecules and events involved in metastasis are discussed in detail. As tea is a very popular beverage, tea polyphenols are expected to be potential chemopreventive agents that can be taken with normal diet and can be nontoxic due to their natural origin. However, individual variations in metabolic pathways, bioavailability, dose, and toxicity are some important factors that can modify the effectiveness of tea polyphenols within the human system.

Neuroprotective effects of N-acetylcysteine via inhibition of matrix metalloproteinase in a mouse model of transient global cerebral ischemia.

N-acetylcysteine (NAC) is known to serve many biological functions including acting as an antioxidant, and electing antiinflammatory effects. Previous reports have revealed that NAC may have neuroprotective effects against the deleterious effects of brain ischemia. Despite of this, the mechanism by which NAC prevents neuronal damage after brain ischemia remains unclear. The current study aimed to investigate this mechanism in a mouse model of transient global brain ischemia. In the present study, mice were subjected to 20 min of transient global brain ischemia, proceeded by intraperitoneal administration of NAC (150 mg/kg) in one group. The mice were then euthanized 72 h after this ischemic insult for collection of experimental tissues. The effect of NAC on neuronal damage and matrix metalloproteinase (MMP)-9 activity were assessed and immunofluorescence, and hippocampal terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay experiments were conducted and results compared between NAC- and vehicle-treated groups. Neuronal damage was primarily observed in the hippocampal CA1 and CA2 regions. In NAC-treated mice, neuronal damage was significantly reduced after ischemia when compared to vehicle-treated animals. NAC also inhibited increased MMP-9 activity after global brain ischemia. NAC increased laminin and NeuN expression and inhibited increases in TUNEL-positive cells, all in the hippocampus. These results suggest that NAC reduces hippocampal neuronal damage following transient global ischemia, potentially via reductions in MMP-9 activity.

Methotrexate an Old Drug with New Tricks.

Methotrexate (MTX) is the first line drug for the treatment of a number of rheumatic and non-rheumatic disorders. It is currently used as an anchor disease, modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA). Despite the development of numerous new targeted therapies, MTX remains the backbone of RA therapy due to its potent efficacy and tolerability. There has been also a growing interest in the use of MTX in the treatment of chronic viral mediated arthritis. Many viruses-including old world alphaviruses, Parvovirus B19, hepatitis B/C virus, and human immunodeficiency virus-have been associated with arthritogenic diseases and reminiscent of RA. MTX may provide benefits although with the potential risk of attenuating patients' immune surveillance capacities. In this review, we describe the emerging mechanisms of action of MTX as an anti-inflammatory drug and complementing its well-established immunomodulatory activity. The mechanisms involve adenosine signaling modulation, alteration of cytokine networks, generation of reactive oxygen species and HMGB1 alarmin suppression. We also provide a comprehensive understanding of the mechanisms of MTX toxic effects. Lastly, we discussed the efficacy, as well as the safety, of MTX used in the management of viral-related rheumatic syndromes.