Evidence to support cultivated fruiting body of Ophiocordyceps sinensis (Ascomycota)'s role in relaxing airway smooth muscle.

ETHNOPHARMACOLOGICAL RELEVANCE: Ophiocordyceps sinensis (O. sinensis) is a genus of Ascomycete fungus that is endemic to the alpine meadows of the Tibetan Plateau and adjoining Himalayas. It has been used traditionally as a tonic to improve respiratory health in ancient China as well as to promote vitality and longevity. Bioactive components found in O. sinensis such as adenosine, cordycepin, 3-deoxyadenosine, L-arginine and polysaccharides have gained increasing interest in recent years due to their antioxidative and other properties, which include anti-asthmatic, antiviral, immunomodulation and improvement of general health. AIM OF THE STUDY: This study's primary aim was to investigate the effect of a cultivated fruiting body of O. sinensis strain (OCS02®) on airways patency and the secondary focus was to investigate its effect on the lifespan of Caenorhabditis elegans. MATERIALS AND METHODS: A cultivated strain, OCS02®, was employed and the metabolic profile of its cold-water extract (CWE) was analysed through liquid chromatography-mass spectrometry (LC-MS). Organ bath approach was used to investigate the pharmacological properties of OCS02® CWE when applied on airway tissues obtained from adult male Sprague-Dawley rats. The airway relaxation mechanisms of OCS02® CWE were explored using pharmacological tools, where the key regulators in airway relaxation and constriction were investigated. For the longevity study, age-synchronised, pos-1 RNAi-treated wild-type type Caenorhabditis elegans at the L4 stage were utilised for a lifespan assay. RESULTS: Various glycopeptides and amino acids, particularly a high concentration of L-arginine, were identified from the LC-MS analysis. In airway tissues, OCS02® CWE induced a significantly greater concentration-dependent relaxation when compared to salbutamol. The relaxation response was significantly attenuated in the presence of NG-Nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) and several K+ channel blockers. The longevity effect induced by OCS02® CWE (5 mg/mL and above) was observed in C. elegans by at least 17%. CONCLUSIONS: These findings suggest that the airway relaxation mechanisms of OCS02® CWE involved cGMP-dependent and cGMP-independent nitric oxide signalling pathways. This study provides evidence that the cultivated strain of OCS02® exhibits airway relaxation effects which supports the traditional use of its wild O. sinensis in strengthening respiratory health.

Investigation of Structural Peculiarities of Smooth Muscle Titin Aggregates, Formed under Different In Vitro Conditions, by Small-Angle X-Ray Scattering and Fourier Transform Infrared Spectroscopy.

Small-angle X-ray scattering (SAXS) and Fourier transform infrared (FTIR) spectroscopy were used to investigate structural peculiarities of two types of amyloid aggregates of smooth muscle titin, which differed in their morphology and ability to disaggregate, and differently bound thioflavin T dye. SAXS showed that the structure/shape of the two titin aggregate types was close to a flat shape. FTIR spectroscopy revealed no differences in the secondary structure of the two types. These data suggest that both types of "flat-shape" titin aggregates are identical in their secondary structure and, as shown previously, have a quaternary cross-ß structure. An assumption was made that the most stable supramolecular complexes of a cross-ß structure, which do not differ in their secondary structure, formed first during the aggregation of smooth muscle titin. Then, depending on ambient conditions, these supramolecular structures could form titin aggregates of different morphology and properties.

Pulmonary surfactant and prostaglandin E2 in airway smooth muscle relaxation of human and male guinea pigs.

Pulmonary surfactant serves as a barrier to respiratory epithelium but can also regulate airway smooth muscle (ASM) tone. Surfactant (SF) relaxes contracted ASM, similar to ß2-agonists, anticholinergics, nitric oxide, and prostanoids. The exact mechanism of surfactant relaxation and whether surfactant relaxes hyperresponsive ASM remains unknown. Based on previous research, relaxation requires an intact epithelium and prostanoid synthesis. We sought to examine the mechanisms by which surfactant causes ASM relaxation. Organ bath measurements of isometric tension of ASM of guinea pigs in response to exogenous surfactant revealed that surfactant reduces tension of healthy and hyperresponsive tracheal tissue. The relaxant effect of surfactant was reduced if prostanoid synthesis was inhibited and/or if prostaglandin E2-related EP2 receptors were antagonized. Atomic force microscopy revealed that human ASM cells stiffen during contraction and soften during relaxation. Surfactant softened ASM cells, similarly to the known bronchodilator prostaglandin E2 (PGE2) and the cell softening was abolished when EP4 receptors for PGE2 were antagonized. Elevated levels of PGE2 were found in cultures of normal human bronchial epithelial cells exposed to pulmonary surfactant. We conclude that prostaglandin E2 and its EP2 and EP4 receptors are likely involved in the relaxant effect of pulmonary surfactant in airways.

Effects of Platelet-Activating Factor (PAF) on the Mechanical Activities of Lower Urinary Tract and Genital Smooth Muscles.

Since its first discovery as a bioactive phospholipid inducing potent platelet aggregation, platelet-activating factor (PAF) has been shown to be involved in a wide variety of inflammatory and allergic disease states. Many pharmacological studies in the 1980s and 1990s also showed that PAF induces endothelium-dependent vascular relaxation and contraction of various smooth muscles (SMs), including those in the airway, gastrointestinal organs, and uterus. However, since the late 1990s, there have been few reports on the SM contractions induced by PAF. The lower urinary tract (LUT), particularly the urinary bladder (UB) has attracted recent attention in SM pharmacology research because patients with LUT dysfunctions including overactive bladder are increasing as the population ages. In addition, recent clinical studies have implicated the substantial role of PAF in the inflammatory state in LUT because its production increases with smoking and with cancer. However, the effects of PAF on mechanical activities of LUT SMs including UBSM have not been investigated to date. Recently, we found that PAF very strongly increased mechanical activities of UBSM in guinea pigs and mice, and partly elucidated the possible mechanisms underlying these actions of PAF. In this review, we describe the effects of PAF on LUT SMs by introducing our recent findings obtained in isolated UBSMs and discuss the physiological and pathophysiological significance. We also introduce our data showing the effects of PAF on the SM mechanical activities of genital tissues (prostate and vas deferens).

Podocan unraveled: Understanding its role in tumor proliferation and smooth muscle regulation.

Podocan, a small leucine-rich repeat protein, is expressed in HIV-associated nephropathy, the cardiovascular system, and smooth muscle. Studies have linked PODN and PODNL to cancers such as osteosarcoma, glioma, and stomach cancer. Research has primarily focused on podocan's role in renal podocytes, injured smooth muscle cells, and various tumor cells. Bioinformatics studies have examined the role of PODN as a biomarker in tumors. Our research summarizes the modulatory role of podocan in smooth muscle and tumor proliferation through its suppression of cell proliferation and promotion of cell differentiation via various signaling pathways, including Wnt/ß-catenin, TGF-ß, and Akt/mTOR. We aim to provide a comprehensive overview of PODN's involvement in smooth muscle, cardiovascular system, and tumors by integrating current and past research. This review aims to enhance understanding and inform in the diagnosis, prognosis, and treatment of various diseases.

IL-13 and IL-17A activate ß1 integrin through an NF-kB/Rho kinase/PIP5K1γ pathway to enhance force transmission in airway smooth muscle.

Integrin activation resulting in enhanced adhesion to the extracellular matrix plays a key role in fundamental cellular processes. Although integrin activation has been extensively studied in circulating cells such as leukocytes and platelets, much less is known about the regulation and functional impact of integrin activation in adherent cells such as smooth muscle. Here, we show that two different asthmagenic cytokines, IL-13 and IL-17A, activate type I and IL-17 cytokine receptor families, respectively, to enhance adhesion of airway smooth muscle. These cytokines also induce activation of ß1 integrins detected by the conformation-specific antibody HUTS-4. Moreover, HUTS-4 binding is increased in the smooth muscle of patients with asthma compared to nonsmokers without lung disease, suggesting a disease-relevant role for integrin activation in smooth muscle. Indeed, integrin activation induced by the ß1-activating antibody TS2/16, the divalent cation manganese, or the synthetic peptide ß1-CHAMP that forces an extended-open integrin conformation dramatically enhances force transmission in smooth muscle cells and airway rings even in the absence of cytokines. We demonstrate that cytokine-induced activation of ß1 integrins is regulated by a common pathway of NF-κB-mediated induction of RhoA and its effector Rho kinase, which in turn stimulates PIP5K1γ-mediated synthesis of PIP2 at focal adhesions, resulting in ß1 integrin activation. Taken together, these data identify a pathway by which type I and IL-17 cytokine receptor family stimulation induces functionally relevant ß1 integrin activation in adherent smooth muscle and help to explain the exaggerated force transmission that characterizes chronic airway diseases such as asthma.

Therapeutic Potential of 1-(2-Chlorophenyl)-6,7-dimethoxy-3-methyl-3,4-dihydroisoquinoline.

The synthesized compound 1-(2-chlorophenyl) 6-7-dimethoxy-3-methyl-3,4-dihydroisoquinoline (DIQ) was investigated as a biological agent. Its potential to affect muscle contractility was predicted through in silico PASS analysis. Based on the in silico analysis, its capabilities were experimentally investigated. The study aimed to investigate the effects of DIQ on the ex vivo spontaneous contractile activity (CA) of smooth muscle (SM) tissue. DIQ was observed to reduce the strength of Ca2+-dependent contractions in SM preparations (SMP), possibly by increasing cytosolic Ca2+ levels through the activation of a voltage-gated L-type Ca2+ channel. DIQ potently affected calcium currents by modulating the function of muscarinic acetylcholine receptors (mAChRs) and 5-hydroxytryptamine (5-HT) receptors at a concentration of 50 µM. Immunohistochemical tests showed a 47% reduction in 5-HT2A and 5-HT2B receptor activity in SM cells and neurons in the myenteric plexus (MP), further confirming the effects of DIQ. Furthermore, a significant inhibition of neuronal activity was observed when the compound was co-administered with 5-HT to SM tissues. The conducted experiments confirm the ability of the isoquinoline analog to act as a physiologically active molecule to control muscle contractility and related physiological processes.

A novel compartmental approach for modeling stomach motility and gastric emptying.

The stomach, a central organ in the Gastrointestinal (GI) tract, regulates the processing of ingested food through gastric motility and emptying. Understanding the stomach function is crucial for treating gastric disorders. Experimental studies in this field often face difficulties due to limitations and invasiveness of available techniques and ethical concerns. To counter this, researchers resort to computational and numerical methods. However, existing computational studies often isolate one aspect of the stomach function while neglecting the rest and employ computationally expensive methods. This paper proposes a novel cost-efficient multi-compartmental model, offering a comprehensive insight into gastric function at an organ level, thus presenting a promising alternative. The proposed approach divides the spatial geometry of the stomach into four compartments: Proximal/Middle/Terminal antrum and Pyloric sphincter. Each compartment is characterized by a set of ordinary differential equations (ODEs) with respect to time to characterize the stomach function. Electrophysiology is represented by simplified equations reflecting the "slow wave behavior" of Interstitial Cells of Cajal (ICC) and Smooth Muscle Cells (SMC) in the stomach wall. An electro-mechanical coupling model translates SMC "slow waves" into smooth muscle contractions. Muscle contractions induce peristalsis, affecting gastric fluid flow velocity and subsequent emptying when the pyloric sphincter is open. Contraction of the pyloric sphincter initiates a retrograde flow jet at the terminal antrum, modeled by a circular liquid jet flow equation. The results from the proposed model for a healthy human stomach were compared with experimental and computational studies on electrophysiology, muscle tissue mechanics, and fluid behavior during gastric emptying. These findings revealed that each "ICC" slow wave corresponded to a muscle contraction due to electro-mechanical coupling behavior. The rate of gastric emptying and mixing efficiency decreased with increasing viscosity of gastric liquid but remained relatively unchanged with gastric liquid density variations. Utilizing different ODE solvers in MATLAB, the model was solved, with ode15s demonstrating the fastest computation time, simulating 180 s of real-time stomach response in just 2.7 s. This multi-compartmental model signifies a promising advancement in understanding gastric function, providing a cost-effective and comprehensive approach to study complex interactions within the stomach and test innovative therapies like neuromodulation for treating gastric disorders.

Factors influencing airway smooth muscle tone: a comprehensive review with a special emphasis on pulmonary surfactant.

A thin film of pulmonary surfactant lines the surface of the airways and alveoli, where it lowers the surface tension in the peripheral lungs, preventing collapse of the bronchioles and alveoli and reducing the work of breathing. It also possesses a barrier function for maintaining the blood-gas interface of the lungs and plays an important role in innate immunity. The surfactant film covers the epithelium lining both large and small airways, forming the first line of defense between toxic airborne particles/pathogens and the lungs. Furthermore, surfactant has been shown to relax airway smooth muscle (ASM) after exposure to ASM agonists, suggesting a more subtle function. Whether surfactant masks irritant sensory receptors or interacts with one of them is not known. The relaxant effect of surfactant on ASM is absent in bronchial tissues denuded of an epithelial layer. Blocking of prostanoid synthesis inhibits the relaxant function of surfactant, indicating that prostanoids might be involved. Another possibility for surfactant to be active, namely through ATP-dependent potassium channels and the cAMP-regulated epithelial chloride channels [cystic fibrosis transmembrane conductance regulators (CFTRs)], was tested but could not be confirmed. Hence, this review discusses the mechanisms of known and potential relaxant effects of pulmonary surfactant on ASM. This review summarizes what is known about the role of surfactant in smooth muscle physiology and explores the scientific questions and studies needed to fully understand how surfactant helps maintain the delicate balance between relaxant and constrictor needs.

G12/13 signaling in asthma.

Shortening of airway smooth muscle and bronchoconstriction are pathognomonic for asthma. Airway shortening occurs through calcium-dependent activation of myosin light chain kinase, and RhoA-dependent calcium sensitization, which inhibits myosin light chain phosphatase. The mechanism through which pro-contractile stimuli activate calcium sensitization is poorly understood. Our review of the literature suggests that pro-contractile G protein coupled receptors likely signal through G12/13 to activate RhoA and mediate calcium sensitization. This hypothesis is consistent with the effects of pro-contractile agonists on RhoA and Rho kinase activation, actin polymerization and myosin light chain phosphorylation. Recognizing the likely role of G12/13 signaling in the pathophysiology of asthma rationalizes the effects of pro-contractile stimuli on airway hyperresponsiveness, immune activation and airway remodeling, and suggests new approaches for asthma treatment.

Smooth muscle electromyography for detecting major alterations in the estrus cycle in rats.

Determining the female animal cycle is crucial in preclinical studies and animal husbandry. Changes in hormone levels during the cycle affect physiological responses, including altered contractility of the visceral smooth muscle. The study aimed to identify estrus and anestrus using smooth muscle electromyographic (SMEMG) measurements, in vivo fluorescent imaging (IVIS) and in vitro organ contractility of the uterus and cecum. The study involved sexually mature female Sprague-Dawley rats, aged 10-12 weeks. The rats received a daily injection of cetrorelix acetate solution for 7 days, while another group served as the control. The animals were subjected to gastrointestinal and myometrial SMEMG. The change in αvß3 integrin activity was measured with IVIS in the abdominal cavity. Contractility studies were performed in isolated organ baths using dissected uterus and cecum samples. Plasma samples were collected for hormone level measurements. A 3-fold increase in spontaneous contraction activity was detected in SMEMG measurements, while a significant decrease in αvß3 integrin was measured in the IVIS imaging procedure. Cetrorelix reduced the level of LH and the progesterone / estradiol ratio, increased the spontaneous activity of the cecum rings, and enhanced KCl-evoked contractions in the uterus. We found a significant change in the rate of SMEMG signals, indicating simultaneous increases in the contraction of the cecum and the non-pregnant uterus, as evidenced by isolated organ bath results. Fluorescence imaging showed high levels of uterine αvß3 integrin during the proestrus-estrus phase, but inhibiting the sexual cycle reduced fluorescence activity. Based on the results, the SMEMG and IVIS imaging methods are suitable for detecting estrus phase alterations in rats.

Bitter tastants relax the mouse gallbladder smooth muscle independent of signaling through tuft cells and bitter taste receptors.

Disorders of gallbladder motility can lead to serious pathology. Bitter tastants acting upon bitter taste receptors (TAS2R family) have been proposed as a novel class of smooth muscle relaxants to combat excessive contraction in the airways and other organs. To explore whether this might also emerge as an option for gallbladder diseases, we here tested bitter tastants for relaxant properties and profiled Tas2r expression in the mouse gallbladder. In organ bath experiments, the bitter tastants denatonium, quinine, dextromethorphan, and noscapine, dose-dependently relaxed the pre-contracted gallbladder. Utilizing gene-deficient mouse strains, neither transient receptor potential family member 5 (TRPM5), nor the Tas2r143/Tas2r135/Tas2r126 gene cluster, nor tuft cells proved to be required for this relaxation, indicating direct action upon smooth muscle cells (SMC). Accordingly, denatonium, quinine and dextromethorphan increased intracellular calcium concentration preferentially in isolated gallbladder SMC and, again, this effect was independent of TRPM5. RT-PCR revealed transcripts of Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, and analysis of gallbladders from mice lacking tuft cells revealed preferential expression of Tas2r108 and Tas2r137 in tuft cells. A TAS2R143-mCherry reporter mouse labeled tuft cells in the gallbladder epithelium. An in silico analysis of a scRNA sequencing data set revealed Tas2r expression in only few cells of different identity, and from in situ hybridization histochemistry, which did not label distinct cells. Our findings demonstrate profound tuft cell- and TRPM5-independent relaxing effects of bitter tastants on gallbladder smooth muscle, but do not support the concept that these effects are mediated by bitter receptors.

Helminth infection driven gastrointestinal hypermotility is independent of eosinophils and mediated by alterations in smooth muscle instead of enteric neurons.

Intestinal helminth infection triggers a type 2 immune response that promotes a 'weep-and sweep' response characterised by increased mucus secretion and intestinal hypermotility, which function to dislodge the worm from its intestinal habitat. Recent studies have discovered that several other pathogens cause intestinal dysmotility through major alterations to the immune and enteric nervous systems (ENS), and their interactions, within the gastrointestinal tract. However, the involvement of these systems has not been investigated for helminth infections. Eosinophils represent a key cell type recruited by the type 2 immune response and alter intestinal motility under steady-state conditions. Our study aimed to investigate whether altered intestinal motility driven by the murine hookworm, Nippostrongylus brasiliensis, infection involves eosinophils and how the ENS and smooth muscles of the gut are impacted. Eosinophil deficiency did not influence helminth-induced intestinal hypermotility and hypermotility did not involve gross structural or functional changes to the ENS. Hypermotility was instead associated with a dramatic increase in smooth muscle thickness and contractility, an observation that extended to another rodent nematode, Heligmosomoides polygyrus. In summary our data indicate that, in contrast to other pathogens, helminth-induced intestinal hypermotility is driven by largely by myogenic, rather than neurogenic, alterations with such changes occurring independently of eosinophils. (<300 words).

Extracellular cAMP elicits contraction of rat vas deferens: Involvement of ecto-5'-nucleotidase and adenosine A1 receptors.

AIMS: It is well established that intracellular cAMP contributes to the relaxation of vas deferens smooth muscle. In many tissues, intracellular cAMP is actively transported to the extracellular space, where it exerts regulatory functions, via its metabolite adenosine. These actions take place through the cAMP conversion to adenosine by ectoenzymes, a process called "extracellular cAMP-adenosine pathway". Herein, we investigated whether, in addition to ATP, extracellular cAMP might be an alternative source of adenosine, influencing the contraction of vas deferens smooth muscle. MAIN METHODS: The effects of cAMP, 8-Br-cAMP and adenosine were analyzed in the isometric contractions of rat vas deferens. cAMP efflux was analyzed by measuring extracellular cAMP levels after exposure of vas deferens segments to isoproterenol and forskolin in the presence or absence of MK-571, an inhibitor of MRP/ABCC transporters. KEY FINDINGS: While 8-Br-cAMP, a cell-permeable cAMP analog, induced relaxation of KCl-precontracted vas deferens, the non-permeant cAMP increased the KCl-induced contractile response, which was mimicked by adenosine, but prevented by inhibitors of ecto-5'-nucleotidase or A1 receptors. Our results also showed that isoproterenol and forskolin increases cAMP efflux via an MRP/ABCC transporter-dependent mechanism, since it is inhibited by MK-571. SIGNIFICANCE: Our data show that activation of ß-adrenoceptors and adenylyl cyclase increases cAMP efflux from vas deferens tissue, which modulates the vas deferens contractile response via activation of adenosine A1 receptors. Assuming that inhibition of vas deferens contractility has been proposed as a strategy for male contraception, the extracellular cAMP-adenosine pathway emerges as a potential pharmacological target that should be considered in studies of male fertility.

PM10 exposure induces bronchial hyperresponsiveness by upreguating acetylcholine muscarinic 3 receptor.

Exposure to particulate matter (PM10) can induce respiratory diseases that are closely related to bronchial hyperresponsiveness. However, the involved mechanism remains to be fully elucidated. This study aimed to demonstrate the effects of PM10 on the acetylcholine muscarinic 3 receptor (CHRM3) expression and the role of the ERK1/2 pathway in rat bronchial smooth muscle. A whole-body PM10 exposure system was used to stimulate bronchial hyperresponsiveness in rats for 2 and 4 months, accompanied by MEK1/2 inhibitor U0126 injection. The whole-body plethysmography system and myography were used to detect the pulmonary and bronchoconstrictor function, respectively. The mRNA and protein levels were determined by Western blotting, qPCR, and immunofluorescence. Enzyme-linked immunosorbent assay was used to detect the inflammatory cytokines. Compared with the filtered air group, 4 months of PM10 exposure significantly increased CHRM3-mediated pulmonary function and bronchial constriction, elevated CHRM3 mRNA and protein expression levels on bronchial smooth muscle, then induced bronchial hyperreactivity. Additionally, 4 months of PM10 exposure caused an increase in ERK1/2 phosphorylation and increased the secretion of inflammatory factors in bronchoalveolar lavage fluid. Treatment with the MEK1/2 inhibitor, U0126 inhibited the PM10 exposure-induced phosphorylation of the ERK1/2 pathway, thereby reducing the PM10 exposure-induced upregulation of CHRM3 in bronchial smooth muscle and CHRM3-mediated bronchoconstriction. U0126 could rescue PM10 exposure-induced pathological changes in the bronchus. In conclusion, PM10 exposure can induce bronchial hyperresponsiveness in rats by upregulating CHRM3, and the ERK1/2 pathway may be involved in this process. These findings could reveal a potential therapeutic target for air pollution induced respiratory diseases.

Tetrodotoxin-resistant mechanosensitivity and L-type calcium channel-mediated spontaneous calcium activity in enteric neurons.

Gut motility undergoes a switch from myogenic to neurogenic control in late embryonic development. Here, we report on the electrical events that underlie this transition in the enteric nervous system, using the GCaMP6f reporter in neural crest cell derivatives. We found that spontaneous calcium activity is tetrodotoxin (TTX) resistant at stage E11.5, but not at E18.5. Motility at E18.5 was characterized by periodic, alternating high- and low-frequency contractions of the circular smooth muscle; this frequency modulation was inhibited by TTX. Calcium imaging at the neurogenic-motility stages E18.5-P3 showed that CaV1.2-positive neurons exhibited spontaneous calcium activity, which was inhibited by nicardipine and 2-aminoethoxydiphenyl borate (2-APB). Our protocol locally prevented muscle tone relaxation, arguing for a direct effect of nicardipine on enteric neurons, rather than indirectly by its relaxing effect on muscle. We demonstrated that the ENS was mechanosensitive from early stages on (E14.5) and that this behaviour was TTX and 2-APB resistant. We extended our results on L-type channel-dependent spontaneous activity and TTX-resistant mechanosensitivity to the adult colon. Our results shed light on the critical transition from myogenic to neurogenic motility in the developing gut, as well as on the intriguing pathways mediating electro-mechanical sensitivity in the enteric nervous system. HIGHLIGHTS: What is the central question of this study? What are the first neural electric events underlying the transition from myogenic to neurogenic motility in the developing gut, what channels do they depend on, and does the enteric nervous system already exhibit mechanosensitivity? What is the main finding and its importance? ENS calcium activity is sensitive to tetrodotoxin at stage E18.5 but not E11.5. Spontaneous electric activity at fetal and adult stages is crucially dependent on L-type calcium channels and IP3R receptors, and the enteric nervous system exhibits a tetrodotoxin-resistant mechanosensitive response. Abstract figure legend Tetrodotoxin-resistant Ca2+ rise induced by mechanical stimulation in the E18.5 mouse duodenum.

T cell and airway smooth muscle interaction: a key driver of asthmatic airway inflammation and remodeling.

Cross talk between T cells and airway smooth muscle (ASM) may play a role in modulating asthmatic airway inflammation and remodeling. Infiltrating T cells have been observed within the ASM bundles of asthmatics, and a wide range of direct and indirect interactions between T cells and ASM has been demonstrated using various in vitro and in vivo model systems. Contact-dependent mechanisms such as ligation and activation of cellular adhesion and costimulatory molecules, as well as the formation of lymphocyte-derived membrane conduits, facilitate the adhesion, bidirectional communication, and transfer of materials between T and ASM cells. T cell-derived cytokines, particularly of the Th1, Th2, and Th17 subsets, modulate the secretome, proliferation, and contractility of ASM cells. This review summarizes the mechanisms governing T cell-ASM cross talk in the context of asthma. Understanding the underlying mechanistic basis is important for directing future research and developing therapeutic interventions targeted toward this complex interaction.

Enteric neural stem cell transplant restores gut motility in mice with Hirschsprung disease.

The goal of this study was to determine if transplantation of enteric neural stem cells (ENSCs) can rescue the enteric nervous system, restore gut motility, reduce colonic inflammation, and improve survival in the Ednrb-KO mouse model of Hirschsprung disease (HSCR). ENSCs were isolated from mouse intestine, expanded to form neurospheres, and microinjected into the colons of recipient Ednrb-KO mice. Transplanted ENSCs were identified in recipient colons as cell clusters in "neo-ganglia." Immunohistochemical evaluation demonstrated extensive cell migration away from the sites of cell delivery and across the muscle layers. Electrical field stimulation and optogenetics showed significantly enhanced contractile activity of aganglionic colonic smooth muscle following ENSC transplantation and confirmed functional neuromuscular integration of the transplanted ENSC-derived neurons. ENSC injection also partially restored the colonic migrating motor complex. Histological examination revealed a significant reduction in inflammation in ENSC-transplanted aganglionic recipient colon compared with that of sham-operated mice. Interestingly, mice that received cell transplant also had prolonged survival compared with controls. This study demonstrates that ENSC transplantation can improve outcomes in HSCR by restoring gut motility and reducing the severity of Hirschsprung-associated enterocolitis, the leading cause of death in human HSCR.

[Pathological changes in the muscular tissue of the colon in diverticular disease]. / Patologicheskie izmeneniya myshechnoi tkani v stenke tolstoi kishki pri divertikulyarnoi bolezni.

The high incidence of colonic diverticular disease (DD) in the general population is a serious public health problem. According to statistics, DD is among the top five most common colorectal diseases. Complicated course of DD is observed in 12-15% of patients, and in 10.7% of cases can lead to death. Algorithms and recommendations for predicting the complicated course of DD for further prevention have not been developed. OBJECTIVE: Comparative analysis of clinical data and structural characteristics of the colonic muscular tissue in patients with different course of DD and without colonic diverticula to identify morphological predictors of a complicated DD. MATERIAL AND METHODS: A comparative analysis of clinical data, pathomorphological and ultrastructural changes of the colonic musculature in the surgical material from 68 patients undergoing left-sided hemicolectomy was carried out. RESULTS: The operative material of 37 patients with complicated course of DD, 19 with uncomplicated course of DD and 12 without diverticula was analyzed. In men, this disease occurs at a younger age than in women (Median age of men 49 (39.5; 61) years, women 66.5 (58; 81) years; U=178, p<0.001). It was shown that the area occupied by connective tissue fibres in the colonic musculature in patients with a complicated DD was 5 times greater (15%) than in observations with an uncomplicated DD (3%) and 50 times greater than in cases without colonic diverticula (0.3%; p<0.001). CONCLUSION: The present study demonstrates age- and sex-specific features of DD, as well as significant differences in the prevalence of fibrosis of the colonic musculature, which can be considered as a potential predictor of a complicated course of DD.