Tissue Barriers最新文献

Impairment of the blood - brain barrier (BBB) and subsequent inflammatory responses contribute to the development of human immunodeficiency virus (HIV)-1-associated neurocognitive disorders (HAND). Apelin-13, the most abundant member of the apelin family, acts as the ligand of the angiotensin receptor-like 1 (APJ). However, its pharmacological function in HAND and its underlying mechanism are unknown. In the current study, we report that the presence of HIV-1 Tat reduced the levels of Apelin-13 and APJ in the cortex tissue of mice. Importantly, Apelin-13 preserved BBB integrity against HIV-1 Tat in mice by increasing the expression of the tight junction protein zonula occludens-1 (ZO-1) and occludin. Interestingly, increased macrophage infiltration, indicated by elevated CD68-positive staining was observed in the cortex after stimulation with HIV-1, which was mitigated by the administration of Apelin-13. Correspondingly, Apelin-13 reduced the expression of monocyte chemoattractant protein-1; (MCP-1). An in vitro two-chamber and two-cell trans-well assay demonstrated that HIV-1 Tat challenge significantly promoted macrophage migration, which was notably attenuated by the introduction of Apelin-13. Accordingly, treatment with Apelin-13 restored the HIV-1 Tat-induced reduction of occludin and ZO-1, while preventing the upregulation of MCP-1 in human brain microvascular endothelial cells (HBMVECs). Our results suggest that Apelin-13 may reduce macrophage infiltration into brain tissues and mitigate BBB dysfunction in patients with HAND.

The contribution of Erk1/2 to endothelial barrier regulation is convoluted and differs depending on the vascular bed. We explored the effects of Erk1/2 inhibition on endothelial barrier maintenance and its relationship with cAMP-dependent barrier strengthening. Thus, myocardial endothelial cells (MyEnd) were isolated and protein expression, localization and activity of structural and signaling molecules involved in maintenance of endothelial function were investigated by Western blot, immunostainings and G-LISA, respectively. The transendothelial electrical resistance (TEER) from confluent MyEnd monolayers was measured and used as a direct indicator of barrier integrity in vitro. Miles assay was performed to evaluate vascular permeability in vivo. Erk1/2 inhibition with U0126 affected neither the structural organization of adherens or tight junctions nor the protein level of their components, However, TEER drop significantly upon U0126 application, but the effect was transitory as the barrier function recovered 30 min after treatment. Erk1/2 inhibition delayed cAMP-mediated barrier strengthening but did not prevent barrier fortification despite diminishing Rac1 activation. Moreover, Erk1/2 inhibition, induced vascular leakage that could be prevented by local cAMP elevation in vivo. Our data demonstrate that Erk1/2 is required to prevent vascular permeability but is not critical for cAMP-mediated barrier enhancement.

Ciliopathies are a group of diseases caused by defects in cilia, hair-like organelles that can have many functions ranging from regulating extracellular fluid flow to sensing mechanical or chemical stimuli. Multiciliated cells (MCCs) with motile cilia are found in locations that include the central nervous system, where they are critical for homeostasis. Specifically, ependymal MCCs line the brain ventricles and central canal of the spinal cord, while other specialized MCCs occupy highly vascularized structures known as the choroid plexuses (ChPs) and produce cerebrospinal fluid (CSF). Now, a recent study has shown that murine ChP MCCs develop nodal-like cilia. Interestingly, ChP cilia were found to undergo resorption during early postnatal stages in part through axoneme regression, and this phenomenon was mirrored in human postmortem ChP samples. Taken together, these findings reveal important new insights about the ultrastructure of MCCs that comprise the mammalian ChP, and may have ramifications for other MCC populations in health and disease states.

Background: Oncostatin M (OSM) may be involved in the promotion of mucosal epithelial barrier dysfunction in patients with eosinophilic chronic rhinosinusitis with nasal polyps (Eos CRSwNP) by inducing matrix metalloproteinase (MMP) -1 and -7. The aim was to evaluate the roles and mechanisms of action of OSM on MMP-1 and -7 synthesis from nasal epithelial cells (NECs).

Methods: OSM, OSM receptor (OSMR), MMP-1 and -7 expression was evaluated in nasal mucosa or primary NECs from scrapings by quantitative polymerase chain reaction (qPCR), immunofluorescence and immunohistochemistry. OSM and other cytokines were used to stimulate air-liquid interface (ALI) cultured NECs. qPCR, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence were used to evaluate the expression of OSMR, MMP-1, -7 and occludin in NECs.

Results: Elevated levels of OSMRβ, MMP-1 and -7 were found in the tissues and scraped NECs of Eos CRSwNP in comparison to them obtained from the inferior turbinate (IT) and control subjects. The levels of OSM and OSMRβ mRNA in tissues were positively correlated with the levels of MMP-1 and -7. OSM stimulation of NECs increased the expression of MMP-1 and -7, and the responses were suppressed by a STAT3 inhibitor, and a PI3K inhibitor respectively. In parallel studies, we found that stimulation with OSM disrupted the localization of occludin, a tight junction protein in NECs. The response was suppressed by a pan-MMP inhibitor.

Conclusion: OSM induces the synthesis and release of MMP-1 and -7 in NECs. Furthermore, MMP-1 and -7 promote mucosal epithelial barrier dysfunction in patients with Eos CRSwNP.

Crohn's disease (CD), a chronic gastrointestinal inflammatory disease, is becoming more widespread worldwide. Crohn's disease is caused by gut microbiota changes, genetics, environmental stresses, and immunological responses. Current treatments attempt to achieve long-term remission and avoid complications, delaying disease progression. Immunosuppressive measures and combination medicines should be started early for high-risk patients. These medicines monitor inflammatory indicators and adjust as needed. The epithelial barrier helps defend against physical, chemical, and immunological threats. When tissues' protective barrier breaks down, the microbiome may reach the layer underneath. Unbalanced microbial populations and inflammation impair healing and adjustment. Inflammatory cells infiltrating sensitive tissues aggravate the damage and inflammation. This approach promotes chronic inflammatory diseases. The epithelial barrier hypothesis states that hereditary and environmental variables cause epithelial tissue inflammation. This review focuses on how epithelial barrier break-down and microbial dysbiosis cause Crohn's disease and current advances in understanding the epithelial barrier, immune system, and microbiome. Additionally, investigate treatments that restore barrier integrity and promote microbial balance. Overall, it stresses the role of epithelial barrier failure and microbial dysbiosis in Crohn's disease development and discusses current advances in understanding the barrier, immunological responses, and microbiota.

Ulcerative colitis (UC) is a chronic and debilitating disorder that falls under the broad category of inflammatory bowel disease (IBD). Therefore, affects the colon and rectum, resulting in inflammation and ulcers in the lining of these organs. Over the years, there has been a significant shift in the management of UC. The focus has moved from achieving symptom-free daily living to attaining mucosal healing. Mucosal healing means completely restoring the colon and rectum's lining, significantly reducing the risk of complications and relapse. Macrophages are a crucial component of the immune system that play a vital role in the regeneration and repair of colonic ulcers. These immune cells are responsible for production of a variety of cytokines and growth factors that facilitate tissue repair. Macrophages are responsible for maintaining a balance between inflammation and healing. When this balance is disrupted, it can lead to chronic inflammation and tissue damage, exacerbating UC symptoms. Thus, this review aims to investigate the contribution of macrophages to mucosal repair and remission maintenance in UC patients.

Tight junctions (TJs) are an important component of cellular connectivity. Claudin family proteins, as a constituent of TJs, determine their barrier properties, cell polarity and paracellular permeability. Claudin-12 is an atypical member of the claudin family, as it belongs to the group of non-classical claudins that lack a PDZ-binding domain. It has been shown that claudin-12 is involved in paracellular Ca²⁺ transients and it is present in normal and hyperplastic tissues in addition to neoplastic tissues. Dysregulation of claudin-12 expression has been reported in various cancers, suggesting that this protein may play an important role in cancer cell migration, invasion, and metastasis. Some studies have shown that claudin-12 gene functions as a tumor suppressor, but others have reported that overexpression of claudin-12 significantly increases the metastatic properties of various tumor cells. Investigating this dual role of claudin-12 is of utmost importance and should therefore be studied in detail. The aim of this review is to provide an overview of the information available to date on claudin-12, including its structure, expression in various tissues and substances that may affect it, with a final focus on its role in cancer.

Diabetes Mellitus presents a formidable challenge as one of the most prevalent and complex chronic diseases, exerting significant strain on both patients and the world economy. It is recognized as a common comorbidity among severely ill individuals, often leading to a myriad of micro- and macro-vascular complications. Despite extensive research dissecting the pathophysiology and molecular mechanisms underlying vascular complications of diabetes, relatively little attention has been paid to potential lung-related complications. This review aims to illuminate the impact of diabetes on prevalent respiratory diseases, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), tuberculosis (TB), pneumonia infections, and asthma, and compare the vascular complications with other vascular beds. Additionally, we explore the primary mechanistic pathways contributing to these complications, such as the expression modulation of blood-tissue-barrier proteins, resulting in increased paracellular and transcellular permeability, and compromised immune responses rendering diabetes patients more susceptible to infections. The activation of inflammatory pathways leading to cellular injury and hastening the onset of these respiratory complications is also discussed.

Although the majority of the population will be protected due to the advent and widespread use of the HPV vaccine, the treatment of cervical cancer for all causes, including HPV-negative cervical cancer, is still worthy of further research. The focal point of this study was Canadine's inhibition of epithelial-mesenchymal transformation (EMT) in cervical cancer. Immunoblotting, wound healing and tumor invasion experiments showed that low concentration of Canadine could inhibit the EMT process, proliferation and migration of HT-3 cells (HPV-negative cell line). Combined with GEO database, it was found that the expression levels of several genes highly expressed in cervical tumor tissues could be inhibited by Canadine, especially MAGEA3. Further experiments confirmed that the inhibition of Canadine on MAGEA3 protein increased with time. The small interference and overexpression plasmid of MAGEA3 were designed and verified. In HT-3 cells, when MAGEA3 levels were directly decreased, mesenchymal phenotypic markers were decreased and epithelial phenotypic markers were increased. The opposite result was obtained by overexpression of MAGEA3. In addition, the inhibition of EMT due to the reduction of endogenous MAGEA3 by Canadine was also offset by the overexpression of exogenous MAGEA3. The study concludes that Canadine inhibits EMT of cervical cancer by inhibiting MAGEA3.

NAFLD is a condition that develops when the liver accumulates excess fat without alcohol consumption. This chronic liver ailment progresses along with insulin resistant and is typically not diagnosed until the patients have cirrhosis. Nuclear hormone receptor superfamily PPARs are essential for metabolism of fatty acids and glucose. In liver, lipid metabolism is regulated by nuclear receptors and PPARα, and PPARβ/δ encourages fatty acid β-oxidation. PPAR-γ, an energy-balanced receptor is a crucial regulator in NAFLD. The partial activation of PPAR-γ could lead to increased level of adiponectin and insulin sensitivity, thus improved NAFLD. Because of less side effects, natural compounds are emerged as potential therapeutic agents for NAFLD by PPARγ agonists. Although the results from preclinical studies are promising, further research is needed to determine the potential dosing and efficacy of mentioned compounds in human subjects. In this review, we summarize the effect of natural PPARγ agonist in the NAFLD.