Background and ObjectivesAdequate sedation with preserved spontaneous breathing and stable hemodynamics is critical for the success and safety of fiberoptic bronchoscopy (FOB). Remimazolam, a novel ultra-short-acting benzodiazepine with rapid metabolism and favorable sedative profiles, has shown promising sedative effects for procedural sedation. However, comparative data on its application in FOB with preserved spontaneous breathing remain limited. This retrospective study aimed to compare the safety and efficacy of remimazolam and propofol for sedation in patients undergoing FOB with preserved spontaneous breathing.Materials and MethodsA retrospective chart review was conducted from October 2024 to October 2025. All patients undergoing FOB with preserved spontaneous breathing were enrolled. Patients were divided into two groups based on the sedative used: remimazolam (Group R) and propofol (Group P). The primary outcome was the sedation success rate. Secondary outcomes included hemodynamic parameters, incidence of adverse events, anesthesia-related times, satisfaction scores of endoscopists and patients.ResultsThirty-six patients in group R and Forty in group P were collected in this retrospective study. Sedation success rate was 100% in both groups. Oxygen saturation (SpO2) levels were higher in group R at beginning of the bronchoscopy, 5, 10, and 15 min after the start of bronchoscopy (P = 0.012, 0.001, 0.017, and 0.006, respectively). Group R had a lower incidence of hypoxemia (16.67% vs. 35.0%, P = 0.034), injection pain (0% vs. 17.5%, P = 0.008), and hypotension (5.56% vs. 22.5%, P = 0.036). Recovery time was shorter in group R (P = 0.017). Onset time, and satisfaction scores were comparable in the two groups.ConclusionOur study uncovered remimazolam demonstrates a comparable success rate to propofol and exhibits favorable safety profiles, including reduced hypoxemia, injection pain, and hypotension during FOB with preserved spontaneous breathing. However, the shorter recovery time in Group R was confounded by the routine use of flumazenil, and the findings are limited by the retrospective design, small sample size and exclusive enrollment of ASA I–II patients, requiring validation in larger, prospective studies.

Obesity, a global public health crisis driven by dysregulated systemic energy homeostasis, is increasingly recognized as a disorder of interorgan communication, with the pancreas and liver serving as central interconnected metabolic hubs. Their bidirectional crosstalk, mediated through neural and humoral pathways, is a key driver of disease progression. Recent breakthroughs have uncovered novel molecular mechanisms amplifying this pathogenic axis: Adipocyte-derived exosomes carrying miR-138-5p directly target pancreatic β-cell SOX4, suppressing insulin secretion and promoting apoptosis, while hepatic RNA demethylase ALKBH5 stabilizes glucagon receptor mRNA and activates lipogenic pathways, exacerbating hyperglycemia and steatosis. Further, colonic inflammation activates hepatic ERK signaling, which is converted into neural signals by the liver and precisely delivered to the pancreas through the liver-pancreas vagus nerve circuit, driving adaptive β-cell proliferation in early obesity by releasing neurotransmitters such as acetylcholine. Traditional pathogenic loops persist: Pancreatic exocrine insufficiency disrupts gut-liver homeostasis, inducing systemic inflammation, and hepatic free fatty acid flux exerts direct and immune-mediated lipotoxicity on pancreatic β-cells, forming a self-perpetuating vicious cycle. Emerging interventions target this axis: GLP-1/GIP dual agonists (e.g. , tirzepatide) demonstrate remarkable efficacy in weight loss and non-alcoholic steatohepatitis remission, while time-restricted feeding (e.g. , 16:8 regimen) reduces liver fat through circadian and metabolic pathway activation, independent of caloric restriction. This review synthesizes novel interorgan signaling mechanisms and 2025 therapeutic breakthroughs, emphasizing the pancreas-liver axis as a critical target for obesity management.

The intestinal lumen harbors a dynamic sensory and responsive network composed of enteric neurons (expressing ion channels such as transient receptor potential vanilloid 1 and K+ channels), enteroendocrine cells, gut microbiota and neuroimmune cells. The enteric nervous system (ENS) - a “second brain” autonomously regulates gastrointestinal functions while closely communicating with the central nervous system via the gut-brain axis (GBA). Its dysfunction is closely associated with metabolic diseases such as type 2 diabetes mellitus and obesity, as well as functional gastrointestinal disorders characterized by visceral hypersensitivity. Semaglutide, a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, has demonstrated remarkable efficacy in treating type 2 diabetes mellitus and obesity, extending far beyond glycemic control. The GBA and ENS are now recognized as key to explaining these effects. As the primary site of semaglutide action, the intestine hosts a complex neuro-endocrine-immune-microbial network whose remodeling remains incompletely elucidated. Emerging evidence suggests that the signaling hub formed by transforming growth factor-β (TGF-β) and brain-derived neurotrophic factor (BDNF) plays a central role in this process. This review summarizes recent advances in semaglutide-mediated regulation of intestinal neuroplasticity, inflammation, and metabolic homeostasis, with a focus on how semaglutide modulates the TGF-β/BDNF signaling hub to reshape intestinal sensory perception. Specifically, upon activation of GLP-1R, semaglutide phosphorylates and inhibits glycogen synthase kinase-3β via the phosphatidylinositol 3-kinase /protein kinase B pathway, thereby relieving its suppression of cyclic adenosine monophosphate-response element-binding protein and promoting BDNF transcription. Concurrently, it downregulates the pro-inflammatory and pro-fibrotic TGF-β and its downstream Smad2/3 phosphorylation, improving inflammation and barrier function. The elevated BDNF further exerts neurotrophic, anti-inflammatory, and neuroprotective effects. Additionally, semaglutide reshapes the gut microbiota, increasing the abundance of beneficial bacteria such as Akkermansia and Bacteroides , repairing dysbiosis, enhancing short-chain fatty acid production, upregulating BDNF, inhibiting neuroinflammation, and indirectly modulating transient receptor potential vanilloid 1 activity. In summary, semaglutide-induced remodeling of intestinal sensory perception involves ENS plasticity, neuro-immune crosstalk, and microbial metabolic regulation, with the TGF-β/BDNF axis serving as a central node in this intricate process. Elucidating this mechanism may provide a basis for expanding the therapeutic scope of GLP-1R agonists to neurological disorders and developing novel GBA-targeted drugs.

Asthma is a heterogeneous respiratory system disease with chronic airway inflammation. Asthma patients exhibit respiratory symptoms including shortness of breath, coughing, chest tightness, and wheezing. The existing medications for controlling asthma lead to a significant reduction in the therapeutic effect due to their numerous adverse reactions and drug resistance. Therefore, there is an urgent need to develop new drugs with few side effects, good curative effect, and high cost-performance ratio. Cyclobenzaprine HCl (CBP) is a centrally acting skeletal muscle relaxant that has previously been used for the treatment of painful muscle spasms. Relevant research reports indicate that CBP has potential anti-inflammatory, analgesic, and antispasmodic effects, but there are no relevant reports on the treatment of asthma by CBP. To study the impact of CBP on asthma, we conducted a series of in vitro and in vivo experiments, including muscle tension measurement, patch clamp experiments, pulmonary function tests, pathological examination of lung tissues, and molecular experiments, etc. We found that CBP can relax the airway smooth muscle stimulated by high-concentration potassium ions (HK+) or acetylcholine (ACh) by regulating the channel currents of L-type voltage-dependent Ca2+ channel (L-VDCC) and nonselective cation channels (NSCC). Moreover, CBP reduced the accumulation of inflammatory cells in the lungs of asthma mice, such as eosinophils and lymphocytes. CBP effectively inhibited the expression of inflammatory factors. Additionally, CBP alleviated asthma airway inflammation by regulating TLR4/MyD88/NF-κB and PI3K/AKT/mTOR signaling pathways. Our data suggest that CBP is expected to become a potential new drug for relieving or treating asthma.

Background: Vandetanib is a small-molecule tyrosine kinase inhibitor. It exerts its therapeutic effects primarily in a range of lung cancers by inhibiting the vascular endothelial growth factor receptor 2. However, it remains unclear whether vandetanib has therapeutic benefits in other lung diseases, particularly asthma. The present study investigated the pioneering use of vandetanib in the treatment of asthma.Methods:In vivo experiments including establishment of an asthma model, measurement of airway resistance measurement and histological analysis were used primarily to confirm the anticontractile and anti-inflammatory effects of vandetanib, while in vitro experiments, including measurement of muscle tension and whole-cell patch-clamp recording, were used to explore the underlying molecular mechanism.Results:In vivo experiments in an asthmatic mouse model showed that vandetanib could significantly alleviate systemic inflammation and a range of airway pathological changes including hypersensitivity, hypersecretion and remodeling. Subsequent in vitro experiments showed that vandetanib was able to relax the precontracted rings of the mouse trachea via calcium mobilization which was regulated by specific ion channels including VDLCC, NSCC, NCX and K+ channels.Conclusions: Taken together, our study demonstrated that vandetanib has both anticontractile and anti-inflammatory properties in the treatment of asthma, which also suggests the feasibility of using vandetanib in the treatment of asthma by reducing abnormal airway contraction and systemic inflammation.

Asthma is an inflammatory disease characterized by airway hyperresponsiveness, airway remodeling, and airway inflammation. In recent years, the prevalence of asthma has been increasing steadily and the pathogenesis of asthma varies from person to person. Due to poor compliance or resistance, existing drugs cannot achieve the desired therapeutic effect. Therefore, developing or screening asthma therapeutic drugs with high curative effects, low toxicity, and strong specificity is very urgent. Duloxetine HCl (DUX) is a selective serotonin and norepinephrine reuptake inhibitor, and it was mainly used to treat depression, osteoarthritis, and neuropathic pain. It was also reported that DUX has potential anti-infection, anti-inflammation, analgesic, antioxidative, and other pharmacological effects. However, whether DUX has some effects on asthma remains unknown. In order to investigate it, a series of ex vivo and in vivo experiments, including biological tension tests, patch clamp, histopathological analysis, lung function detection, oxidative stress enzyme activity detection, and molecular biology experiments, were designed in this study. We found that DUX can not only relax high potassium or ACh precontracted tracheal smooth muscle by regulating L-type voltage-dependent Ca 2+ channel (L-VDCC) and nonselective cation channel (NSCC) ion channels but also alleviate asthma symptoms through anti-inflammatory and antioxidative response regulated by PI3K/AKT/mTOR and Nrf2/HO-1 signaling pathways. Our data suggests that DUX is expected to become a potential new drug for relieving or treating asthma.

Background Tyrosine kinase and phosphoinositide kinase pathways play important roles in asthma formation. As a dual tyrosine and phosphoinositide kinase inhibitor, PP121 has shown anticancer efficacy in multiple tumors. However, the study of PP121 in pulmonary diseases is still limited. Herein, we investigated the therapeutic activities of PP121 in asthma treatment. Methods Tension measurements and patch clamp recordings were made to investigate the anticontractile characteristics of PP121 in vitro. Then, an asthma mouse model was established to further explore the therapeutic characteristics of PP121 via measurement of respiratory system resistance, histological analysis and western blotting. Results We discovered that PP121 could relax precontracted mouse tracheal rings (mTRs) by blocking certain ion channels, including L-type voltage-dependent Ca 2+ channels (L-VDCCs), nonselective cation channels (NSCCs), transient receptor potential channels (TRPCs), Na + /Ca 2+ exchangers (NCXs) and K + channels, and accelerating calcium mobilization. Furthermore, PP121 relieved asthmatic pathological features, including airway hyperresponsiveness, systematic inflammation and mucus secretion, via downregulation of inflammatory factors, mucins and the mitogen-activated protein kinase (MAPK)/Akt signaling pathway in asthmatic mice. Conclusion In summary, PP121 exerts dual anti-contractile and anti-inflammatory effects in asthma treatment, which suggests that PP121 might be a promising therapeutic compound and shed new light on asthma therapy.

The objective of this project was to find a bronchodilatory compound from herbs and clarify the mechanism. We found that the ethanol extract of Folium Sennae (EEFS) can relax airway smooth muscle (ASM). EEFS inhibited ASM contraction, induced by acetylcholine, in mouse tracheal rings and lung slices. High-performance liquid chromatography assay showed that EEFS contained emodin. Emodin had a similar reversal action. Acetylcholine-evoked contraction was also partially reduced by nifedipine (a selective inhibitor of L-type voltage-dependent Ca2+ channels, LVDCCs), YM-58483 (a selective inhibitor of store-operated Ca2+ entry, SOCE), as well as Y-27632 (an inhibitor of Rho-associated protein kinase). In addition, LVDCC- and SOCE-mediated currents and cytosolic Ca2+ elevations were inhibited by emodin. Emodin reversed acetylcholine-caused increases in phosphorylation of myosin phosphatase target subunit 1. Furthermore, emodin, in vivo, inhibited acetylcholine-induced respiratory system resistance in mice. These results indicate that EEFS-induced relaxation results from emodin inhibiting LVDCC, SOCE, and Ca2+ sensitization. These findings suggest that Folium Sennae and emodin may be new sources of bronchodilators.

The purpose of this study was to screen a bronchodilator from old drugs and elucidate the underlying mechanism. Paracetamol (acetaminophen) is a widely used analgesic and antipyretic drug. It has been reported that it inhibits the generation of prostaglandin and histamine, which play roles in asthma. These findings led us to explore whether paracetamol could be a potential bronchodilator. Paracetamol inhibited high K+- and acetylcholine (ACH)-induced precontraction of mouse tracheal and bronchial smooth muscles. Moreover, the ACH-induced contraction was partially inhibited by nifedipine (selective blocker of LVDCCs), YM-58483 (selective inhibitor of store-operated Ca2+ entry (SOCE), canonical transient receptor potential 3 (TRPC3) and TRPC5 channels) and Y-27632 (selective blocker of ROCK, a linker of the Ca2+ sensitization pathway). In single airway smooth muscle cells, paracetamol blocked the currents sensitive to nifedipine and YM-58483, and inhibited intracellular Ca2+ increases. In addition, paracetamol inhibited ACH-induced phosphorylation of myosin phosphatase target subunit 1 (MYPT1, another linker of the Ca2+ sensitization pathway). Finally, in vivo paracetamol inhibited ACH-induced increases of mouse respirator system resistance. Collectively, we conclude that paracetamol inhibits ASM contraction through blocking LVDCCs, SOCE and/or TRPC3 and/or TRPC5 channels, and Ca2+ sensitization. These results suggest that paracetamol might be a new bronchodilator.

AIMS:This study focused on investigating whether NS8593 reverses airway smooth muscle (ASM) contraction and the underlying mechanism.MAIN METHODS:ASM contraction in mouse tracheal rings and lung slices was measured. Currents mediated by voltage dependent Ca2+ channels (VDCCs) and ACH-activated channels were measured using the whole-cell patch-clamp technique in single tracheal smooth muscle cells (TSMCs). Intracellular Ca2+ level and cell length were measured using an LSM 700 laser confocal microscope and a Zen 2010 software. Mouse respiratory system resistance (Rrs) was assessed using a FlexiVent FX system.KEY FINDINGS:High K+ (80 mM K+) and ACH induced ASM contraction in mouse tracheal rings and lung slices, which was partially relaxed by nifedipine (blocker of L-type VDCCs, LVDCCs), YM-58483 (blocker of store-operated Ca2+ entry (SOCE), transient receptor potential C3 (TRPC3) and TRPC5 channels), respectively. However, the contraction was completely reversed by NS8593, whereas, slightly relaxed by formoterol. ACH activated inward currents, which displayed linear and reversed around 0 mV, indicating the currents were mediated by non-selective cation channels (NSCCs). Moreover, these currents were blocked by YM-58483. In addition, such currents were abolished by NS8593, implicating that NS8593 inhibits the same channels. Besides, NS8593 inhibited increases of intracellular Ca2+ and the associated cell shortening. Finally, NS8593 inhibited ACH-induced increases of mouse respirator system resistance (Rrs).SIGNIFICANCE:Our results indicate that NS8593 inhibits LVDCCs and NSCCs, resulting in decreases of intracellular Ca2+ and then leading to ASM relaxation. These data suggest that NS8593 might be a new bronchodilator.

目的:研究异莲心碱对高K+预收缩小鼠离体气管平滑肌(ASM)的舒张作用及其机制.方法:利用张力换能器检测异莲心碱对高K+诱导的ASM预收缩和Ca2+内流的影响;利用膜片钳技术和钙成像系统分别检测异莲心碱对ASM细胞膜L型电压依赖性Ca2+通道(LVDCC)电流以及细胞内Ca2+浓度([Ca2+]i)的影响.结果:异莲心碱可显著舒张高K+预收缩的ASM,且其舒张作用呈现浓度依赖性,当浓度为100μmol/L时最大舒张比达到(95.3±3.9)％.此外,利用膜片钳全细胞记录技术测量LVDCC电流,电流可被异莲心碱完全阻断;在高K+诱导下气管平滑肌细胞中Fura-2的340/380 nm荧光比值稳定在0.63±0.10,而异莲心碱加入后比值显著下降至0.36±0.05(P<0.01);在[Ca2+]i峰点加入异莲心碱,340/380 nm荧光比值从0.74±0.02迅速降至0.42±0.05(P<0.01);异莲心碱抑制高K+诱导的Ca2+内流引起的ASM收缩.结论:异莲心碱可阻断小鼠离体气管平滑肌细胞LVDCC电流,LVDCC介导的Ca2+内流停止,[Ca2+]i降低,导致ASM舒张,提示异莲心碱可能是潜在的气管舒张剂.

The aim of this study was to investigate the inhibitory effect and the underlying mechanism of ethacrynic acid (EA) on the contraction in mice. BL-420S force measuring system was used to measure the tension of mouse tracheal rings. The whole cell patch clamp technique was utilized to record the channel currents of airway smooth muscle (ASM) cells. The calcium imaging system was used to determine the intracellular Ca2+ concentration ([Ca2+]i) in ASM cells. The results showed that EA significantly inhibited the high K+ (80 mmol/L) and acetylcholine (ACh, 100 µmol/L)-induced contraction of mouse tracheal rings in a dose-dependent manner. The maximal relaxation percentages were (97.02 ± 1.56)% and (85.21 ± 0.03)%, and the median effective concentrations were (40.28 ± 2.20) μmol/L and (56.22 ± 7.62) μmol/L, respectively. EA decreased the K+ and ACh-induced elevation of [Ca2+]i from 0.40 ± 0.04 to 0.16 ± 0.01 and from 0.50 ± 0.01 to 0.39 ± 0.01, respectively. In addition, EA inhibited L-type voltage-dependent calcium channel (LVDCC) and store-operated calcium channel (SOCC) currents in ASM cells, and Ca2+ influx. Moreover, EA decreased the resistance of the respiratory system (Rrs) in vivo in mice. These results indicated that EA inhibits LVDCC and SOCC, which results in termination of Ca2+ influx and decreases of [Ca2+]i, leading to relaxation of ASM. Taken together, EA might be a potential bronchodilator.

AIMS:Benidipine is a dihydropyridine (DHP) derived Ca2+ antagonist, can block triple Ca2+ channels (L, N, and T). It has been used as a safety anti-hypertensive drug because of its long-acting relaxant effect on vascular smooth muscle (VSM). However, whether benidipine has similar pharmacological actions in airway smooth muscle (ASM) is unknown. This research aims to reveal the relaxant property and Ca2+ antagonistic effect of benidipine on ASM.MAIN METHODS:The relaxant property of mouse ASM was investigated by tissue tension tests, and Ca2+ antagonistic effect was evaluated through patch-clamp techniques.KEY FINDINGS:Benidipine caused dose-dependent relaxations on high K+ (80 mM) induced precontraction in mouse ASM, which relied on inhibition of extracellular Ca2+ influx, and 1 μM benidipine totally blocked L-type voltage-dependent Ca2+ channels (LVDCCs) currents in airway smooth muscle cells (ASMCs). Benidipine also showed dose-dependent inhibition of ACh-induced precontraction with or without the LVDCCs blocker nifedipine, and 100 μM benidipine blocked ACh-stimulated Ca2+ influx through not only LVDCCs but also non-selective cation channels (NSCCs).SIGNIFICANCE:Benidipine blocked LVDCCs and NSCCs to abolish these channels-mediated Ca2+ influx, which relaxed precontracted ASM. This study represented benidipine with a new potential medicinal value for ASM hypercontractility.

Azithromycin (AZM) has been used for the treatment of asthma and chronic obstructive pulmonary disease (COPD); however, the effects and underlying mechanisms of AZM remain largely unknown. The effects of AZM on airway smooth muscles (ASMs) and the underlying mechanisms were studied using isometric muscle force measurements, the examination of lung slices, imaging, and patch-clamp techniques. AZM completely inhibited acetylcholine (ACH)-induced precontraction of ASMs in animals (mice, guinea pigs, and rabbits) and humans. Two other macrolide antibiotics, roxithromycin and Klaricid, displayed a decreased inhibitory activity, and the aminoglycoside antibiotics penicillin and streptomycin did not have an inhibitory effect. Precontractions were partially inhibited by nifedipine (selective inhibitor of L-type voltage-dependent Ca2+ channels (LVDCCs)), Pyr3 (selective inhibitor of TRPC3 and/or STIM/Orai channels, which are nonselective cation channels (NSCCs)), and Y-27632 (selective inhibitor of Rho-associated kinase (ROCK)). Moreover, LVDCC- and NSCC-mediated currents were inhibited by AZM, and the latter were suppressed by the muscarinic (M) 2 receptor inhibitor methoctramine. AZM inhibited LVDCC Ca2+ permeant ion channels, M2 receptors, and TRPC3 and/or STIM/Orai, which decreased cytosolic Ca2+ concentrations and led to muscle relaxation. This relaxation was also enhanced by the inhibition of Ca2+ sensitization. Therefore, AZM has potential as a novel and potent bronchodilator. The findings of this study improve the understanding of the effects of AZM on asthma and COPD.

BACKGROUND/AIMS:Tetraethylammonium chloride (TEA) induces oscillatory contractions in mouse airway smooth muscle (ASM); however, the generation and maintenance of oscillatory contractions and their role in ASM are unclear.METHODS:In this study, oscillations of ASM contraction and intracellular Ca2+ were measured using force measuring and Ca2+ imaging technique, respectively. TEA, nifedipine, niflumic acid, acetylcholine chloride, lithium chloride, KB-R7943, ouabain, 2-Aminoethoxydiphenyl borate, thapsigargin, tetrodotoxin, and ryanodine were used to assess the mechanism of oscillatory contractions.RESULTS:TEA induced depolarization, resulting in activation of L-type voltage-dependent Ca2+ channels (LVDCCs) and voltage-dependent Na+ (VNa) channels. The former mediated Ca2+ influx to trigger a contraction and the latter mediated Na+ entry to enhance the contraction via activating LVDCCs. Meanwhile, increased Ca2+-activated Cl- channels, inducing depolarization that resulted in contraction through LVDCCs. In addition, the contraction was enhanced by intracellular Ca2+ release from Ca2+ stores mediated by inositol (1,4,5)-trisphosphate receptors (IP3Rs). These pathways together produce the contractile phase of the oscillatory contractions. Furthermore, the increased Ca2+ activated the Na+-Ca2+ exchanger (NCX), which transferred Ca2+ out of and Na+ into the cells. The former induced relaxation and the latter activated Na+/K+-ATPase that induced hypopolarization to inactivate LVDCCs causing further relaxation. This can also explain the relaxant phase of the oscillatory contractions. Moreover, the depolarization induced by VNa channels and NCX might be greater than the hypopolarization caused by Na+/K+-ATPase alone, inducing LVDCC activation and resulting in further contraction.CONCLUSIONS:These data indicate that the TEA-induced oscillatory contractions were cooperatively produced by LVDCCs, VNa channels, Ca2+-activated Cl- channels, NCX, Na+/K+ ATPase, IP3Rs-mediated Ca2+ release, and extracellular Ca2+.

Because of the serious side effects of the currently used bronchodilators, new compounds with similar functions must be developed. We screened several herbs and found that Polygonum aviculare L . contains ingredients that inhibit the precontraction of mouse and human airway smooth muscle (ASM). High K + -induced precontraction in ASM was completely inhibited by nifedipine, a selective blocker of L-type voltage-dependent Ca 2+ channels (LVDCCs). However, nifedipine only partially reduced the precontraction induced by acetylcholine chloride (ACH). Additionally, the ACH-induced precontraction was partly reduced by pyrazole-3 (Pyr3), a selective blocker of TRPC3 and stromal interaction molecule (STIM)/Orai channels. These channel-mediated currents were inhibited by the compounds present in P . aviculare extracts, suggesting that this inhibition was mediated by LVDCCs, TRPC3 and/or STIM/Orai channels. Moreover, these channel-mediated currents were inhibited by quercetin, which is present in P . aviculare extracts. Furthermore, quercetin inhibited ACH-induced precontraction in ASM. Overall, our data indicate that the ethyl acetate fraction of P . aviculare and quercetin can inhibit Ca 2+ -permeant LVDCCs, TRPC3 and STIM/Orai channels, which inhibits the precontraction of ASM. These findings suggest that P . aviculare could be used to develop new bronchodilators to treat obstructive lung diseases such as asthma and chronic obstructive pulmonary disease.

β2-adrenoceptor agonists are commonly used as bronchodilators to treat obstructive lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), however, they induce severe side effects. Therefore, developing new bronchodilators is essential. Herbal plants were extracted and the extracts’ effect on airway smooth muscle (ASM) precontraction was assessed. The ethyl alcohol extract of semen cassiae (EESC) was extracted from Semen cassia. The effects of EESC on the ACh- and 80 mM K+-induced sustained precontraction in mouse and human ASM were evaluated. Ca2+ permeant ion channel currents and intracellular Ca2+ concentration were measured. HPLC analysis was employed to determine which compound was responsible for the EESC-induced relaxation. The EESC reversibly inhibited the ACh- and 80 mM K+-induced precontraction. The sustained precontraction depends on Ca2+ influx, and it was mediated by voltage-dependent L-type Ca2+ channels (LVDCCs), store-operated channels (SOCs), TRPC3/STIM/Orai channels. These channels were inhibited by aurantio-obtusin, one component of EESC. When aurantio-obtusin removed, EESC’s action disappeared. In addition, aurantio-obtusin inhibited the precontraction of mouse and human ASM and intracellular Ca2+ increases. These results indicate that Semen cassia-contained aurantio-obtusin inhibits sustained precontraction of ASM via inhibiting Ca2+-permeant ion channels, thereby, which could be used to develop new bronchodilators.

The effects of hypertonic solution on airway smooth muscle (ASM) contraction and the underlying mechanisms are largely unknown. We found that hypertonic saline (HS) inhibited acetylcholine (ACh)-induced contraction of ASM from the mouse trachea and human bronchi. In single mouse ASM cells (ASMCs), ACh induced an increase in intracellular Ca2+ that was further enhanced by 5% NaCl, indicating that the HS-induced inhibition of ASM contraction was not mediated by a decrease in cytosolic Ca2+ . The Rho-associated kinase (ROCK) inhibitor Y-27632 relaxed ACh-induced precontraction of mouse tracheal rings. However, such inhibition was not observed after the relaxation induced by 5% NaCl. Moreover, the incubation of mouse tracheal rings with 5% NaCl decreased ACh-induced phosphorylation of myosin light chain 20 and myosin phosphatase target subunit 1. These data indicate that HS inhibits the contraction of ASM by inhibiting Ca2+ sensitization, not by decreasing intracellular Ca2+ .

The phosphoinositide phosphatase, myotubularin-related protein 14 (MTMR14), has been reported to play an important role in the regulation of muscle performance, autophagy, and aging in mice. We previously showed that MTMR14-knockout (KO) mice gain weight earlier than their wild-type (WT) littermates even on a normal chow diet (NCD), suggesting that this gene might also be involved in regulating metabolism. In the present study, we evaluated the effect of MTMR14 deficiency on high-fat diet (HFD)-induced obesity, lipid accumulation, metabolic disorders, and inflammation in WT and MTMR14-KO mice fed with NCD or HFD. To this end, MTMR14-KO mice fed with HFD showed significantly increased body weight, blood glucose levels, serum triglyceride (TG) levels, and total cholesterol (TC) levels as compared to their age-matched WT control. Additionally, lipid accumulation also increased in the KO mice. Simultaneously, the expression of metabolism-associated genes (Glut4, adiponectin, and leptin) was different in the liver, muscle, and fatty tissue of MTMR14-KO mice fed with HFD. More importantly, the expression of several inflammation-associated genes (TNF-α, IL-6, IL-1β, and MCP-1) dramatically increased in the liver, muscle, and fatty tissue of MTMR14-KO mice relative to control. Taken together, these results suggest that MTMR14 deficiency accelerates HFD-induced metabolic dysfunction and inflammation. Furthermore, the results showed that exacerbated metabolic dysfunction and inflammation may be regulated via the PI3K/Akt and ERK signaling pathways.

The effects of Ca 2+ sparks on cerebral artery smooth muscle cells (CASMCs) and airway smooth muscle cells (ASMCs) tone, as well as the underlying mechanisms, are not clear.In this investigation, we elucidated the underlying mechanisms of the distinct effects of Ca 2+ sparks on cerebral artery smooth muscle cells (CASMCs) and airway smooth muscle cells (ASMCs) tone.In CASMCs, owing to the functional loss of Ca 2+ -activated Cl -(Clca) channels, Ca 2+ sparks activated large-conductance Ca 2+ -activated K + channels (BKs), resulting in a decreases in tone against a spontaneous depolarization-caused high tone in the resting state.In ASMCs, Ca 2+ sparks induced relaxation through BKs and contraction via Clca channels.However, the integrated result was contraction because Ca 2+ sparks activated BKs prior to Clca channels and Clca channels-induced depolarization was larger than BKs-caused hyperpolarization.However, the effects of Ca 2+ sparks on both cell types were determined by L-type voltage-dependent Ca 2+ channels (LVDCCs).In addition, compared with ASMCs, CASMCs had great and higher amplitude Ca 2+ sparks, a higher density of BKs, and higher Ca 2+ and voltage sensitivity of BKs.These differences enhanced the ability of Ca 2+ sparks to decrease CASMC and to increase ASMC tone.The higher Ca 2+ and voltage sensitivity of BKs in CASMCs than ASMCs were determined by the β1 subunits.Moreover, Ca 2+ sparks showed the similar effects on human CASMC and ASMC tone.In conclusions, Ca 2+ sparks decrease CASMC tone and increase ASMC tone, mediated by BKs and Clca channels, respectively, and finally determined by LVDCCs.