Corticosteroids are used in the treatment of many diseases; however, they also induce various side effects. Dexamethasone is one of the most potent corticosteroids, and it has been reported to induce the side effect of impaired salivary gland function. This study aimed to evaluate the effects of dexamethasone on mouse submandibular gland function to gain insight into the mechanism of dexamethasone-induced salivary hypofunction. The muscarinic agonist carbachol (CCh) induced salivary secretion and was not affected by short-term dexamethasone treatment but was decreased following long-term dexamethasone administration. The expression levels of the membrane proteins Na-K-2Cl cotransporter, transmembrane member 16A, and aquaporin 5 were comparable between the control and long-term dexamethasone treatment groups. The CCh-induced increase in calcium concentration was significantly lower in the presence of extracellular Ca in the long-term dexamethasone treatment group compared to that in the control group. Furthermore, CCh-induced salivation in the absence of extracellular Ca and Ca ionophore A23187-induced salivation was comparable between the control and long-term dexamethasone treatment groups. Moreover, salivation induced by the Ca-ATPase inhibitor thapsigargin was diminished in the long-term dexamethasone treatment group. In summary, these results demonstrate that short-term dexamethasone treatment did not impair salivary gland function, whereas long-term dexamethasone treatment diminished store-operated Ca entry, resulting in hyposalivation in mouse submandibular glands.
Acinar Cells ; drug effects ; metabolism ; Animals ; Calcium ; metabolism ; Calcium Signaling ; drug effects ; Carbachol ; pharmacology ; Dexamethasone ; therapeutic use ; Mice ; Muscarinic Agonists ; pharmacology ; Saliva ; metabolism ; Salivation ; drug effects ; Submandibular Gland ; drug effects ; metabolism

The autonomic nervous system contributes to prostate cancer proliferation and metastasis. However, the exact molecular mechanism remains unclear. In this study, muscarinic acetylcholine receptor M1 (CHRM1) expression was measured via immunohistochemical analysis in human prostate cancer tissue array slides. PC-3, LNCaP, and A549 cells were treated with pirenzepine or carbachol, and the cell migration and invasion abilities were evaluated. Western blotting and quantitative real-time PCR were performed to measure GLI family zinc finger 1 (GLI1), patched 1 (PTCH1), and sonic hedgehog (SHH) expression levels. High expression of CHRM1 was found in early-stage human prostate cancer tissues. In addition, the selective CHRM1 antagonist pirenzepine inhibited PC-3, LNCaP, and A549 cell migration and invasion, but the agonist carbachol promoted the migration and invasion of these three cell lines. Muscarinic signaling can be relayed by hedgehog signaling. These data show that CHRM1 is involved in the regulation of prostate cancer migration and invasion through the hedgehog signaling pathway.
Carbachol/pharmacology* ; Cell Movement/genetics* ; Cell Proliferation ; Hedgehog Proteins/genetics* ; Humans ; Male ; Muscarinic Agonists/pharmacology* ; Muscarinic Antagonists/pharmacology* ; Patched-1 Receptor/genetics* ; Pirenzepine/pharmacology* ; Prostatic Neoplasms/pathology* ; Receptor, Muscarinic M1/genetics* ; Zinc Finger Protein GLI1/genetics*

Administration, Inhalation ; Adrenal Cortex Hormones ; therapeutic use ; Adrenergic beta-Agonists ; therapeutic use ; Anti-Asthmatic Agents ; therapeutic use ; Antibodies, Monoclonal, Humanized ; therapeutic use ; Asthma ; prevention & control ; therapy ; Guideline Adherence ; Humans ; Molecular Targeted Therapy ; Muscarinic Antagonists ; therapeutic use ; Omalizumab ; therapeutic use ; Practice Guidelines as Topic ; Primary Prevention ; Quality Improvement ; Sublingual Immunotherapy

After the approval and introduction of mirabegron, tadalafil, and botulinum toxin A for treatment of lower urinary tract symptoms/overactive bladder, focus of interest has been on their place in therapy versus the previous gold standard, antimuscarinics. However, since these agents also have limitations there has been increasing interest in what is coming next - what is in the pipeline? Despite progress in our knowledge of different factors involved in both peripheral and central modulation of lower urinary tract dysfunction, there are few innovations in the pipe-line. Most developments concern modifications of existing principles (antimuscarinics, beta3-receptor agonists, botulinum toxin A). However, there are several new and old targets/drugs of potential interest for further development, such as the purinergic and cannabinoid systems and the different members of the transient receptor potential channel family. However, even if there seems to be good rationale for further development of these principles, further exploration of their involvement in lower urinary tract function/dysfunction is necessary.
Adrenergic beta-3 Receptor Agonists/therapeutic use ; Botulinum Toxins, Type A/therapeutic use ; Drug Therapy, Combination ; Humans ; Molecular Targeted Therapy/methods/trends ; Muscarinic Antagonists/therapeutic use ; Neuromuscular Agents/therapeutic use ; Urinary Bladder, Overactive/*drug therapy

No abstract available.
Adrenergic beta-3 Receptor Agonists/therapeutic use ; Humans ; Muscarinic Antagonists/therapeutic use ; Precision Medicine/methods/*trends ; Urinary Bladder, Overactive/*therapy

BACKGROUND/AIMS: Gastric peristalsis begins in the orad corpus and propagates to the pylorus. Directionality of peristalsis depends upon orderly generation and propagation of electrical slow waves and a frequency gradient between proximal and distal pacemakers. We sought to understand how chronotropic agonists affect coupling between corpus and antrum. METHODS: Electrophysiological and imaging techniques were used to investigate regulation of gastric slow wave frequency by muscarinic agonists in mice. We also investigated the expression and role of cholinesterases in regulating slow wave frequency and motor patterns in the stomach. RESULTS: Both acetycholinesterase (Ache) and butyrylcholine esterase (Bche) are expressed in gastric muscles and AChE is localized to varicose processes of motor neurons. Inhibition of AChE in the absence of stimulation increased slow wave frequency in corpus and throughout muscle strips containing corpus and antrum. CCh caused depolarization and increased slow wave frequency. Stimulation of cholinergic neurons increased slow wave frequency but did not cause depolarization. Neostigmine (1 muM) increased slow wave frequency, but uncoupling between corpus and antrum was not detected. Motility mapping of contractile activity in gastric muscles showed similar effects of enteric nerve stimulation on the frequency and propagation of slow waves, but neostigmine (> 1 muM) caused aberrant contractile frequency and propagation and ectopic pacemaking. CONCLUSIONS: Our data show that slow wave uncoupling is difficult to assess with electrical recording from a single or double sites and suggest that efficient metabolism of ACh released from motor neurons is an extremely important regulator of slow wave frequency and propagation and gastric motility patterns.
Animals ; Cholinergic Neurons ; Cholinesterases* ; Metabolism ; Mice* ; Motor Neurons ; Muscarinic Agonists ; Muscle, Smooth ; Muscles ; Neostigmine ; Peristalsis ; Pylorus ; Stomach

Cognitive deficit is frequently observed in patients with schizophrenia. It is significantly associated with functional outcome. In the past 20 years, due to significant advances on the concept of schizophrenia, cognitive deficit has been accepted as a core feature. In the DSM-5, cognitive deficit does not introduce diagnostic criteria of schizophrenia, but did one dimension of diagnosis of psychosis. Existing schizophrenia drugs are effective in treatment of positive symptoms of schizophrenia, but lack of effectiveness on improving cognitive function. Led by NIMH (National Institute of Mental Health), the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) meeting was conducted in order to achieve consensus on measuring tools and neuropharmacological targets for clinical trials for development of new drugs for improvement of cognitive function in schizophrenia. At the MATRICS consensus meeting, glutamatergic modulators and nicotinic and muscarinic agonists are expected to be promising, but should be proven by a double-blind placebo-controlled multicenter study for patients.
Cognition ; Consensus ; Diagnosis ; Drug Therapy ; Humans ; Muscarinic Agonists ; National Institute of Mental Health (U.S.) ; Psychotic Disorders ; Schizophrenia*

Malakoplakia is a rare granulomatous disease that occurs commonly in the urinary tract and secondarily in the gastrointestinal tract. Most reported cases of malakoplakia are associated with immunosuppressive diseases or chronic prolonged illness. Here, we report a rare case of malakoplakia in a young healthy adolescent without any underlying disease. A 19-year-old female was referred to our hospital following the discovery of multiple rectal polyps with sigmoidoscopy. She had no specific past medical history but complained of recurrent abdominal pain and diarrhea for 3 months. A colonoscopy revealed diverse mucosal lesions including plaques, polyps, nodules, and mass-like lesions. Histological examination revealed a sheet of histiocytes with pathognomonic Michaelis-Gutmann bodies. We treated the patient with ciprofloxacin, the cholinergic agonist bethanechol, and a multivitamin for 6 months. A follow-up colonoscopy revealed that her condition was resolved with this course of treatment.
Anti-Bacterial Agents/therapeutic use ; Bethanechol/therapeutic use ; Biopsy ; Ciprofloxacin/therapeutic use ; *Colon/drug effects/pathology ; *Colonic Diseases/diagnosis/therapy ; Colonoscopy ; Drug Therapy, Combination ; Female ; Humans ; *Intestinal Mucosa/drug effects/pathology ; *Malacoplakia/diagnosis/therapy ; Muscarinic Agonists/therapeutic use ; Treatment Outcome ; Vitamins/therapeutic use ; Young Adult

Animals ; Arecoline ; pharmacology ; Cholinergic Agonists ; pharmacology ; Female ; Guinea Pigs ; In Vitro Techniques ; Male ; Muscle Contraction ; drug effects ; Muscle, Smooth ; physiology ; Pyloric Antrum ; physiology ; Receptor, Muscarinic M3 ; metabolism

In the present review article, we present an overview of beta-adrenoceptor (beta-AR) subtype expression at the mRNA and receptor protein levels in the human detrusor, the in vitro and in vivo bladder function of the beta3-AR, the in vivo effect of beta3-AR agonists on detrusor overactivity in animal models, and the available results of clinical trials of beta3-AR agonists for treating overactive bladder (OAB). There is a predominant expression of beta3-AR mRNA in human bladder, constituting 97% of total beta-AR mRNA. Also, functionally, the relaxant response of human detrusor to catecholamines is mainly mediated through the beta3-ARs. Moreover, the presence of beta1-, beta2-, and beta3-AR mRNAs in the urothelium and suburothelial layer of human bladder has been identified. Stimulation of urothelial beta-ARs results in the release of nitric oxide and an unknown substance inhibiting detrusor contractions from the urothelium. Intravenous application of CL316,243, a selective beta3-AR agonist, in rats selectively inhibits mechano-sensitive Adelta-fiber activity of the primary bladder afferents. A number of selective beta3-AR agonists are currently being evaluated in clinical trials for OAB with promising preliminary results. In conclusion, the beta3-AR agonists are the most notable alternative class of agents to antimuscarinics in the pharmacological treatment of OAB. The beta3-AR agonists act to facilitate bladder storage function probably through at least two mechanisms: first, direct inhibition of the detrusor, and second, inhibition of bladder afferent neurotransduction.
Adrenergic beta-Agonists ; Afferent Pathways ; Animals ; Catecholamines ; Contracts ; Dioxoles ; Humans ; Models, Animal ; Muscarinic Antagonists ; Nitric Oxide ; Rats ; RNA, Messenger ; Urinary Bladder ; Urinary Bladder, Overactive ; Urothelium