Dopamine regulates gastrointestinal mucosal barrier. Mucus plays important roles in the protection of intestinal mucosa. Here, the regulatory effect of dopamine on rat colonic mucus secretion was investigated. RT-PCR, immunofluorescence, Periodic Acid-Schiff reagent assay, Alcian blue-Periodic Acid-Schiff staining, and enzyme-linked immunosorbent assay were used to observe the expression of dopamine receptor and the direct effect of dopamine on the colonic mucus. Mice injected intraperitoneally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) destroying enteric dopamine (DA) neurons, rats microinjected with 6-hydroxydopamine (6-OHDA) into the bilateral substantia nigra damaging central dopaminergic neurons, and dopamine D5 receptor-downregulated transgenic mice were used to detect the effect of endogenous enteric dopamine or dopamine receptors on distal colonic mucus. Our results indicated that D5 immunoreactivity was widely distributed on the colonic goblet cells. Dopamine dose-dependently increased rat distal colonic mucus secretion in vitro. D1-like receptor antagonist SCH23390 inhibited dopamine (1 μΜ)-induced distal colonic mucus secretion. D1-like receptor agonist SKF38393 promoted mucin 2 (MUC2) secretion and increased the intracellular cAMP level of colonic mucosa. D5 receptor-downregulated transgenic mice showed a decreased colonic MUC2 content. MPTP-treated mice exhibited lower colonic dopamine content and decreased colonic mucus content. 6-OHDA rats had an increase in the dopamine content in colonic mucosa but decreases in the protein levels of D1 and D5 receptors and MUC2 content in the colonic mucosa. These findings reveal that dopamine is able to promote distal colonic mucus secretion through the D5 receptor, which provides important evidence to better understand the possible role of dopamine in the colonic mucosal barrier.

Monoamine oxidase-B is abundant in the colonic muscular layer including myenteric plexus of rat and human. Long-term administration of rasagiline can increase colonic DA thereby inhibiting colonic motility, suggesting that colonic MAO-B could be a potential drug target for colonic dysmotility.

ObjectivesExploring biomarkers monitoring latent tuberculosis infection (LTBI) treatment effectiveness would benefit optimizing the therapeutic regimen. This study aims to identify potential mycobacteria-specific antigen-induced cytokines associated with host responses to preventive treatment.MethodsBased on a randomized controlled trial on LTBI treatment among individuals with chest radiography abnormalities suggestive of prior tuberculosis (TB), the dynamically changed cytokine levels in QuantiFERON-TB Gold In-Tube (QFT) supernatants were estimated during the treatment by bead-based multiplex assays and enzyme-linked immunosorbent assay.ResultsIn total, 63 treated participants and 32 untreated controls were included in the study. The levels of 13 background-corrected mycobacteria-specific antigen-stimulated cytokines [basic fibroblast growth factor (FGF), growth-regulated oncogene (GRO)-α, interleukin (IL)-1α, IL-1ra, IL-12 (p70), stem cell factor (SCF), tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), IL-8, interferon (IFN)-α2, IL-5, IL-12 (p40), leukemia inhibitory factor (LIF), and IL-17A] were found to be statistically different between before and after treatment in treated participants, while no statistically differences were observed in untreated controls. Among these 13 cytokines, the level of IL-8 was significantly lower in the QFT reversed group than that in the non-reversed group (p = 0.028) among treated participants, while such a difference was not found for untreated controls (p = 0.292).ConclusionOur results suggested that the lower level of mycobacteria-specific antigen-induced IL-8 might be associated with the host’s positive response to LTBI treatment.

Constipation and defecatory dysfunctions are frequent symptoms in patients with Parkinson’s disease (PD). The pathology of Lewy bodies in colonic and rectal cholinergic neurons suggests that cholinergic pathways are involved in colorectal dysmotility in PD. However, the underlying mechanism is unclear. The aim of the present study is to examine the effect of central dopaminergic denervation in rats, induced by injection 6-hydroxydopamine into the bilateral substania nigra (6-OHDA rats), on colorectal contractive activity, content of acetylcholine (ACh), vasoactive intestinal peptide (VIP) and expression of neural nitric oxide synthase (nNOS) and muscarinic receptor (MR). Strain gauge force transducers combined with electrical field stimulation (EFS), gut transit time, immunohistochemistry, ELISA, western blot and ultraperformance liquid chromatography tandem mass spectrometry were used in this study. The 6-OHDA rats exhibited outlet obstruction constipation characterized by prolonged transit time, enhanced contractive tension and fecal retention in colorectum. Pretreatment with tetrodotoxin significantly increased the colorectal motility. EFS-induced cholinergic contractions were diminished in the colorectum. Bethanechol chloride promoted colorectal motility in a dose-dependent manner, and much stronger reactivity of bethanechol chloride was observed in 6-OHDA rats. The ACh, VIP and protein expression of nNOS was decreased, but M2R and M3R were notably upregulated in colorectal muscularis externa. Moreover, the number of cholinergic neurons was reduced in sacral parasympathetic nucleus (SPN) of 6-OHDA rats. In conclusion, central nigrostriatal dopaminergic denervation is associated with decreased cholinergic neurons in SPN, decreased ACh, VIP content, and nNOS expression and upregulated M2R and M3R in colorectum, resulting in colorectal dysmotility, which contributes to outlet obstruction constipation. The study provides new insights into the mechanism of constipation and potential therapeutic targets for constipation in PD patients.

BackgroundEnlarging tuberculosis (TB) preventive treatment among at-risk populations is a critical component of the End TB Strategy. It is urgently needed to develop suitable latent tuberculosis infection (LTBI) testing and treatment tools according to local TB epidemic and available resources in worldwide.MethodsBased on an open-labeled randomised controlled trial conducted since 2015 among rural residents aged 50–70 years with LTBI, the protective efficacy of the 6-week twice-weekly regimen of rifapentine plus isoniazid was further evaluated in a 5-year follow-up survey.ResultsA total of 1298 treated participants and 1151 untreated controls were included in the 5-year protective efficacy analysis. In the per-protocol analysis, the incidence rate was 0.49/100 person-years (95% confidence interval (CI): 0.30–0.67) in the untreated control group and 0.19/100 person-years (95% CI: 0.07–0.32) in the treated group, the protection rate was 61.22%. Subgroup analysis showed that the protection rate was 76.82% in the per-protocol analysis among participants with baseline IFN-γ levels in the highest quartile (≥3.25 IU·mL−1). The multiple logistic regression analysis indicated that participants with baseline BMI <18.5 kg·m−2 and with pulmonary fibrotic lesions had increased hazard of developing active disease with an adjusted hazard ratio (aHR) of 3.64 (95% CI: 1.20–11.00) and 5.99 (95% CI: 2.20–16.27), respectively. In addition, individuals with higher baseline IFN-γ levels showed an increased risk of TB occurrence (aHR 2.27, 95% CI 1.13–4.58).ConclusionsOur findings suggested the 6-week twice-weekly regimen of rifapentine plus isoniazid for LTBI treatment might be an optional tool for TB control in Chinese population.