基于“气道神经源性炎症-TRP通路”探讨慢性咳嗽发病机制及中医治疗

咳嗽临床常见，尤其是胸部影像学无明显异常的慢性咳嗽，病因复杂、易误诊误治，逐渐受到重视，国内外相继颁发相关指南，目前认为咳嗽高敏感性是其重要的病理生理机制。中医将慢性咳嗽归于"久咳""久嗽"范畴，在病因病机、治法方药上积累了丰富的临床经验，史利卿教授团队针对该病开展了专项临床及基础研究15年，根据传统中医理论及其突出临床症状提出"风邪伏肺"病机，应用祛风宣肺法治疗效果显著。文章结合西医学相关咳嗽机制研究进展及既往研究结果，初步探讨祛风宣肺法治疗该病的疗效机制，丰富慢性咳嗽风邪伏肺致咳相关学术理论的科学内涵，有利于提高中医药防治慢性咳嗽学术水平。     

Larotrectinib for the treatment of TRK fusion solid tumors

Introduction: TRK fusions occur across a wide range of cancers in children and adults. These fusions drive constitutive expression and ligand-independent activation of the TRK kinase and are oncogenic. Larotrectinib is the first highly potent and selective small molecule ATP competitive inhibitor of all three TRK kinases to enter clinical development.

Areas covered: This review covers the current preclinical and clinical evidence for TRK inhibitors for TRK fusion cancers, focusing on larotrectinib.

Expert commentary: Larotrectinib has demonstrated a remarkable 75% centrally confirmed objective response rate in patients with TRK fusion cancers in phase 1 and phase 2 clinical trials with generally mild side effects. Responses appear independent of the patient’s age, underlying histology, and specific fusion partner and are durable in many patients. Larotrectinib is likely to be the first FDA-approved histology-agnostic molecularly targeted therapy. The evolving role of molecular profiling of advanced cancers is discussed.     

Interleukin-34 drives macrophage polarization to the M2 phenotype in autoimmune hepatitis

BackgroundAutoimmune hepatitis is a chronic inflammatory disease, the abnormal immunological function is the main pathogenesis. Interleukin-34 is a newly identified cytokine that shares the same receptor as colony stimulating factor-1.MethodsWe used interleukin-34 knockout and wild-type mice in a Con A-induced hepatitis model and cocultured RAW264.7 macrophage cells with interleukin-34. We then detected associated inflammatory cytokine and chemokine levels to elucidate the role of interleukin-34.ResultsIn this study, we found that the loss of interleukin-34 resulted in higher sensitivity to Con A-induced hepatitis. RAW264.7 macrophage cells were able to differentiate to the M2 phenotype upon interleukin-34 stimulation.ConclusionsWe conclude that interleukin-34 may protect the liver from Con A-mediated hepatitis by driving M2 macrophage polarization and suppressing inflammation.     

New insights into necrotizing enterocolitis: From laboratory observation to personalized prevention and treatment

Background/purpose

Necrotizing enterocolitis (NEC) is a devastating disease of prematurity that develops after feeding, often without warning, and results in diffuse intestinal necrosis leading to sepsis and death in many cases. The lack of improvement in overall survival is influenced by nonspecific diagnostic modalities as well as inexact and nonpersonalized treatment strategies.

Detection of recombinant and endogenous mouse melatonin receptors by monoclonal antibodies targeting the C‐terminal domain

Melatonin receptors play important roles in the regulation of circadian and seasonal rhythms, sleep, retinal functions, the immune system, depression, and type 2 diabetes development. Melatonin receptors are approved drug targets for insomnia, non‐24‐hour sleep‐wake disorders, and major depressive disorders. In mammals, two melatonin receptors (MTRs) exist, MT₁ and MT₂, belonging to the G protein‐coupled receptor (GPCR) superfamily. Similar to most other GPCRs, reliable antibodies recognizing melatonin receptors proved to be difficult to obtain. Here, we describe the development of the first monoclonal antibodies (mABs) for mouse MT₁ and MT₂. Purified antibodies were extensively characterized for specific reactivity with mouse, rat, and human MT₁ and MT₂ by Western blot, immunoprecipitation, immunofluorescence, and proximity ligation assay. Several mABs were specific for either mouse MT₁ or MT₂. None of the mABs cross‐reacted with rat MTRs, and some were able to react with human MTRs. The specificity of the selected mABs was validated by immunofluorescence microscopy in three established locations (retina, suprachiasmatic nuclei, pituitary gland) for MTR expression in mice using MTR‐KO mice as control. MT₂ expression was not detected in mouse insulinoma MIN6 cells or pancreatic beta‐cells. Collectively, we report the first monoclonal antibodies recognizing recombinant and native mouse melatonin receptors that will be valuable tools for future studies.     

Calcilytics inhibit the proliferation and migration of human prostate cancer PC-3 cells

The carcinogenesis and development of prostate cancer are mediated by enhanced Ca²⁺ signaling. In the present study, the pharmacological profile of the Ca²⁺-sensing receptor (CaSR) antagonists (calcilytics) was examined in human prostate cancer PC-3 cells. NPS2143 and Calhex 231 blocked extracellular Ca²⁺-induced increases in cytosolic [Ca²⁺]. NPS2143 and Calhex 231 inhibited cell proliferation (IC₅₀ = 7.4 and 10.3 μM, respectively) and migration. The exposure to NPS2143 or Calhex 231 down-regulated CaSR protein expression. These results demonstrated that calcilytics inhibited cell proliferation/migration and down-regulated CaSR expression in human prostate cancer cells, suggesting their potential as novel therapeutic drugs for prostate cancer.     

Cross-species comparison of the metabolism and excretion of selexipag

1. The metabolism of the prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-333679) has been investigated in liver microsomes and hepatocytes of rats, dogs, and monkeys. MRE-269 formation is the main pathway of selexipag metabolism, irrespective of species. Some interspecies differences were evident for both compounds in terms of both metabolic turnover and metabolic profiles. The metabolism of MRE-269 was slower than that of selexipag in all three species.

2. The metabolism of selexipag was also studied in bile-duct-cannulated rats and dogs after a single oral and intravenous dose of [¹⁴C]selexipag. MRE-269 acyl glucuronide was found in both rat and dog bile. Internal acyl migration reactions of MRE-269 glucuronide were identified in an experiment with the synthetic standard MRE-6001.

3. MRE-269 was the major component in the faeces of rats and dogs. In ex vivo study using rat and dog faeces, selexipag hydrolysis to MRE-269 by the intestinal microflora is considered to be a contributory factor in rats and dogs.

4. A taurine conjugate of MRE-269 was identified in rat bile sample. Overall, selexipag was eliminated via multiple routes in animals, including hydrolysis, oxidative metabolism, conjugation, intestinal deconjugation, and gut flora metabolism.