Gefapixant,a Novel P2X3 Antagonist,Protects against Post Myocardial Infarction Cardiac Dysfunction and Remodeling Via Suppressing NLRP3 Inflammasome

Objective The ATP responsive P2 purinergic receptors can be subdivided into metabotropic P2X family and ionotropic P2Y family.Among these,P2X3 is a type of P2X receptor which is specifically expressed on nerves,especially on pre-ganglionic sensory fibers.This study investigates whether gefapixant possesses the potential of inhibiting cardiac sympathetic hypersensitivity to protect against cardiac remodeling in the context of myocardial infarction.Methods The Sprague-Dawley rats were divided randomly into three groups:sham group-myocardial infarction group,and myocardial infarction with gefapixant treatment group.Myocardial infarction was induced by left anterior descending branch ligation.The gefapixant solution was intraperitoneally injected each time per day for 7 days and the appropriate dosage of gefapixant was determined according to the results of hematoxylin-eosin(HE)staining and myocardial injury biomarkers.Conditions of cardiac function were assessed by echocardiograph and cardiac fibrosis was evaluated by Western blotting and immunofluorescence staining of collagen I and collagen III.The sympathetic innervation was detected by norepinephrine concentration(pg/mL),in-vivo electrophysiology,and typical sympathetic biomarkers.Inflammatory cell infiltration was shown from immunofluorescence staining and pro-inflammatory signaling pathway activation was checked by immunohistology,quantitative realtime PCR(qPCR)and Western blotting.Results It was found that gefapixant injection of 10 mg/kg per day had the highest dosage-efficacy ratio.Furthermore,gefapixant treatment improved cardiac pump function as shown by increased LVEF and LVFS,and decreased LVIDd and LVIDs.The expression levels of collagen I and collagen III,and TNF-αwere all decreased by P2X3 inhibition.Mechanistically,the decreased activation of nucleotide-binding and oligomerization domain-like receptors family pyrin-domain-containing 3(NLRP3)inflammasome and subsequent cleavage of caspase-1 which modulated interleukin-1β(IL-1β)and IL-18 level in heart after gefapixant treatment were associated with the suppressed cardiac inflammation.Conclusion It is suggested that P2X3 inhibition by gefapixant ameliorates post-infarct autonomic nervous imbalance,cardiac dysfunction,and remodeling possibly via inactivating NLRP3 inflammasome.

A method for evaluating paleo hydrocarbon pools and predicting secondary reservoirs:a case study of the Sangonghe Formation in the Mosuowan area,Junggar Basin

Taking the Jurassic Sangonghe Formation in the Mosuowan-Mobei area of the Junggar Basin as an example, this paper provides a method that evaluates paleo hydrocarbon pools and predicts secondary reservoirs. Through Quantitative Grain Fluorescence （QGF） experiments, well-tie seismic correlation, and paleo structure analysis, the scale and distribution of paleo hydrocarbon pools in the study area are outlined. Combining current structural features and fault characteristics, the re-migration pathways of paleo oil and gas are depicted. Based on barrier conditions on the oil re-migration pathways and current reservoir distribution, we recognize three types of secondary reservoirs. By analyzing structural evolution and sand body-fault distribution, the major control factors of secondary reservoirs are specified and, consequently, favorable zones for secondary reservoirs are predicted. The results are mainly as follows. （1） In the primary accumulation period in the Cretaceous, paleo hydrocarbon pools were formed in the Sangonghe Formation of the Mosuowan uplift and their size and distribution were extensive and the exploration potential for secondary reservoirs should not be ignored. Besides, paleo reservoirs were also formed in the Mobei uplift, but just small scale. （2） In the adjustment period in the Neogene, traps were reshaped or destroyed and so were the paleo reservoirs, resulting in oil release. The released oil migrated linearly northward along the structural highs of the Mobei uplift and the Qianshao low-relief uplift and then formed secondary reservoirs when it met new traps. In this process, a structural ridge cooperated with sand bodies and faults, applying unobstructed pathways for oil and gas re-migration. （3） The secondary hydrocarbon pools are classified into three types： low-relief anticlinal type, lithologic pinch-out type and fault block type. The distribution of the first type is controlled by a residual low uplift in the north flank of the paleo-anticline. The second type is distributed in the lithologic pinch-out zones on the periphery of the inherited paleo uplift. The third type is controlled by fault zones of which the strikes are perpendicular to the hydrocarbon re-migration pathways. （4） Four favorable zones for secondary reservoirs are predicted： the low-relief structural zone of the north flank of the Mosuowan paleo-anticline, the fault barrier zone on the western flank of the Mobei uplift, the Qianshao low-relief uplift and the north area of the Mobei uplift that parallels the fault zone. The study above effectively supports the exploration of the Qianshao low-relief uplift, with commercial oil discovered in the Qianshaol well. Besides, the research process in this paper can also be applied to other basins to explore for secondary reservoirs.