OBJECTIVE: To compare the effect of combination of intradermal needling with oral motor therapy and simple oral motor therapy on salivation in children with cerebral palsy. METHODS: A total of 60 children with salivation in cerebral palsy were randomized into an observation group and a control group, 30 cases in each group. The observation group was treated with intradermal needling (kept for 24 hours each time at Jiache [ST 6], Dicang [ST 4], tongue three needles, etc. ) and oral motor therapy, while the control group was only given oral motor therapy. The intradermal needling was performed 3 times a week, and oral motor therapy was performed 5 times a week, 4 weeks as a course, totally 3 courses of treatment were required. The classification of teacher drooling scale (TDS), drooling severity and Kubota water swallow test, dysphagia disorders survey (DDS) score were compared before treatment and after 4, 8 and 12 weeks of treatment in both groups, and the clinical efficacy was evaluated. RESULTS: After 8 weeks of treatment in the observation group and after 12 weeks of treatment in the two groups, the classification of TDS and drooling severity were improved (P<0.05), and the observation group was better than the control group after 12 weeks of treatment (P<0.05). After 8 and 12 weeks of treatment, the DDS scores of oral period in the observation group were lower than those before treatment (P<0.05). The total effective rate in the observation group was 83.3% (25/30), which was higher than 53.3% (16/30) in the control group (P<0.05). CONCLUSION The combination of intradermal needling with oral motor therapy can improve salivation symptoms and swallowing function in children with cerebral palsy, the effect is better than oral motor therapy alone, and the effect is earlier.
Acupuncture Points ; Acupuncture Therapy ; Cerebral Palsy/therapy* ; Child ; Deglutition Disorders/therapy* ; Humans ; Salivation ; Sialorrhea/therapy* ; Treatment Outcome

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

OBJECTIVE: To investigate the protective effect of Zengye Decoction (, ZYD) on the submandibular glands (SMGs) in nonobese diabetic (NOD) mice. METHODS: Twenty-seven female NOD mice were randomly equally divided into 3 groups: the model group, the hydroxychloroquine (HCQ) group, and the ZYD group. Nine C57/B6 mice served as the normal group. After 1-week acclimation, the HCQ and ZYD groups were intragastrically administered with HCQ and ZYD, respectively, and the normal and model groups were administered with normal saline. Changes in the salivary flow rate were observed. Mice from all 4 groups were sacrificed at the age of 20 weeks. The serum and SMGs were collected. Serum cytokines gamma-interferon (IFN-γ), interleukin-10 (IL-10) were detected by enzyme-linked immunosorbent assay. Histological changes in the submandibular glands were examined by hematoxylin and eosin staining. The mRNA expression of IFN-γ, IL-10 and vasoactive intestinal peptide (VIP) in the submandibular glands were measured by real-time polymerase chain reaction. RESULTS: Compared with the model group, the salivary flow of the ZYD group significantly increased (P<0.05), the extent of the histological changes was ameliorated (P<0.05), and the Th1/Th2 cytokine imbalance was remedied (P<0.05). In the ZYD-treated mice, the VIP mRNA was up-regulated (P<0.05). CONCLUSIONS ZYD is beneficial in protecting structure and function of SMGs in NOD mice. The mechanism may be associated with the correction of the Th1/Th2 cytokine imbalance, and with the prevention of a progressive decline of the VIP level.
Animals ; Cytokines ; blood ; Drugs, Chinese Herbal ; pharmacology ; Female ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Salivation ; drug effects ; Sjogren's Syndrome ; drug therapy ; immunology ; Submandibular Gland ; drug effects ; pathology ; Th1 Cells ; immunology ; Th2 Cells ; immunology ; Vasoactive Intestinal Peptide ; genetics

OBJECTIVE: To evaluate the secretory function of parotid glands by dynamic magnetic resonance (MR) sialography and determine the clinical performance of this technique in diagnosing and evaluating Sjögren's syndrome (SS) patients. MATERIALS AND METHODS: This study enrolled 29 healthy volunteers (25 women and 4 men; mean age, 34.8 ± 6.3 years; age range, 26–47 years) and 25 primary SS (pSS) patients (23 women and 2 men; mean age, 37.7 ± 7.9 years; age range, 25–50 years) with decreased secretory function. The volume of the parotid gland ducts was precisely measured for both groups at single pre- and 6 post-gustatory-stimulated phases. Time-dependent volume change ratio curves were generated, four parameters were derived from the curves: the slope of the increase in the first post-stimulation phase (slope(1st)), the peak value, the time-to-peak, the total saliva secretion post-stimulation. All values were used to quantitatively evaluate the secretory function of the parotid gland. The repeated measurement analysis, Mann-Whitney U test and receiver operating characteristic curve were applied. RESULTS: Time-dependent volume change ratio curves demonstrated that there is a statistically significant difference between the two groups (F = 8.750; p = 0.005). A quickly increasing curve was shown in the volunteer group, whereas a slowly increasing curve was shown in the pSS patient group. The slope(1st), peak value and total saliva secretion post-stimulation of the patient group were significantly lower than those of the volunteer group (p = 0.005, p = 0.003, and p = 0.002, respectively). The time-to-peak between the two groups was not significantly different (p = 0.383). The slope(1st) can be used as a discriminator to diagnose SS patients (p = 0.015; odds ratio = 4.234; area under the curve = 0.726). CONCLUSION: Dynamic MR sialography is proven to be an effective method in evaluating salivary gland function and has a great potential in diagnosing and evaluating pSS patients.
Autoimmune Diseases ; Female ; Healthy Volunteers ; Humans ; Male ; Methods ; Odds Ratio ; Parotid Gland ; ROC Curve ; Saliva ; Salivary Glands ; Salivation ; Sialadenitis ; Sialography ; Volunteers

Sjögren's syndrome (SS) is a chronic heterogeneous disease that mainly affects exocrine glands, leading to sicca syndromes such as xerostomia. Despite the second highest prevalence rate among systemic autoimmune diseases, its pathophysiology remains largely unknown. Here we report that SKG mice, a cardinal model of Th17 cell-mediated arthritis, also develop a secondary form of SS-like disorder upon systemic exposure to purified curdlan, a type of β-glucan. The reduced production of saliva was not caused by focal immune cell infiltrates but was associated with IgG deposits in salivary glands. Sera from curdlan-injected SKG mice contained elevated titers of IgG (predominantly IgG1), autoantibody to the muscarinic type 3 receptor (M3R) and inhibited carbachol-induced Ca2+ signaling in salivary acinar cells. These results suggest that the Th17 cells that are elicited in SKG mice promote the production of salivary gland-specific autoantibodies including anti-M3R IgG; the antibodies are then deposited on acinar cells and inhibit M3R-mediated signaling required for salivation, finally leading to hypofunction of the salivary glands. This type II hypersensitivity reaction may explain the origin of secondary SS occurring without focal leukocyte infiltrates.
Acinar Cells ; Animals ; Antibodies ; Arthritis ; Autoantibodies ; Autoimmune Diseases ; Exocrine Glands ; Hypersensitivity ; Immunoglobulin G ; Leukocytes ; Mice ; Prevalence ; Saliva ; Salivary Glands ; Salivation ; Sjogren's Syndrome ; Th17 Cells ; Xerostomia

Muscarinic acetylcholine receptors (mAChRs), including M1-M5 subtypes, are classic receptors in regulating water, ion, and solute transport in salivary gland. Our work focuses on the studies on the expression pattern and function of mAChR in the submandibular gland (SMG), and the underlying mechanism involved in the mAChR-regulated secretion, together with the effect of parasympathectomy on the salivary secretion. Microvascular autotransplantation of SMG into the temporal fossa provides a continuous and endogenous source of fluids, and is currently an effective method for treating severe keratoconjunctivitis sicca. By using RT-PCR, Western blotting, and immunofluorescence, our data demonstrated that the expression of M1 and M3 subtypes were decreased in latent period in rabbit SMG autotransplantation model, whereas carbachol stimulation promoted the salivary secretion, as well as M1 and M3 expressions. By contrast, mAChRs were hypersensitive in epiphora SMGs, whereas atropine gel and botulinum toxin A application significantly inhibited the hypersecretion in both animal models and patients. Furthermore, the possible intracellular signal molecules involved in the mAChR-modulated salivary secretion were explored. Activation of mAChR upregulated the expression of aquaporin 5 (AQP5), the main transporter that mediated water secretion through transcellular pathway, and led to AQP5 trafficking from lipid rafts to non-lipid microdomain. Extracellular signal-regulated kinase 1/2 (ERK1/2) was involved in the mAChR-regulated AQP5 content. mAChR activation also modulated the expression, distribution, and function of tight junction proteins, and increased paracellular permeability. ERK1/2/β-arrestin2/clathrin/ubiquitin signaling pathway was responsible for the mAChR-regulated downregulation of tight junction molecule claudin-4. Cytoskeleton filamentous actin (F-actin) was also involved in the distribution and barrier function of epithelial tight junctions. Besides, endothelial tight junctions were opened by mAChR agonist-evoked salivation in the mice. Furthermore, parasympathetic denervation increased resting salivary secretion in the long terminrats and minipigs. Taken together, our work demonstrated that mAChR regulated saliva secretion via transcellular and paracellular pathways in SMG epithelium as well as tight junction opening in SMG endothelium. Modulation of mAChR might be a promising strategy to ameliorate SMG dysfunction.
Animals ; Aquaporin 5 ; Carbachol ; Humans ; Mice ; Rabbits ; Receptors, Muscarinic ; Salivation ; Submandibular Gland

Alcohol intake is known to affect various organs in the human body, causing reduction of salivation in the oral cavity. Hypo-salivation effect of alcohol is a common feature, but the mechanism in salivary glands is still poorly studied. Therefore, in this study, the changes in salivary secretion and water channel protein (aquaporin5, AQP5) in salivary glands of mice were investigated after ethanol administration. Animals were divided in to 4 groups with the control, 4 g/kg ethanol, 8 g/kg ethanol and 16 g/kg ethanol administration groups. One hour after ethanol administration, saliva was collected from the oral cavity, and the animals were killed and parotid and submandibular glands were extracted to analyze the histopathology, AQP5 immunihistochemistry and AQP5 protein level. According to the results, the salivation rate decreased irrespective of the ethanol dose in mice, and viscosities increased with increase in ethanol dose. However, there were no pathological changes in parotid and submandibular glands due to ethanol administration. Expression of AQP5 in parotid and submandibular glands decreased with increase ethanol administration These results indicate that the reduction of salivary secretion due to acute alcohol intake is closely related to decrease of the water channel protein such as AQP5 in parotid glands and submandibular glands, rather than the damage of salivary glands.
Animals ; Aquaporin 5 ; Eating ; Ethanol ; Human Body ; Mice ; Mouth ; Parotid Gland ; Saliva ; Salivary Glands ; Salivation ; Submandibular Gland ; Viscosity ; Water

Calcium has versatile roles in diverse physiological functions. Among these functions, intracellular Ca²⁺ plays a key role during the secretion of salivary glands. In this review, we introduce the diverse cellular components involved in the saliva secretion and related dynamic intracellular Ca²⁺ signals. Calcium acts as a critical second messenger for channel activation, protein translocation, and volume regulation, which are essential events for achieving the salivary secretion. In the secretory process, Ca²⁺ activates K⁺ and Cl⁻ channels to transport water and electrolyte constituting whole saliva. We also focus on the Ca²⁺ signals from intracellular stores with discussion about detailed molecular mechanism underlying the generation of characteristic Ca²⁺ patterns. In particular, inositol triphosphate signal is a main trigger for inducing Ca²⁺ signals required for the salivary gland functions. The biphasic response of inositol triphosphate receptor and Ca²⁺ pumps generate a self-limiting pattern of Ca²⁺ efflux, resulting in Ca²⁺ oscillations. The regenerative Ca²⁺ oscillations have been detected in salivary gland cells, but the exact mechanism and function of the signals need to be elucidated. In future, we expect that further investigations will be performed toward better understanding of the spatiotemporal role of Ca²⁺ signals in regulating salivary secretion.
Calcium Signaling ; Calcium ; Chloride Channels ; Inositol ; Inositol 1,4,5-Trisphosphate Receptors ; Protein Transport ; Saliva ; Salivary Glands ; Salivation ; Second Messenger Systems ; Secretory Pathway ; Water

This research is to estimate the toxicity of Atractylodis Rhizoma Alba (ARA) in F344 rats and to find a dose level for the 13 weeks toxicity study. A hot water extract of ARA (ARWE) was administered orally to F344 rats at dose levels of 0 (vehicle control), 500, 1000, 2000, 3500, and 5000 mg/kg/day for 2 weeks. Each group was composed to five male and five female F344 rats. According to the result, there were no ARWE-related adverse changes in mortality, body weights, food consumption, urinalysis, hematology, clinical chemistry, gross finding at necropsy, and organ weight examination. Salivation was observed in 3500 and 5000 mg/kg/day in male and female rats but it could not have found any relationship with ARWE administration. Based on our findings, ARWE may not cause toxicity in rats under the experimental conditions. Therefore, dose level of 5000 mg/kg/day as a highest treatment group in 13-week exposure study is recommended for further toxicity assessment.
Animals ; Body Weight ; Chemistry, Clinical ; Female ; Hematology ; Humans ; Male ; Mortality ; Organ Size ; Rats ; Rats, Inbred F344* ; Salivation ; Toxicity Tests ; Urinalysis ; Water

OBJECTIVETo observe the effect of Yangfei Ziyin Decoction (YZD) on symptoms, serum levels of TNF-alpha, IL-6, and aquaporin-5 (AQP-5), and pathology of Sj6gren's syndrome (SS) model mice.

METHODSTotally 60 mice were divided into 6 groups according to random digit table, i.e., the model group, the normal control group, the high, medium, low dose YZD groups (administered with YZD at 36.7, 18.4, 9.2 g/kg, 0.2 mL/10 g), the Chinese patent medicine group [CPM, administered with total glucosides of paeony at 0.6 g/kg], 10 mice in each group. All intervention was performed for six successive days in a week, with an interval of one day, a total of 50 days. Body weight, salivary secretion, food and water intake were measured at day10, 20, 30, 40, and 50, respectively. At day 50 blood was collected. Submandibular gland, thymus, and spleen were weighed. Serum levels of TNF-alpha, IL-6, and AQP-5 were detected by ELISA. Pathological changes of submandibular gland were observed. Results Compared with the normal control group, there was no change in water intake of mice in the model group, but with reduced salivary secretion (P < 0.01, P < 0.05). Thymus/spleen/submandibular gland weight and index increased in the model group (P < 0.01, P < 0.05). Compared with the model group at the same time point, salivary secretion increased in the CPM group and 3 YZD groups (P < 0.01 , P < 0.05). Compared with the model group, thymus/spleen/submandibular gland weight and index decreased in the CPM group (P < 0.01, P < 0.05). Thymus/submandibular gland weight and index decreased in the low dose YZD group (P < 0.01, P < 0.05). Thymus/submandibular gland weight and index, and spleen index decreased in high and medium dose YZD groups (P < 0.01 , P < 0.05). Levels of TNF-alpha and IL-6 decreased, but AQP-5 level increased in the CPM group (P < 0.05). AQP-5 level increased in high and medium dose YZD groups (P < 0.01 , P < 0.05). In the model group alveoli and duct of salivary gland were destroyed, alveoli and duct were irregular, epithelial cells were degenerated, necrotic, and desquamated. Mild-to-moderate lymphocytic infiltration occurred around submandibular gland. Pathological changes were alleviated in the CPM group and 3 YZD groups.

CONCLUSIONYZD could improve clinical symptoms, serum levels of TNF-alpha, IL-6, AQP-5, and pathological changes of SS model mice.

Animals ; Aquaporin 5 ; Disease Models, Animal ; Drugs, Chinese Herbal ; therapeutic use ; Glucosides ; Interleukin-6 ; Mice ; Paeonia ; Salivation ; Sjogren's Syndrome ; drug therapy ; Submandibular Gland ; Tumor Necrosis Factor-alpha