Smooth Contraction Research Articles

Analysis of the effect of phloroglucinol on pregnancy outcomes involving frozen embryo transfers in patients with endometriosis: A retrospective case-control study.

Abnormal contraction of uterus and vascular smooth muscle lead to the formation of hypoxia environment in uterus. Abnormal contraction may be the basis of dysmenorrhea, endometriosis, infertility and other diseases. Phloroglucinol is a non-atropine and non-papaverine smooth muscle spasmolytic agent, which can reduce the abnormal contraction of uterine smooth muscle. This study investigated the effect of phloroglucinol on frozen embryo transfer in patients with endometriosis. The data of patients with endometriosis who underwent a frozen embryo transfer in Shanghai Changzheng Hospital from August 2018 to August 2021, comprising a total of 453 cycles, were retrospectively analyzed. The patients for whom phloroglucinol was included over 217 cycles were administered intramuscully 40 mg phloroglucinol starting on the day of progesterone administration, then once daily up to day 7 after the embryo transfer. Those for whom phloroglucinol was not administered over 236 cycles were used as the control group. The age of 35 years was used as a boundary in this study to observe the pregnancy outcomes of patients in the two different age groups. The biochemical pregnancy rate (63.13% vs. 51.27%), embryo implantation rate (44.64% vs. 33.60%), clinical pregnancy rate (59.64% vs. 48.30%), and live birth rate (52.99% vs. 36.86%) after the administration of phloroglucinol were higher than for patients in the control group, and the early abortion rate (7.75% vs. 20.18%) was also lower. The differences were statistically significant (P < 0.05). In particular, in the age group <35 years old, the embryo implantation rate (51.81% vs. 39.38%), clinical pregnancy rate (69.34% vs. 57.55%), and the live birth rate (63.50% vs. 44.60%) after phloroglucinol intervention rose significantly, and the abortion rate dropped (6.32% vs. 17.5%), indicating a statistically significant difference (P < 0.05). However, pregnancy outcomes showed no difference in the age group ≥35 years old (P > 0.05). Continuous low-dose phloroglucinol pretreatment before and after frozen embryo transfer can improve both the clinical pregnancy and live birth rates and reduce the risk of abortion in younger infertile patients with endometriosis.

Airway Smooth Muscle Regulated by Oxidative Stress in COPD.

Since COPD is a heterogeneous disease, a specific anti-inflammatory therapy for this disease has not been established yet. Oxidative stress is recognized as a major predisposing factor to COPD related inflammatory responses, resulting in pathological features of small airway fibrosis and emphysema. However, little is known about effects of oxidative stress on airway smooth muscle. Cigarette smoke increases intracellular Ca2+ concentration and enhances response to muscarinic agonists in human airway smooth muscle. Cigarette smoke also enhances proliferation of these cells with altered mitochondrial protein. Hydrogen peroxide and 8-isoprostans are increased in the exhaled breath condensate in COPD. These endogenous oxidants cause contraction of tracheal smooth muscle with Ca2+ dynamics through Ca2+ channels and with Ca2+ sensitization through Rho-kinase. TNF-α and growth factors potentiate proliferation of these cells by synthesis of ROS. Oxidative stress can alter the function of airway smooth muscle through Ca2+ signaling. These phenotype changes are associated with manifestations (dyspnea, wheezing) and pathophysiology (airflow limitation, airway remodeling, airway hyperresponsiveness). Therefore, airway smooth muscle is a therapeutic target against COPD; oxidative stress should be included in treatable traits for COPD to advance precision medicine. Research into Ca2+ signaling related to ROS may contribute to the development of a novel agent for COPD.

Differentially Expressed Genes and Signalling Pathways Regulated by High Selenium Involved in Antioxidant and Immune Functions of Goats Based on Transcriptome Sequencing.

The objective of this study is to observe the effect of high selenium on the antioxidant and immune functions of growing goats based on transcriptome sequencing. Eighteen goats were randomly divided into three groups: (1) the control (CON) group was fed a basal diet, and (2) the treatment 1 group (LS) and treatment 2 group (HS) were fed a basal diet with 2.4 and 4.8 mg/kg selenium-yeast (SY), respectively. The results indicate that HS treatment significantly (p < 0.05) increased the apparent digestibility of either extract and significantly increased (p < 0.05) total antioxidant capacity, whereas it significantly (p < 0.05) decreased plasma aspartate aminotransferase and malondialdehyde relative to the control group. The LS treatment had significantly (p < 0.05) increased glutathione S-transferase and catalase compared to CON. A total of 532 differentially expressed genes (DEGs) between the CON and HS were obtained using transcriptome sequencing. Kyoto Encyclopedia of Genes and Genomes analysis identified upregulated (p < 0.05) DEGs mainly related to vascular smooth muscle contraction, alpha-linolenic acid metabolism, biosynthesis of unsaturated fatty acids, the VEGF signalling pathway, and proteoglycans in cancer; downregulated (p < 0.05) DEGs mainly related to the NOD-like receptor signalling pathway, influenza A, cytokine-cytokine receptor interaction, haematopoietic cell lineage, and African trypanosomiasis. Ontology analyses of the top genes show that the identified DEGs are mainly involved in the regulation of granulocyte macrophage colony-stimulating factor production for biological processes, the external side of the plasma membrane for cellular components, and carbohydrate derivative binding for molecular functions. Seven genes are considered potential candidate genes for regulating antioxidant activity, including selenoprotein W, 1, glutathione peroxidase 1, glutathione S-transferase A1, tumour necrosis factor, tumour necrosis factor superfamily member 10, tumour necrosis factor superfamily member 8, and tumour necrosis factor superfamily member 13b. The experimental observations indicate that dietary supplementation with 4.8 mg/kg SY can enhance antioxidant and immune functions by improving muscle immunity, reducing the concentrations of inflammatory molecules, and modulating antioxidant and inflammatory signalling pathways in growing goats.

Effects of aqueous ginger extract on smooth muscle contraction in bovine cecum: in vitro study.

Intestinal hypomotility cause health risks and economic losses and is considered as an important digestive disorder that efforts to find prokinetic drugs can solve this major problem. This study investigated the effects of Zingiber officinale aqueous extract (ZOAE) on caecal smooth muscle contractions in healthy cows. To perform in vitro tests, cecum strips connected to the organ bath. Ginger aqueous extract caused concentration-dependent contraction in caecal smooth muscle with an effective threshold concentration of 6.00 mg L-1. The strongest contraction was caused at a concentration of 100 mg L-1 with an average contraction of 141%. To evaluate the possible mechanisms underlying the contractile effect on cecum strips, atropine, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) and verapamil completely inhibited aqueous extract induced smooth muscle contractions, while addition of hexamethonium had no effect on the contraction process. The lack of reduction of contractions caused by the extract in the presence of hexamethonium indicates that presence of acetylcholine-like constituents independent of nicotinic receptors. The inhibitory properties of atropine and 4-DAMP indicate that at least part of the prokinetic effect of the extract is due to stimulating the muscarinic receptors, especially M3 receptors. Also, verapamil inhibitory function proves that the extract acting by L-type calcium channels. The results suggest that the ZOAE has a potential prokinetic effect which may provide a pharmacological base to its medicinal or prophylactic use in caecal motility disorders.

Pan-Cancer Analysis of Prognostic and Immune Infiltrates for the TMEM65, Especially for the Breast Cancer.

Transmembrane protein 65 (TMEM65) is an inner mitochondrial membrane protein, which played important role in mediating autophagy, smooth muscle contraction, protein glycosylation, and immune response. In recent years, the interest had risen for exploring the function of the TMEM genes in the cancer fields. As a consequence, in our pan-cancer research of the TMEM65, we explored the function of the gene in kinds of database and tried to apply the finding in the clinical practice. In this research, we provide a comprehensive investigation of TMEM65 expression in a pan-cancer manner containing 33 cancer types. We evaluated the association of TMEM65 with the prognosis, immune infiltration, drug sensitivity analysis, GSVA enrichment analysis, TMB, MSI, NEO, and hotspot mechanisms. TMEM65 was abnormally expressed in 24 types of cancers and showed correlation with the OS for 6 cancers and PFI for 9 cancers and kpI for 3 types. Moreover, the TME score, CD8 T effector, and immune checkpoint scoring systems showed a close correlation with the TMEM65. Moreover, TMEM65 was strongly correlated with some of the most common tumor-related genes and certain pathways (TGF beta signaling, TNFA signaling, hypoxia, pyroptosis, DNA repairing, autophagy, ferroptosis, and other related genes). Additionally, the TMEM65 showed correlations with the tumor mutational burden (TMB), microsatellite instability (MSI), NEO, and drug sensitivity. Finally, we confirmed several pathways by the GSEA and GSVA for the TMEM65 at the breast cancer aspects. Nomogram prediction model was also established for the breast tumors based on the TMEM65 level and other variables. Above all, the TMEM65 played important roles in predicting the prognosis of the cancers and correlated with the tumor immunity in the pan-cancer analysis.

Possible role of transient receptor potential melastatin 4 channels in adrenergic contractions in mouse prostate smooth muscles.

Transient receptor potential melastatin 4 (TRPM4) cation channels are expressed in prostate glands. However, the precise role of these channels in prostate contractility remains unclear. In this study, we examined whether TRPM4 channels were involved in adrenergic contractions in the mouse prostate gland. Adrenergic contractile responses elicited by noradrenaline or electrical field stimulation of the sympathetic nerve were isometrically recorded, and the effects of 9-phenanthrol, a specific TRPM4 channel inhibitor, on those contractile responses were investigated in mouse ventral prostate preparations. 9-phenanthrol (10 or 30 μM) inhibited noradrenaline- and sympathetic nerve-evoked contractions in a concentration-dependent manner. A similar inhibitory effect was observed with another TRPM4 channel inhibitor, 4-chloro-2-(2-(naphthalene-1-yloxy) acetamido) benzoic acid (NBA; 10 μM). Inhibition by 9-phenanthrol and NBA were much greater at lower noradrenaline concentrations and lower stimulus frequencies than those of higher concentrations or frequencies. However, 9-phenanthrol did not inhibit the noradrenaline-induced contractile response when the membrane potential was decreased to approximately 0 mV in the 140 mM K+ medium. Moreover, 9-phenanthrol does not affect noradrenaline-induced increases in spontaneous contractions of cardiac atrial preparation. This agent inhibited noradrenaline-induced contractions in the posterior aorta preparation. However, the inhibitory effect was significantly weaker than that observed in the prostate gland. These results suggest that TRPM4 channels are involved in adrenergic contractions in the mouse prostate gland, possibly through membrane depolarization by their opening; therefore, they might be potential candidates for treating benign prostatic hyperplasia.

S-22-4: GENOME WIDE ASSOCIATION STUDY OF FIBROMUSCULAR DYSPLASIA REVEALS MECHANISTIC LINKS WITH BLOOD PRESSURE REGULATION AND OTHER VASCULAR DISEASES

Introduction: Fibromuscular dysplasia (FMD) is a non-atherosclerotic arteriopathy of unknown etiology, afflicting mostly middle-aged women. It is characterized by stenotic lesions of the vascular wall in middle-size arteries, sometimes associated with dissection, aneurysm or tortuosity. Renovascular hypertension is a major presentation of FMD and 50–85% of FMD patients are hypertensive. Methods &amp; Results: We report results from the first genome-wide association meta-analysis of six studies including 1556 FMD cases and 7100 controls. We identified four robustly associated loci (PHACTR1, LRP1, ATP2B1, and LIMA1). Using colocalization and transcriptome-wide association analysis with arterial expression datasets, we found PHACTR1, LRP1 and ATP2B1 as target genes at FMD loci and identified one additional locus (SLC24A3). We analysed chromatin accessibility in artery-derived primary cells and found that FMD associated variants were located in arterial specific regulatory elements active in smooth muscle cells. Target genes were broadly involved in mechanisms related to actin cytoskeleton and intracellular calcium homeostasis, central to vascular contraction. All FMD loci were also associated to at least one blood pressure trait. Colocalization analysis supported the same genetic variants to cause association to FMD and systolic blood pressure at PHACTR1, ATP2B1 and LIMA1 loci, and for FMD and pulse pressure at PHACTR1, LRP1 and ATP2B1 loci. Using genome-wide genetic correlation, we found a significant association between FMD and blood pressure. Mendelian Randomization analysis supported genetically determined systolic blood pressure to significantly increase the risk of FMD. However, we confirmed using adjusted and stratified analyses that hypertension status alone was not driving the association with FMD at top loci. We also report an important genetic overlap of FMD with migraine, intracranial aneurysm, coronary artery disease and myocardial infarction. Conclusion: Our study confirms FMD as a polygenic disease following a complex genetic mode of inheritance. We find that FMD shares an important part of its genetic basis with blood pressure regulation, involving in particular several genes related to intracellular calcium homeostasis and vascular smooth muscle contraction. These results are consistent with previous studies showing systemic alterations in vascular contraction in FMD patients, even outside of affected arterial beds. While the mechanisms through which FMD may cause renovascular hypertension are well known, further studies will be required to determine how alterations in vascular contraction may lead to the arterial remodeling observed in FMD.

Exercise Reduces Airway Smooth Muscle Contraction in Asthmatic Rats via Inhibition of IL-4 Secretion and Store-Operated Ca2+ Entry Pathway.

Increased evidence has shown that aerobic exercise reduces airway hyperresponsiveness in asthmatic individuals. However, the underlying mechanisms of action remain elusive. This study aimed to investigate the effect of exercise on airway smooth muscle (ASM) contractile function in asthmatic rats, and uncover the possible involvement of interleukin 4 (IL-4) and the store-operated Ca2+ entry (SOCE) pathway. In this study, chicken ovalbumin was used to induce asthma in male Sprague-Dawley rats. The exercise group received moderate-intensity aerobic exercise training for 4 weeks. IL-4 concentrations in bronchoalveolar lavage fluid (BALF) samples were evaluated by enzyme linked immunosorbent assay. The contractile function of the ASM was investigated using tracheal ring tension experiments and intracellular Ca2+ imaging techniques. Western blot analysis was used to evaluate expression levels of calcium-release activated calcium (CRAC) channel protein (Orai) and stromal interaction molecule 1 (STIM1) in ASM. Our data showed that the carbachol-stimulated, SOCE-mediated contraction of rat ASM was significantly increased in asthmatic rats, which could be abolished by exercise. Pharmacological studies revealed that GSK5498A and BTP-2, selective blockers of CRAC channels significantly inhibited SOCE-induced ASM contraction. In addition, exercise inhibited the up-regulation of IL-4 in BALF as well as STIM1 and Orai expression in the ASM of asthmatic rats. In line with these observations, we demonstrated that pretreatment of the ASM with IL-4 up-regulated the expression level of STIM1, Orai1 and Orai2, thereby promoting SOCE-mediated ASM contraction. The data in this study reveal that aerobic exercise may improve the ASM contractile function in asthmatic rats by inhibiting IL-4 secretion and by down-regulating the expression of STIM1, Orai1 and Orai2, thus decreasing excessive SOCE-mediated ASM contraction in asthmatic rats.

The Effect of Long-Term Tamsulosin Monotherapy and Tamsulosin - Dutasteride Combination Therapy on PKC-α Enzyme Expression in Prostate Stromal Tissue.

The α-adrenergic receptor antagonist is the most effective medical therapy to reduce the dynamic component in patients with BPH. However, long-term administration of receptor antagonists can cause upregulation of mRNA receptor expression, resulting in tolerance of drug effectiveness. PKC-α is involved in the process of prostate smooth muscle contraction through activation of the voltage-gated Ca2+ conducted canal, influenced by androgen hormones, especially testosterone, and has an isoform with Twist1, a transcription factor that plays a role in up-regulation of androgen receptors. The aim of the study was to compare the effect of long-term tamsulosin monotherapy and tamsulosin - dutasteride combination therapy in PKC-α enzyme expression in prostate stromal tissue of Rattus norvegicus rats of Wistar strain. Out of 80 samples of Rattus norvegicus rats were divided into 8 groups with different interventions: negative control group, positive control group, tamsulosin monotherapy administration for 1 day, 3 day, and 6 day groups, and tamsulosin - dutasteride combination therapy for 1 day, 3 day, and 6 day groups. BPH was induced with 3 mg/kg of testosterone proprionate for 3 weeks, continued with drugs administration according to intervention grouping. Prostate stromal tissue was taken and prepared for PKC-α enzyme measurement with ELISA method. There was a significant difference (p<0.05) in the effect of tamsulosin monotherapy and tamsulosin-dutasteride combination therapy on the PKC-α expression. There was a strong positive relationship between the duration of tamsulosin-dutasteride combination therapy on the PKC-α expression, which means the longer the duration of the combination of tamsulosin-dutasteride combination the higher the PKC-α expression. Administration of long-term tamsulosin - dutasteride combination therapy causes upregulation PKC-α expression more than tamsulosin only.

Effects of Microbeam Irradiation on Rodent Esophageal Smooth Muscle Contraction.

High-dose-rate radiotherapy has shown promising results with respect to normal tissue preservation. We developed an ex vivo model to study the physiological effects of experimental radiotherapy in the rodent esophageal smooth muscle. We assessed the physiological parameters of the esophageal function in ex vivo preparations of the proximal, middle, and distal segments in the organ bath. High-dose-rate synchrotron irradiation was conducted using both the microbeam irradiation (MBI) technique with peak doses greater than 200 Gy and broadbeam irradiation (BBI) with doses ranging between 3.5-4 Gy. Neither MBI nor BBI affected the function of the contractile apparatus. While peak latency and maximal force change were not affected in the BBI group, and no changes were seen in the proximal esophagus segments after MBI, a significant increase in peak latency and a decrease in maximal force change was observed in the middle and distal esophageal segments. No severe changes in physiological parameters of esophageal contraction were determined after high-dose-rate radiotherapy in our model, but our results indicate a delayed esophageal function. From the clinical perspective, the observed increase in peak latency and decreased maximal force change may indicate delayed esophageal transit.

Three-dimensional multi-field modelling of gastric arrhythmias and their effects on antral contractions

The contraction activation of smooth muscle in the stomach wall (SW) is coordinated by slow electrical waves. The interstitial cells of Cajal (ICC), specialised pacemaker cells, initiate and propagate these slow waves. By establishing an electrically coupled network, each ICC adjusts its intrinsic pacing frequency to a single dominant frequency, to be a key aspect in modelling the electrophysiology of gastric tissue. In terms of modelling, additional fields associated with electrical activation, such as voltage-dependent calcium influx and the resulting deformation, have hardly been considered so far. Here we present a three-dimensional model of the electro-chemomechanical activation of gastric smooth muscle contractions. To reduce computational costs, an adaptive multi-scale discretisation strategy for the temporal resolution of the electric field is used. The model incorporates a biophysically based model of gastric ICC pacemaker activity that aims to simulate stable entrainment and physiological conduction velocities of the electrical slow waves. Together with the simulation of concomitant gastric contractions and the inclusion of a mechanical feedback mechanism, the model is used to study dysrhythmias of gastric slow waves induced by abnormal stretching of the antral SW. The model is able to predict the formation of stretch-induced gastric arrhythmias, such as the emergence of an ectopic pacemaker in the gastric antrum. The results show that the ectopic event is accompanied by smooth muscle contraction and, although it disrupts the normal propagation pattern of gastric slow electrical waves, it can also catalyse the process of handling indigestible materials that might otherwise injure the gastric SW.

Investigations of plausible pharmacodynamics supporting the antispasmodic, bronchodilator, and antidiarrheal activities of Berberis lycium Royle. Via in silico, in vitro, and in vivo studies

Ethnopharmacological relevanceBerberis lycium Royle, a member of the Berberidaceae family, is a high-value medicinal plant with a documented history of usage in traditional medicine and has demonstrated significant therapeutic results among local populations throughout the globe. It is used traditionally in many parts of Pakistan to treat diarrhea, abdominal spasms, coughs, and chest problems. Aim of the studyTo investigate the antispasmodic, bronchodilator, and antidiarrheal effects of B. lycium and its possible underlying mechanisms through in silico, in vitro, and in vivo studies. Materials and methodsLC ESI–MS/MS analysis was used to identify bioactive components within the hydromethanolic extract of B. lycium. In silico studies, including network pharmacology and molecular docking, were utilized to investigate the antispasmodic and bronchodilator properties of the extract's bioactive components. In vitro pharmacological studies were conducted using isolated rabbit jejunum, trachea, urinary bladder, and rat ileum preparations. In vivo antidiarrheal activities were conducted in mice, including castor oil-induced diarrhea, intestinal transit, and castor oil-induced enteropooling. ResultsThe LC ESI–MS/MS analysis of the hydromethanolic extract of B. lycium identified 38 bioactive compounds. Network pharmacology study demonstrated that the mechanism of BLR for the treatment of diarrhea might involve IL1B, TLR4, PIK3R1, TNF, PTPRC, IL2, PIK3CD, and ABCB1, whereas, for respiratory ailments, it may involve PIK3CG, TRPV1, STAT3, ICAM1, ACE, PTGER2, PTGS2, TNF, MMP9, NOS2, IL2, CCR5, HRH1, and VDR. Molecular docking research revealed that chlorogenic acid, epigallocatechin, isorhamnetin, quinic acid, gallic acid, camptothecin, formononetin-7-O-glucoside, velutin, caffeic acid, and (S)-luteanine exhibited a higher docking score than dicyclomine with validated proteins of smooth muscle contractions such as CACB2_HUMAN, ACM3_HUMAN, MYLK_HUMAN, and PLCG1_HUMAN. In vitro investigations demonstrated that Blr.Cr, Blr.EtOAc, and Blr.Aq relaxed spontaneously contracting jejunum preparations; carbachol (1 μM)-induced and K+ (80 mM)-induced jejunum, trachea, and urinary bladder contractions in a concentration-dependent manner, similar to dicyclomine. Moreover, Blr.Cr, Blr.EtOAc, and Blr.Aq exhibited a rightward shift in Ca+2 and carbachol cumulative response curves, similar to dicyclomine, demonstrating the coexistence of antimuscarinic and Ca+2 antagonistic mechanisms due to the presence of alkaloids and flavonoids. In vivo antidiarrheal activities showed that the hydromethanolic extract was significantly effective against castor oil-induced diarrhea and castor oil-induced enteropooling, similar to loperamide, and charcoal meal intestinal transit, similar to atropine, in mice at doses of 50, 100, and 200 mg/kg body weight, which supports its traditional use in diarrhea. ConclusionThe dual blocking mechanism of muscarinic receptors and Ca+2 channels behind the smooth muscle relaxing activity reveals the therapeutic relevance of B. lycium in diarrhea, abdominal spasms, coughs, and chest problems.

Mechanism of Oxytocin-Induced Contraction in Rat Gastric Circular Smooth Muscle

Oxytocin produces an excitatory effect on gastric muscle through the activation of receptors present on stomach smooth muscle cells. However, the intracellular mechanisms that mediate oxytocin excitatory effects are still largely unknown. Therefore, we aimed to investigate the signaling pathways involved in oxytocin-induced contractions in gastric smooth muscle, shedding light on phospholipase C (PLC)-β1 signaling and its downstream molecules, including inositol 1,4,5- trisphosphate (IP3) and myosin light chain kinase (MLCK). The contractions of gastric smooth muscle from male rats were measured in an organ bath set up in response to exogenous oxytocin 10-7 M, in the presence and absence of inhibitors of the indicated signaling molecules. Oxytocin (10-9-10-5 M) induced dose-dependent stomach smooth muscle contraction. Pre-incubation with atosiban, an oxytocin receptor inhibitor, abolished the oxytocin-induced contraction. Moreover, PLC β1 inhibitor (U73122) and IP3 inhibitor Xestospongin C inhibited oxytocin-induced muscle contraction to various degrees. Verapamil, a calcium channel blocker, inhibited oxytocin-induced contraction, and pre-incubation of the strips, with both verapamil and Xestospongin C, further inhibited the excitatory effect of oxytocin. Chelation of intracellular calcium with BAPT-AM (1,2-bis-(o-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid) significantly inhibited the effect of oxytocin on muscle contraction. Finally, pre-incubation of the strips with the Ca2+/calmodulin-dependent protein kinase selective inhibitor STO-609 significantly inhibited the contraction induced by oxytocin. These results suggest that oxytocin directly stimulates its cell surface receptor to activate PLC β1, which in turn liberates IP3, which eventually elevates intracellular calcium, the prerequisite for smooth muscle contraction.

Effects of rosmarinic acid, carnosic acid, rosmanol, carnosol, and ursolic acid on the pathogenesis of respiratory diseases.

This review aimed to identify preclinical and clinical studies examining the effects of rosmarinic acid (RA), carnosic acid (CaA), rosmanol (RO), carnosol (CA), and ursolic acid (UA) against allergic and immunologic disorders. Various online databases, including PubMed, Science Direct, EMBASE, Web of Sciences, Cochrane trials, and Scopus, were searched from inception until October 2022. Due to the suppression of the nuclear factor-κB (NF-κB) pathway, the main factor in allergic asthma, RA may be a promising candidate for the treatment of asthma. The other ingredients comprising CA and UA reduce the expression of interleukin (IL)-4, IL-5, and IL-13 and improve airway inflammation. Rosemary's anti-cancer effect is mediated by several mechanisms, including DNA fragmentation, apoptosis induction, inhibition of astrocyte-upregulated gene-1 expression, and obstruction of cell cycle progression in the G1 phase. The compounds, essentially found in Rosemary essential oil, prevent smooth muscle contraction through its calcium antagonistic effects, inhibiting acetylcholine (ACH), histamine, and norepinephrine stimulation. Additionally, CA exhibits a substantially greater interaction with the nicotinic ACH receptor than a family of medications that relax the smooth muscles, making it a potent antispasmodic treatment. The components have demonstrated therapeutic effects on the immune, allergy, and respiratory disorders.

Sustained contractile force regulated by rho-kinase and protein kinase C in sheep carotid arterial smooth muscle.

The time course of smooth muscle contraction can be divided into two phases, the initial phase is associated with force development while the sustained phase is associated with force maintenance. Cumulative evidence suggests that the two phases are regulated by different signaling pathways, and that rho-kinase (ROCK) and protein kinase C (PKC) play an important role in regulating isometric force in sustained contractions. Since the maintenance of sustained force is critical to the function of vascular smooth muscle, unravelling the complex mechanism of force maintenance is crucial for understanding the cell biology of the muscle. The present study examined the effects of ROCK and PKC on the level of phosphorylation of the 20-kD myosin light chain (MLC20) and isometric force during a sustained contraction. We used partial activation and inhibition of ROCK and PKC to reduce the isometric force by 50% of the maximal isometric force in fully activated muscle, Fmax. We then examined the level of MLC20 phosphorylation in each case. We found that in partially activated muscle the level of MLC20 phosphorylation required to maintain 50% Fmax was much lower than that required in muscles where 50% reduction in Fmax was achieved by partial inhibition of ROCK and PKC. The results can be explained by a model containing a contractile apparatus and a cytoskeletal scaffold where force generated by the contractile apparatus is transmitted to the extracellular domain through the cytoskeleton. The results indicate that ROCK and PKC play an important role in force transmission through the cytoskeleton.

Effects of Achillea millefolium extract on spontaneous and oxytocin-induced isolated rat uterine contractions

Objective: Achillea millefolium (AM) is widely used in traditional medicine in a wide geography due to its effects on the female reproductive system. However, its effect on uterine smooth muscle contractions is unknown. Our study aims to investigate the effects of AM on spontaneous and oxytocin-induced isolated rat uterine contractions. &#x0D; &#x0D; Method: Myometrial strips were obtained from 32 adult Wistar Albino rats. Contraction amplitudes and frequencies were recorded by isolated tissue bath system after either of the following: administration of only Krebs-Hanseleit (KBH) solution, administration of Achillea millefolium extract (AME); administration of KBH or AME after inducing contractions with oxytocin. The differences at the level of p

Network pharmacology and LC-MS approachs to explore the active compounds and mechanisms of Yuanjiang decoction for treating bradyarrhythmia

BackgroundYuanjiang decoction (YJD), a traditional Chinese medicinal prescription, has been found to have a significant heart rate-increasing effect and is effective in the treatment of symptomatic bradyarrhythmia in previous studies. However, its specific components and potential mechanisms remain unclear. MethodsIn this study, we detected and identified the main compounds of YJD using liquid chromatography-mass spectrometry (LC-MS). Through the approach of network pharmacology, we predicted the core targets of the active components, bradyarrhythmia targets, and obtained potential anti-bradyarrhythmia targets of YJD. We further performed protein to protein interaction (PPI), gene ontology (GO) enrichment analyses and kyoto encyclopedia of genes and genomes (KEGG) signaling pathway analyses for core targets, and constructed network of key active ingredients-core targets of YJD. Finally, molecular docking and molecular dynamics simulation were performed for key active ingredients and core targets. ResultsThe YJD contains a total of 35 main chemical components. The key active ingredients-core targets network contains 36 nodes and 90 edges, including 20 key active ingredients and 16 core targets. The core targets in the PPI network were TP53, TNF, HRAS, PPARG, IL1B, KCNH2, SCN5A, IDH1, LMNA, ACHE, F2, DRD2, CALM1, KCNQ1, TNNI3, IDH2 and TNNT2. KEGG pathway analysis showed that YJD treatment of bradyarrhythmia mainly involves neuroactive ligand-receptor interaction, adrenergic signaling in cardiomyocytes, cAMP signaling pathway, calcium signaling pathway, cholinergic synaptic and serotonergic synapse signaling pathway. The biological processes mainly include regulation of hormone levels, regulation of cardiac contraction, chemical synaptic transmission, circadian rhythm, positive regulation of heart rate, smooth muscle contraction, response to metal ion, oxidation-reduction process, neurotransmitter transport and import across plasma membrane. Molecular docking and molecular dynamics simulation results showed that hesperidin and tetrahydropalmatine had higher affinity with DRD2 and KCNQ1, respectively. ConclusionThis study reveals the pharmacodynamic material basis of YJD and its potential multicomponent–multitarget–multipathway pharmacological effects, predicted its potential anti-bradyarrhythmia mechanism may be related to the regulation of myocardial autonomic nervous function and related ion channels. Our work demonstrates that YJD has great potential for treating bradyarrhythmias as a complementary medicine, and the results can provide a theoretical basis for the development and clinical application of YJD.

Three-Dimensional Organization of Chicken Genome Provides Insights into Genetic Adaptation to Extreme Environments.

The high-throughput chromosome conformation capture (Hi-C) technique is widely used to study the functional roles of the three-dimensional (3D) architecture of genomes. However, the knowledge of the 3D genome structure and its dynamics during extreme environmental adaptations remains poor. Here, we characterized 3D genome architectures using the Hi-C technique for chicken liver cells. Upon comparing Lindian chicken (LDC) liver cells with Wenchang chicken (WCC) liver cells, we discovered that environmental adaptation contributed to the switching of A/B compartments, the reorganization of topologically associated domains (TADs), and TAD boundaries in both liver cells. In addition, the analysis of the switching of A/B compartments revealed that the switched compartmental genes (SCGs) were strongly associated with extreme environment adaption-related pathways, including tight junction, notch signaling pathway, vascular smooth muscle contraction, and the RIG-I-like receptor signaling pathway. The findings of this study advanced our understanding of the evolutionary role of chicken 3D genome architecture and its significance in genome activity and transcriptional regulation.

Integrated Mechanisms of Polarity-Based Extracts of Cucumis melo L. Seed Kernels for Airway Smooth Muscle Relaxation via Key Signaling Pathways Based on WGCNA, In Vivo, and In Vitro Analyses.

The present study aimed to determine the mechanisms responsible for calcium-mediated smooth muscle contractions in C. melo seeds. The phytochemicals of C. melo were identified and quantified with the aid of Liquid Chromatography Electrospray Ionization Tandem Mass Spectrometric (LC/ESI-MS/MS) and high-performance liquid chromatography (HPLC), and then tested in-vitro and in vivo to confirm involvement in smooth muscle relaxation. Allergic asthma gene datasets were acquired from the NCBI gene expression omnibus (GEO) and differentially expressed gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), and functional enrichment analysis were conducted. Additionally, molecular docking of key genes was carried out. Kaempferol, rutin, and quercetin are identified as phytochemical constituents of C. melo seeds. Results indicated that C. melo seeds exhibit a dose-dependent relaxant effect for potassium chloride (80 mM)- induced spastic contraction and calcium antagonistic response in calcium dose-response curves. The functional enrichment of WGCNA and DEG asthma-associated pathogenic genes showed cytokine-mediated pathways and inflammatory responses. Furthermore, CACNA1A, IL2RB, and NOS2 were identified as key genes with greater binding affinity with rutin, quercitrin, and kaempferol in molecular docking. These results show that the bronchodilator and antidiarrheal effects of C. melo were produced by altering the regulatory genes of calcium-mediated smooth muscle contraction.

Avermectin induces cardiac toxicity in early embryonic stage of zebrafish

Avermectin is a widely used insecticide, and it is mainly effective against animal parasites and insects. Given its extensive use in agriculture, a large amount of avermectin is accumulated in natural waters. Avermectin is a neurotoxin that affects the autonomous behavior of zebrafish and inhibits neurological responses in invertebrates via GABA-chloride channels. In this study, we used zebrafish as a model organism to explore the lethal teratogenic effects of different avermectin concentrations. We found that 50-μg/L avermectin could cause significant malformation abnormalities during the development of zebrafish heart, changes in heart rate, and significant reduction in hatching rate and body length. Transcriptome data revealed that 499 genes were upregulated and 877 genes were downregulated at 72 h post-fertilization (hpf), whereas 1805 genes were upregulated and 836 genes were downregulated at 120 hpf. According to gene ontology (GO) enrichment analysis, avermectin affected cardiac circulation and myocardial fiber development. KEGG analysis revealed that avermectin treatment significantly altered the activity of signal pathways associated with cardiac rhythm and vascular smooth muscle contraction. The main target of avermectin was identified as the heart, as it affected heart development and function by altering cardiac-related gene expression that led to a heart defect phenotype. Our findings indicate that developing zebrafish are sensitive to avermectin, which targets the heart.