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 ; Libério, Michelle S ; Nelson, Colleen C ; 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.

项与 ARV-1803 相关的新闻（医药）

2024-04-10

·BioPharmaDive

J&J, Rallybio partner on drug development for rare fetal condition

Dive Brief:Biotechnology company Rallybio is partnering with Johnson & Johnson, announcing a collaboration Wednesday to develop new treatments for a rare disorder known as fetal and neonatal alloimmune thrombocytopenia, or FNAIT.As part of the deal, Rallybio will receive $6.6 million in equity investment from J&Js venture capital arm. The biotech is currently developing an antibody dubbed RLYB212 to prevent FNAIT and plans to start a Phase 2 trial during the second half of this year.J&J will also provide funding to Rallybio to raise awareness around J&Js drug nipocalimab, which the pharmaceutical company is testing as a treatment for pregnant individuals that have alloimmunized, which describes the development of antibodies that can cross the placenta and destroy platelet cells in the fetus.Dive Insight:While rare, FNAIT can be life-threatening, leading to miscarriages, stillbirths or lifelong neurological disabilities of the infant.Alloimmunization stems from an immune incompatibility between the pregnant person and the fetus in a platelet protein. When allo-antibodies from the mother destroy these blood-clotting cells in the fetus, thrombocytopenia can result.Currently, there is no preventive treatment. Rallybios candidate is a monoclonal antibody aimed at a protein called HPA-1a, which the company thinks could prevent alloimmunization from happening.J&Js nipocalimab works differently, targeting another protein known as FcRN. Its been studied in autoantibody diseases like generalized myasthenia gravis as well as rheumatological conditions like lupus.J&J is also testing it in alloimmunized pregnant individuals who are at a high risk of a related blood disorder known as hemolytic disease of the fetus and newborn. The pharma disclosed results from a small trial early last year, and a Phase 3 study is now enrolling.Our complementary approaches, if successful, would ensure that pregnant individuals at risk of developing FNAIT have a potential treatment option regardless of their alloimmunization status, said CEO of Rallybio Stephen Uden in a statement.Rallybio is also conducting a natural history study to better understand the disease and how it manifests differently depending on race and ethnicity. Results will inform future testing of RLYB212. As of March, more than 9,000 individuals had been screened, the company said.Rallybio will also receive an upfront payment of $500,000 from J&J and up to $3.7 million of additional funding to support its natural history study.J&Js support underscores the tremendous unmet need for new therapies that can reduce the risk of FNAIT and our commitment to delivering new options for those who are pregnant, said Uden in an email to BioPharma Dive. '

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