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

Melatonin is a neurotransmitter that modulates various physiological phenomena including regulation and maintenance of the circadian rhythm. Nicotinic acetylcholine receptors (nAChRs) play an important role in oral functions including orofacial muscle contraction, salivary secretion, and tooth development. However, knowledge regarding physiological crosstalk between melatonin and nAChRs is limited. In the present study, the melatonin-mediated modulation of nAChR functions using bovine adrenal chromaffin cells, a representative model for the study of nAChRs, was investigated. Melatonin inhibited the nicotinic agonist dimethylphenylpiperazinium (DMPP) iodide-induced cytosolic free Ca²⁺ concentration ([Ca²⁺](i)) increase and norepinephrine secretion in a concentration-dependent manner. The inhibitory effect of melatonin on the DMPP-induced [Ca²⁺](i) increase was observed when the melatonin treatment was performed simultaneously with DMPP. The results indicate that melatonin inhibits nAChR functions in both peripheral and central nervous systems.
Calcium Signaling ; Central Nervous System ; Chromaffin Cells ; Circadian Rhythm ; Cytosol ; Dimethylphenylpiperazinium Iodide ; Melatonin ; Muscle Contraction ; Neurotransmitter Agents ; Nicotinic Agonists ; Norepinephrine ; Physiological Phenomena ; Receptors, Nicotinic ; Tooth

Parkinson's disease is one of the most common neurodegenerative disorders world widely. Although curable therapies are practically not available yet, symptomatic managements using anti-Parkinson medications have shown to be quite effective to improve patients' quality of life. The discovery of dopaminergic deficits in Parkinson's disease in 1960s have brought about the human clinical trials of levodopa, which opened an “Era of Dopamine” in treatment history of the Parkinson's disease. Levodopa still remains gold standard. Dopamine agonists have proved their efficacies and delayed the development of long-term complications of levodopa use. Inhibitors of respective enzyme monoamine oxidase-B and catechol-O-methyltransferase, anticholinergics, and amantadine strengthen the therapeutic effects via either monotherapy or adjunctive way. Strategy of continuous dopaminergic stimulation and disease modification are weighing in current advances. This article is providing evidence-based review of pharmacological treatment of Parkinson's disease from early to advanced stages as well as management its unavoidable adverse reactions.
Amantadine ; Catechol O-Methyltransferase ; Cholinergic Antagonists ; Dopamine Agonists ; Drug Therapy ; Humans ; Levodopa ; Neurodegenerative Diseases ; Parkinson Disease ; Quality of Life ; Therapeutic Uses

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*

OBJECTIVETo explore the effect of nicotine on the autophagy level of human periodontal ligament cells (hPDLCs).

METHODSPeriodontal tissues collected from premolars for orthodontic treatment reasons were used to culture hPDLCs. Western blot analysis was performed to test the most optimal time and concentration of nicotine on the autophagy level of the hPDLCs. Transmission electron microscope and immunofluorescence observation were carried out to detect the form of autophagosomes and expression of autophagy related protein LC3 in hPDLCs under this optimal condition.

RESULTSProtein expression of LC3Ⅱ was up regulated with the 12 h nicotine stimulating. Besides that, the up regulation of the protein expression of LC3Ⅱ was concentration dependent and nicotine with a concentration of 1×10⁻⁵ mol·L⁻¹ was the most optimal condition. Transmission electron microscope and immunofluorescence observations indicated that nicotine would activate the autophagy level of hPDLCs by increasing the number of autophagosomes and up regulating the expression of autophagy related protein LC3.

CONCLUSIONSNicotine could increase autophagy level of hPDLCs, thus affecting the occurrence and development of smoking related periodontitis.

Autophagy ; Blotting, Western ; Cell Culture Techniques ; Cells, Cultured ; Humans ; Microtubule-Associated Proteins ; Nicotine ; pharmacology ; Nicotinic Agonists ; pharmacology ; Periodontal Ligament ; Periodontitis ; Up-Regulation

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*