BACKGROUNDObesity-related asthma is a kind of nonallergic asthma with excessive neutrophil infiltration in the airways. However, the underlying mechanisms have been poorly elucidated. Among the adipokines related to obesity, leptin is related to the inflammatory response. However, little is understood about how leptin acts on the leptin receptor (obR) in neutrophilic airway inflammation in obesity-associated asthma. We explored the inflammatory effects of leptin/obR signaling in an obesity-related neutrophilic airway inflammation mouse model.METHODSWe established a neutrophilic airway inflammation mouse model using lipopolysaccharide (LPS)/ovalbumin (OVA) sensitization and OVA challenge (LPS + OVA/OVA) in lean, obese, or db/db (obR deficiency) female mice. Histopathological, bronchoalveolar lavage fluid (BALF) inflammatory cell, and lung inflammatory cytokine analyses were used to analyze airway inflammation severity. Western blotting, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), and enzyme-linked immunosorbent assay (ELISA) were used to evaluate the underlying mechanisms. In vitro bone marrow-derived macrophage (BMDM) and bone marrow-derived neutrophil experiments were performed.RESULTSWe found that the serum leptin level was higher in obese than in lean female mice. Compared to LPS/OVA + OVA-treated lean female mice, LPS/OVA + OVA-treated obese female mice had higher peribronchial inflammation levels, neutrophil counts, Th1/Th17-related inflammatory cytokine levels, M1 macrophage polarization levels, and long isoform obR activation, which could be decreased by the obR blockade (Allo-Aca) or obR deficiency, suggesting a critical role of leptin/obR signaling in the pathogenesis of obesity-related neutrophilic airway inflammation in female mice. In in vitro experiments, leptin synergized with LPS/IFN-γ to promote the phosphorylation of the long isoform obR and JNK/STAT3/AKT signaling pathway members to increase M1 macrophage polarization, which was reversed by Allo-Aca. Moreover, leptin/obR-mediated M1 macrophage activity significantly elevated CXCL2 production and neutrophil recruitment by regulating the JNK/STAT3/AKT pathways. In clinical studies, obese patients with asthma had higher serum leptin levels and M1 macrophage polarization levels in induced sputum than non-obese patients with asthma. Serum leptin levels were positively correlated with M1 macrophage polarization levels in patients with asthma.CONCLUSIONSOur results demonstrate leptin/obR signaling plays an important role in the pathogenesis of obesity-related neutrophilic airway inflammation in females by promoting M1 macrophage polarization.

2021-05-01·Endocrine-Related Cancer2区 · 医学

Leptin antagonism inhibits prostate cancer xenograft growth and progression

2区 · 医学

Article

作者: Wade, John D ; McPherson, Stephen ; Taherian Fard, Atefeh ; Philp, Lisa K ; Bartonicek, Nenad ; Rockstroh, Anja ; Otvos, Laszlo ; Sadowski, Martin C ; Gunter, Jennifer H ; Bidgood, Charles L ; Lehman, Melanie ; Nelson, Colleen C ; Libério, Michelle S ; Tevz, Gregor

Hyperleptinaemia is a well-established therapeutic side effect of drugs inhibiting the androgen axis in prostate cancer (PCa), including main stay androgen deprivation therapy (ADT) and androgen targeted therapies (ATT). Given significant crossover between the adipokine hormone signalling of leptin and multiple cancer-promoting hallmark pathways, including growth, proliferation, migration, angiogenesis, metabolism and inflammation, targeting the leptin axis is therapeutically appealing, especially in advanced PCa where current therapies fail to be curative. In this study, we uncover leptin as a novel universal target in PCa and are the first to highlight increased intratumoural leptin and leptin receptor (LEPR) expression in PCa cells and patients' tumours exposed to androgen deprivation, as is observed in patients' tumours of metastatic and castrate resistant (CRPC) PCa. We also reveal the world-first preclinical evidence that demonstrates marked efficacy of targeted leptin-signalling blockade, using Allo-aca, a potent, specific, and safe LEPR peptide antagonist. Allo-aca-suppressed tumour growth and delayed progression to CRPC in mice bearing LNCaP xenografts, with reduced tumour vascularity and altered pathways of apoptosis, transcription/translation, and energetics in tumours determined as potential mechanisms underpinning anti-tumour efficacy. We highlight LEPR blockade in combination with androgen axis inhibition represents a promising new therapeutic strategy vital in advanced PCa treatment.

2018-03-01·Acta Ophthalmologica3区 · 医学

Influence of exercise on the structure of the anterior chamber of the eye

3区 · 医学

Article

作者: Li, Mu ; Yan, Xiaoqin ; Zhao, Yin ; Zhang, Hong ; Song, Yinwei

AbstractPurposeTo measure changes in anterior chamber structure before and after exercise in healthy individuals using anterior segment optical coherence tomography (ASOCT).MethodsThirty‐two healthy young individuals performed jogging for 20 min. Eye blinking rate was recorded during rest and exercise. The anterior chamber angle (ACA), angle opening distance at 500 μm from the scleral spur (AOD500), trabecular‐iris space area at 500 μm from the scleral spur (TISA500), iris concavity (IC), iris concavity ratio (CR), iris thickness at 750 μm from the scleral spur (IT750), anterior chamber depth (ACD), anterior chamber width (ACW), pupil diameter (PD), intraocular pressure (IOP), blood pressure (BP) and heart rate (HR) were recorded before and after exercise. Anterior chamber angle (ACA), AOD500, TISA500, IC, IT750, ACD, ACW and PD were measured with ASOCT.ResultsCompared with rest, the blinking rate during exercise did not change significantly (13.04 ± 5.80 versus 13.52 ± 5.87 blinks/min, p = 0.645). The average IOP (15.4 ± 2.4 versus 12.4 ± 2.1 mmHg), ACA (35.96 ± 11.35 versus 40.25 ± 12.64 degrees), AOD500 (0.800 ± 0.348 versus 0.942 ± 0.387 mm), TISA500 (0.308 ± 0.155 versus 0.374 ± 0.193 mm2), IC (−0.078 ± 0.148 versus −0.153 ± 0.159 mm) and CR (−0.027 ± 0.050 versus −0.054 ± 0.056) changed significantly (all p < 0.001), while the average IT750 (0.463 ± 0.084 versus 0.465 ± 0.086 mm; p = 0.492), ACD (3.171 ± 0.229 versus 3.175 ± 0.238 mm; p = 0.543) and ACW (11.768 ± 0.377 versus 11.755 ± 0.378 mm; p = 0.122) showed no significant change after exercise.ConclusionThe blinking rate did not change significantly during exercise, while ACA, AOD500 and TISA500 increased after exercise. Exercise also induced or increased IC. These changes in anterior chamber structure were only associated with exercise, but not with the postexercise change in PD or IOP.

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