Osteopontin: A Novel Therapeutic Target for Respiratory Diseases.

Osteopontin (OPN) is a multifunctional phosphorylated protein that is involved in physiological and pathological events. Emerging evidence suggests that OPN also plays a critical role in the pathogenesis of respiratory diseases. OPN can be produced and secreted by various cell types in lungs and overexpression of OPN has been found in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pulmonary hypertension (PH), pulmonary fibrosis diseases, lung cancer, lung infection, chronic obstructive pulmonary disease (COPD), and asthma. OPN exerts diverse effects on the inflammatory response, immune cell activation, fibrosis and tissue remodeling, and tumorigenesis of these respiratory diseases, and genetic and pharmacological moudulation of OPN exerts therapeutic effects in the treatment of respiratory diseases. In this review, we summarize the recent evidence of multifaceted roles and underlying mechanisms of OPN in these respiratory diseases, and targeting OPN appears to be a potential therapeutic intervention for these diseases.

Adipokines in pulmonary hypertension: angels or demons?

Pulmonary hypertension (PH) is a devastating cardiopulmonary disorder with poor prognosis and limited curative options. Recent studies revealed a strong association between adipose tissue dysfunction (e.g., obesity) and PH. Adipokines are bioactive polypeptides with pleiotropic effects mainly produced by adipose tissue, and it is suggested that imbalanced production of adipokines in obesity may play a key role in the pathogenesis of PH. Alternations in the production and secretion of adipokines have been observed in PH patients and rodents PH models. In this review, we summarize the expressions and functions of several well-recognized adipokines, the roles of adipokines in the pathogenesis of PH and recent advances in the pharmacological and molecular modulation of adipokines in the treatment of PH. We found that several adipokines (e.g., leptin, resistin, and chemerin) have been demonstrated to display pro-proliferation, pro-inflammatory, and pro-oxidative properties and exacerbate PH. Other adipokines (e.g., adiponectin, apelin, and omentin-1) have anti-proliferation, anti-inflammatory, anti-fibrotic and anti-oxidative impacts on the pulmonary vascular remodeling of PH and are suggested as protective factors against PH, and targeting imbalanced adipokines appears to be a potential novel therapeutic strategy for the treatment of PH.

FAP is a prognostic marker, but not a viable therapeutic target for clinical translation in HNSCC.

PURPOSE: PD-1 targeted immunotherapy has imparted a survival benefit to advanced head and neck squamous cell carcinoma (HNSCC), but less than 20% patients produce a durable response to this therapy. Here we aimed to investigate the potential biomarkers for predicting the clinical outcome and resistance to PD-1 targeted immunotherapy in HNSCC patients, and to examine the involvement of FAP+ cancer-associated fibroblasts (CAFs). METHODS: Bioinformatics methods were applied to analyze multiple datasets and explore the role of PD-1 and FAP in HNSCC. Immunohistochemistry was used to detect the expression of FAP protein. Fap gene knockout mice (Fap-/-) and L929 cells with different levels of Fap overexpression (L929-Fap-Low/High) were established to demonstrate the role of FAP+ CAFs in tumor development and immune checkpoint blockade (ICB) resistance. RESULTS: The expression level of PD-1 gene was positively correlated with better overall survival and therapeutic response to PD-1 blockade in HNSCC, but not all tumors with high expression of both PD-1 and PD-L1 were responsive. Moreover, FAP gene was overexpressed in pan-cancer tissues, and could serve as a prognostic biomarker for several cancers, including HNSCC. However, FAP protein was undetectable in mouse MTCQ1 tumors and barely expressed in human HNSCC tumors. Furthermore, FAP+ CAFs did not promote tumor growth or enhance the resistance to PD-1 inhibitor treatment. CONCLUSION: Although FAP+ CAFs have attracted increasing attention for their role in cancer, the feasibility and efficacy of FAP-targeting therapies for HNSCC remain doubtful.

Overexpression Of miR138 Ameliorates Spared Sciatic Nerve Injury-Induced Neuropathic Pain Through The Anti-Inflammatory Response In Mice.

BACKGROUND: The emerging role of inflammation in the initiation and maintenance of neuropathic pain has been confirmed. Previous studies have reported that miR138 has neuroprotective and anti-inflammatory effects in animal models of spinal cord injury and in human coronary artery endothelial cell injury, while its effect on neuropathic pain is still not known. As the mechanism of neuropathic pain remains unclear, we investigated whether miR138 is involved in the development of neuropathic pain and the role of miR138 in the modulation of inflammation in the spinal cord in a mouse model of neuropathic pain induced by spared sciatic nerve injury (SNI). MATERIALS AND METHODS: Firstly, the expression of miR138 in spinal cord was evaluated on days 1, 3, 5, 7, 9 and 14 after SNI. And then, LV-miR-control and LV-miR138 were intrathecally injected 1 week before the surgery followed by investigation of the expression of miR138, mechanical allodynia and thermal hyperalgesia on day 1, 3, 5, 7, 9, 14 after SNI. Ipsilateral L4-L6 spinal cord tissue was harvested on day 14 post-SNI and detected by Western blotting, enzyme-linked immunosorbent assay or immunohischemistry. RESULTS: We observed decreased expression of miR138 and increased expression of proinflammatory cytokines, along with activated microglia, astrocytes and nuclear factor-κВ (NF-κВ), in the spinal cord dorsal horn after SNI. Moreover, the intrathecal upregulation of miR138 significantly alleviated SNI-induced mechanical allodynia and thermal hyperalgesia, downregulated the production of proinflammatory cytokines, and deactivated microglia, astrocytes and NF-κВ. CONCLUSION: The results indicate that miR138 contributes to the development of neuropathic pain and that the overexpression of miR138 alleviates pain hypersensitivity by inhibiting proinflammatory cytokine production and glial activation, which suggests a novel target for reducing neuropathic pain.

Effects of HCN Channels in the Rostral Ventrolateral Medulla Contribute to the Cardiovascular Effects of Propofol.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels were reported to express in the well-known vasomotor region, rostral ventrolateral medulla (RVLM), and can be inhibited by propofol. However, whether HCN channels in RVLM contribute to propofol-induced cardiovascular depression remains unclear. We recorded the hemodynamic changes when either continuous intravenous infusions or microinjections of propofol and ZD-7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride; HCN channel blocker) in RVLM. Expressions of HCN channels in RVLM neurons of mice of different ages were examined by quantitative real-time polymerase chain reaction and Western blotting. The effects of propofol and ZD-7288 on HCN channels and the excitability of RVLM neurons were examined by electrophysiological recording. Propofol (1.25, 2.5, 5, and 7.5 mg/kg per minute, i.v., 10 minutes) decreased mean arterial pressure (MAP) and heart rate (HR) in a concentration-dependent manner in wild-type mice that were markedly attenuated in HCN1 knockout mice. Bilateral microinjection of propofol (1%, 0.1 µl) in RVLM caused a sharp and pronounced drop in MAP and HR values, which were abated by pretreatment with ZD-7288. In electrophysiological recording, propofol (5, 10, and 20 µM) concentration-dependently inhibited HCN current, increased input resistance, decreased firing rate, and caused membrane hyperpolarization in RVLM neurons. These actions of propofol were attenuated by ZD-7288 pretreatment. The mRNA and protein level of HCN channels increased in an age-dependent manner, which may contribute to the age-dependent increase in the sensitivity to propofol. Our results indicated that the inhibition of HCN channels in RVLM neurons may contribute to propofol-induced cardiovascular inhibition.

Pro-resolving mediator maresin 1 ameliorates pain hypersensitivity in a rat spinal nerve ligation model of neuropathic pain.

BACKGROUND: Pro-resolving mediators (PRMs) are considered as emerging analgesics for chronic pain. Maresin 1 (MaR1) is a newly identified member of PRMs, and recent studies implicate its potential role in some pain conditions. As the function of MaR1 in neuropathic pain remains unclear, we investigated the effects of MaR1 on pain hypersensitivity and the underlying mechanism using a rat spinal nerve ligation (SNL) model of neuropathic pain. MATERIALS AND METHODS: MaR1 (100 ng/10 µL) or commensurable artificial cerebrospinal fluid was delivered via intrathecal catheter from days 3 to 5 post-SNL followed by assessment of mechanical allodynia and thermal hyperalgesia. Ipsilateral L4-L5 spinal cord tissue was collected on day 7 post-SNL and assessed by Western blotting, enzyme-linked immunosorbent assay or immunohistochemistry. RESULTS: Intrathecal MaR1 significantly attenuated mechanical allodynia and thermal hyperalgesia from day 5 to day 7 post-SNL, which was associated with decreased spinal levels of glial markers, GFAP and IBA1. It was also found that intrathecal MaR1 downregulated phosphorylation levels of NF-κB p65 and its nuclear translocation, as well as decreased protein levels of pro-inflammatory cytokines, TNF-α, IL-1ß and IL-6. Further, MaR1 treatment restored PSD95 and synapsin II levels, suggesting that MarR1 also protected synaptic integrity. CONCLUSION: Our results indicate that MaR1 ameliorates the SNL-induced neuropathic pain by regulating glial activities and pro-inflammatory cytokines release. The present study offers insight into the potential of MaR1 as a novel intervention to ameliorate neuropathic pain.

HCN channels contribute to the sensitivity of intravenous anesthetics in developmental mice.

It is widely accepted that the induction dose of anesthetics is higher in infants than in adults, although the relevant molecular mechanism remains elusive. We previously showed neuronal hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels contribute to hypnotic actions of propofol and ketamine. Interestingly, the expression of HCN channels in neocortex significantly changes during postnatal periods. Thus, we postulated that changes in HCN channels expression might contribute to sensitivity to intravenous anesthetics. Here we showed the EC50 for propofol- and ketamine-induced loss-of-righting reflex (LORR) was significantly lower for P35 than for P14 mice. Cerebrospinal fluid concentrations of propofol and ketamine were significantly higher in P14 mice than in P35 mice, with similar propofol- and ketamine-induced anesthesia at the LORR EC50. Western blotting indicated that the expression of HCN channels in neocortex changed significantly from P14 to P35 mice. In addition, the amplitude of HCN currents in the neocortical layer 5 pyramidal neurons and the inhibition of propofol and ketamine on HCN currents dramatically increased with development. Logistic regression analysis indicated that the changes of HCN channels were correlated with the age-related differences of propofol- and ketamine-induced anesthesia. These data reveal that the change of HCN channels expression with postnatal development may contribute to sensitivity to the hypnotic actions of propofol and ketamine in mice.