A comprehensive assessment of the association between common drugs and psychiatric disorders using Mendelian randomization and real-world pharmacovigilance database.

BACKGROUND: Medications prescribed for chronic diseases can lead to short-term neuropsychiatric symptoms, but their long-term effects on brain structures and psychiatric conditions remain unclear. METHODS: We comprehensively analyzed the FDA Adverse Event Reporting System database and conducted drug target Mendelian Randomization (MR) studies on six categories of common drugs, 477 brain imaging-derived phenotypes (IDPs) and eight psychiatric disorders. Genetic instruments were extracted from expression quantitative trait loci (eQTLs) in blood, brain, and other target tissues, protein quantitative trait loci (pQTLs) in blood, and genome-wide association studies (GWAS) of hemoglobin and cholesterol. Summary statistics for brain IDPs, psychiatric disorders, and gut microbiome were obtained from the BIG40, Psychiatric Genomics Consortium, and MiBioGen. A two-step MR and mediation analysis were employed to screen possible mediators of drug-IDP effects from 119 gut microbiota genera and identify their mediation proportions. FINDINGS: Among 19 drug classes, six drugs were found to be associated with higher risks of psychiatric adverse events, while 11 drugs were associated with higher risks of gastrointestinal adverse events in the FAERS analysis. We identified ten drug-psychiatric disorder associations, 202 drug-IDP associations, 16 drug-microbiota associations, and four drug-microbiota-IDP causal links. For example, PPARG activation mediated HbA1c reduction caused a higher risk of bipolar disorder (BD) II. Genetically proxied GLP-1R agonists were significantly associated with an increase in the volume of the CA3-head of the right hippocampus and the area of the left precuneus cortex, both of which have been shown to correlate with cognition in previous studies. INTERPRETATION: Common drugs may affect brain structure and risk of psychiatric disorder. Oral medications in particular may exert some of these effects by influencing gut microbiota. This study calls for greater attention to be paid to the neuropsychiatric adverse effects of drugs and encourages drug repurposing. FUNDING: National Natural Science Foundation of China (grant No. 82330035, 82130043, 82172685, and 82001223), National Natural Science Foundation of Hunan Province (grant No. 2021SK1010), and the Science Foundation for Distinguished Young Scholars of Changsha (grant No. kq2209006).

Vagal afferents mediate antinociception of estrogen in a rat model of visceral pain: the involvement of intestinal mucosal mast cells and 5-hydroxytryptamine 3 signaling.

UNLABELLED: Estrogen reportedly facilitates visceral nociception at the spinal or supraspinal level. The present study was aimed to investigate whether estrogen modulates visceral pain through the vagal pathway. Ovariectomized rats received estradiol, which was administered subcutaneously (to act through both the vagal and spinal pathways) or intraduodenally (to preferentially act through the vagal pathway). Luminally applied estradiol induced a rapid and significant decrease in the visceromotor response to colorectal distension, with increased c-Fos expression in nodose ganglion neurons. Systemically injected estradiol increased visceromotor response and c-Fos expression in both nodose and dorsal root ganglion (T6-12) neurons. The antinociceptive effect of estrogen was abolished by surgical vagotomy or chemical denervation of vagal afferents. Both luminally and systemically administered estradiol elicited selective 5-hydroxytryptamine secretion from the duodenum. Granisetron, a 5-hydroxytryptamine 3 receptor antagonist, reversed the antinociceptive effect of estrogen. Intestinal mucosal mast cell stabilizers prevented estradiol-induced antinociception and 5-hydroxytryptamine secretion. Ultrastructural analysis revealed that estradiol caused piecemeal degranulation of intestinal mucosal mast cells. The actions of estradiol were inhibited by an estrogen receptor ß antagonist and mimicked by an estrogen receptor ß agonist. These results suggest that estrogen can trigger vagus-mediated antinociception, which is masked by its spinally mediated pronociception. PERSPECTIVE: This study is the first to show a vagus-mediated estrogenic antinociception, in which the nongenomic estrogen receptor ß-mediated, intestinal mucosal mast cell-derived 5-hydroxytryptamine/5-hydroxytryptamine 3 receptor pathway is involved. This work may provide new insights into the sex hormone modulation of visceral sensitivity related to irritable bowel syndrome and indicate potential therapeutic targets to manage this disease.

Downregulation of apurinic/apyrimidinic endonuclease 1/redox factor-1 enhances the sensitivity of human pancreatic cancer cells to radiotherapy in vitro.

UNLABELLED: Abstract Background: Radiotherapy is an important treatment for the patients with advanced pancreatic cancer. Emerging studies determined apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) might associate with the resistance of human pancreatic cancer cells to radiotherapy. AIMS: To investigate whether downregulation of APE1/Ref-1 expression by ribonucleic acid interference would increase the sensitivity of chromic-P32 phosphate to pancreatic cancer cells. METHODS: The plasmids containing APE-specific and unspecific short hairpin were transfected into Patu-8898 cells. Stable cell clones were selected by G418. The mRNA expression of APE1/Ref-1 was detected by semiquantitative reverse transcription-polymerase chain reaction and the protein expression of APE1/Ref-1 was detected by Western blot analysis; cell proliferation was studied by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and colony formation assay; apoptosis was detected by flow cytometry. RESULTS: After 24 hours irradiation, APE1/Ref-1 mRNA and protein expression were upregulated, in a concentration-dependent manner. Suppression of APE1/Ref-1 by siRNA increased the pancreatic cancer cells hypersensitive to (32)P-CP. In the combination of (32)P-CP and siRNA group, MTT assay showed that the cell inhibition increased to (74.33%±9.02%), the surviving fraction in the colony formation assay was only 25.00%, and the apoptosis rate was up to (16.77%±0.98%). CONCLUSIONS: Knockdown APE1/Ref-1 gene expression may significantly sensitize the Patu-8988 cells to radiotherapy, which may be a useful target for modifying radiation resistance of pancreatic cancer cells to irradiation.

Effect of domperidone therapy on nocturnal dyspeptic symptoms of functional dyspepsia patients.

AIM: To investigate the incidence of nocturnal dyspeptic symptoms in patients with functional dyspepsia (FD) and whether prokinetic drugs can alleviate them. METHODS: Eighty-five consecutive Chinese patients with FD were included in this study. One week after single-blinded placebo run-in treatment, baseline nocturnal intragastric pH, bile reflux and nocturnal dyspeptic symptoms of eligible patients, including epigastric pain or discomfort, abdominal distention and belching, were investigated with questionnaires. Patients exhibiting nocturnal dyspeptic symptoms were randomly and double-blindly assigned to domperidone group or placebo group. Nocturnal intragastric pH and percentage of duodenogastric bile reflux time were determined after treatment. RESULTS: Of the 85 FD patients, 2 females without nocturnal symptoms, who responded to placebo run-in treatment, were excluded from the study, 30 (36.1%) exhibited nocturnal dyspeptic symptoms with increased duodenogastric bile reflux time (intragastric bilirubin absorbance > 0.14) and mean gastric pH (confirming the existence of bile reflux) (P = 0.021, 0.023) at night were included in the study. Of these 30 patients, 21 (70%) had overt nocturnal duodenogastric bile reflux, which was significantly higher than that of those without nocturnal symptoms (P = 0.026). The 30 patients were allocated to domperidone group or placebo group (n = 15). The nocturnal duodenogastric bile reflux and gastric pH were significantly decreased after domperidone treatment (P = 0.015, 0.021). The severity score of nocturnal dyspeptic symptoms was also significantly decreased after domperidone treatment (P = 0.010, 0.015, 0.026), which was positively correlated with the reduced nocturnal bile reflux or gastric pH (r = 0.736, 0.784, 0.753 or r = 0.679, 0.715, 0.697, P = 0.039, 0.036, 0.037 or P = 0.043, 0.039, 0.040). CONCLUSION: A subgroup of Chinese FD patients show overt nocturnal dyspeptic symptoms, which may be correlated with the excessive nocturnal duodenogastric bile reflux. Domperidone therapy can alleviate these symptoms.

Effects of thalidomide in experimental models of post-endoscopic retrograde cholangiopancreatography pancreatitis.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the pathogenesis of acute pancreatitis and related systemic complications. The authors hypothesized that it may also play an important role in the development of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). The aim of the study was to evaluate the effectiveness of thalidomide, an immunomodulator that exerts an inhibitory action on TNF-alpha by enhancing mRNA degradation, in reducing post-ERCP pancreatitis in a rat model. METHODS: A total of 200 mg/kg thalidomide was given intragastric once a day (total 8 days) before the experimental models of post-ERCP pancreatitis were established. After 24 h, histology and edema of pancreas, serum amylase, and TNF-alpha mRNA in the pancreatic tissue were evaluated. RESULTS: Intraductal contrast infusion caused increases in serum amylase, edema, histological grade, and TNF-alpha mRNA of pancreas. The prophylactic use of thalidomide significantly reduced serum amylase, pancreatic edema and the histologic grade of pancreatitis accompanied by a decrease in mRNA expression of TNF-alpha in the pancreatic tissue. CONCLUSIONS: Prophylactic intragastric administration of thalidomide provides a protective effect in post-ERCP pancreatitis. The mechanism of the protective effects of thalidomide seems to be the reduction of expression of TNF-alpha mRNA in pancreatic tissue.

Effects of bile reflux on gastric mucosal lesions in patients with dyspepsia or chronic gastritis.

AIM: To investigate the influences of bile reflux on profiles of gastric mucosal lesions in patients with dyspepsia or chronic gastritis. METHODS: A total of 49 patients diagnosed with dyspepsia and chronic gastritis underwent 24-h ambulatory and simultaneous monitoring of intragastric bilirubin absorbance and pH values, and then they were divided into bile reflux positive group and bile reflux negative group. Severity of pathological changes in gastric mucosa including active inflammation, chronic inflammation, intestinal metaplasia, atrophy and dysplasia as well as Helicobacter pylori (H pylori) infection at the corpus, incisura and antrum were determined respectively according to update Sydney system criteria. The profiles of gastric mucosal lesions in the two groups were compared, and correlations between time-percentage of gastric bilirubin absorbance >0.14 and severity of gastric mucosal lesions as well as time-percentage of gastric pH >4 were analyzed respectively. RESULTS: Thirty-eight patients (21 men and 17 women, mean age 44.2 years, range 25-61 years) were found existing with bile reflux (gastric bilirubin absorbance >0.14) and 11 patients (7 men and 4 women, mean age 46.2 years, range 29-54 years) were bile reflux negative. In dyspepsia patients with bile reflux, the mucosal lesions such as active inflammation, chronic inflammation, intestinal metaplasia, atrophy or H pylori infection in the whole stomach, especially in the corpus and incisura, were significantly more severe than those in dyspepsia patients without bile reflux. Moreover, the bile reflux time was well correlated with the severity of pathological changes of gastric mucosa as well as H pylori colonization in the near-end stomach, especially in the corpus region. No relevance was found between the time of bile reflux and pH >4 in gastric cavity. CONCLUSION: Bile reflux contributes a lot to mucosal lesions in the whole stomach, may facilitate H pylori colonization in the corpus region, and has no influence on acid-exposing status of gastric mucosa in patients with dyspepsia or chronic gastritis.

Nitric oxide synthase distribution in esophageal mucosa and hemodynamic changes in rats with cirrhosis.

AIM:To observe the nitric oxide synthase (NOS) distribution in the esophageal mucosa and hemodynamic changes in cirrhotic rats.METHODS:NOS distribution in the lower esophagus of rats with carbon tetrachloride-induced cirrhosis was assessed by using NADPH-diaphorase (NADPH-d) histochemical method.Concentration of NO in serum were measured by fluorometric assay. Mean arterial pressure (MAP), cardiac output (CO), cardiac index (CI), splanchnic vascular resistance (SVR), and splanchnic blood flow (SBF) were also determined using (57)Co-labled microsphere technique.RESULTS:Intensity of NOS staining in the esophageal epithelium of cirrhotic rats was significantly stronger than that in controls. There was a NOS-positive staining area in the endothelia of esophageal submucosal vessels of cirrhotic rats, but the NOS staining was negative in normal rats. NO concentration of serum in cirrhotic rats were significantly higher in comparison with that of controls. Cirrhotic rats had significantly lower MAP, SVR and higher SBF than those of the controls.CONCLUSION:Splanchnic hyperdynamic circulatory state was observed in rats with cirrhosis. The endogenous NO may play an important role in development of esophageal varices and in changes of hemodynamics in cirrhosis.