Maternal health during pregnancy has a direct impact on the risk and severity of neurodevelopmental disorders (NDDs) in the offspring, especially in the case of drug exposure. However, little progress has been made to assess the risk of drug exposure during pregnancy due to ethical constraints and drug use factors. We collected and manually curated sub-pathways and pathways (sub-/pathways) and drug information to propose an analytical framework for predicting drug candidates. This framework linked sub-/pathway activity and drug response scores derived from gene transcription data and was applied to human fetal brain development and six NDDs. Further, specific and pleiotropic sub-/pathways/drugs were identified using entropy, and sex bias was analyzed in conjunction with logistic regression and random forest models. We identified 19 disorder-associated and 256 regionally pleiotropic and specific candidate drugs that targeted risk sub-/pathways in NDDs, showing temporal or spatial changes across fetal development. Moreover, 5443 differential drug-sub-/pathways exhibited sex-biased differences after filling in the gender labels. A user-friendly NDDP visualization website ( https://ndd-lab.shinyapps.io/NDDP ) was developed to allow researchers and clinicians to access and retrieve data easily. Our framework overcame data gaps and identified numerous pleiotropic and specific candidates across six disorders and fetal developmental trajectories. This could significantly contribute to drug discovery during pregnancy and can be applied to a wide range of traits.
Humans ; Female ; Pregnancy ; Neurodevelopmental Disorders/metabolism* ; Male ; Prenatal Exposure Delayed Effects ; Fetal Development/drug effects* ; Drug Discovery/methods* ; Brain/metabolism*

Background and Aims:Adhesive intestinal obstruction(AIO)is a type of mechanical bowel obstruction caused by abdominal or intestinal adhesions,and its onset and progression are closely associated with impaired intestinal mucosal barrier function.Danshen injection,a commonly used traditional Chinese medicine preparation with properties of promoting blood circulation and removing blood stasis,has shown therapeutic potential in various gastrointestinal diseases by improving microcirculation and promoting vasodilation.However,its specific mechanism of action in AIO remains unclear.This study was conducted to investigate the effects and potential mechanisms of Danshen injection on intestinal mucosal barrier function in a rat model of AIO.Methods:Forty rats with experimentally induced AIO were equally randomized into four groups:the model group(receiving intraperitoneal saline)and three Danshen-treated groups administered low,medium,and high doses of Danshen injection(1,2,and 4 mL/kg,respectively),once daily for 7 consecutive d.An additional 10 healthy rats received saline injections in the same manner and served as the normal control group.After the final intervention,all rats were euthanized under anesthesia.Hematoxylin and eosin(HE)staining was performed to evaluate the histopathological morphology of small intestinal tissues.Levels of D-lactic acid and endotoxin in peripheral blood were measured using enzyme-linked immunosorbent assay(ELISA).The expression levels of mucin 2(MUC2),mucin 3(MUC3),and human defensin 5(HD5)—key components of the intestinal mucus layer and innate immune response—were analyzed using quantitative real-time PCR(qRT-PCR).Colorimetric assays were conducted to assess oxidative stress markers in intestinal tissue,including nitric oxide synthase(NOS),malondialdehyde(MDA),superoxide dismutase(SOD),and glutathione peroxidase(GSH-Px).Western blot was used to determine the protein expression levels of endogenous antioxidant pathway components:nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),and NAD(P)H:quinone oxidoreductase 1(NQO1).Results:HE staining showed no significant histological changes in the intestinal tissues of the normal control group,with a mucosal injury score of 0.The model and treatment groups exhibited varying degrees of villous disorganization and tissue edema,with injury scores of 4.69±0.62,3.36±0.41,2.29±0.22,and 1.53±0.14 in the model,low-,medium-,and high-dose groups,respectively(all P＜0.05 vs.model group).Compared with the normal control group,the other groups showed significantly increased levels of D-lactic acid and endotoxin in the blood(all P＜0.05);elevated expression of MUC2 and MUC3,reduced HD5 expression(all P＜0.05);increased NOS and MDA levels,decreased SOD and GSH-Px levels(all P＜0.05);downregulated expression of Nrf2,HO-1,and NQO1 proteins in intestinal tissues(all P＜0.05).These changes were significantly attenuated in the Danshen-treated groups in a dose-dependent manner(all P＜0.05).Conclusion:Danshen injection can alleviate intestinal mucosal injury in AIO rats,possibly by activating the Nrf2/HO-1/NQO1 signaling pathway and reducing oxidative stress,thereby enhancing the intestinal mucosal barrier function.

Background and Aims:Adhesive intestinal obstruction(AIO)is a type of mechanical bowel obstruction caused by abdominal or intestinal adhesions,and its onset and progression are closely associated with impaired intestinal mucosal barrier function.Danshen injection,a commonly used traditional Chinese medicine preparation with properties of promoting blood circulation and removing blood stasis,has shown therapeutic potential in various gastrointestinal diseases by improving microcirculation and promoting vasodilation.However,its specific mechanism of action in AIO remains unclear.This study was conducted to investigate the effects and potential mechanisms of Danshen injection on intestinal mucosal barrier function in a rat model of AIO.Methods:Forty rats with experimentally induced AIO were equally randomized into four groups:the model group(receiving intraperitoneal saline)and three Danshen-treated groups administered low,medium,and high doses of Danshen injection(1,2,and 4 mL/kg,respectively),once daily for 7 consecutive d.An additional 10 healthy rats received saline injections in the same manner and served as the normal control group.After the final intervention,all rats were euthanized under anesthesia.Hematoxylin and eosin(HE)staining was performed to evaluate the histopathological morphology of small intestinal tissues.Levels of D-lactic acid and endotoxin in peripheral blood were measured using enzyme-linked immunosorbent assay(ELISA).The expression levels of mucin 2(MUC2),mucin 3(MUC3),and human defensin 5(HD5)—key components of the intestinal mucus layer and innate immune response—were analyzed using quantitative real-time PCR(qRT-PCR).Colorimetric assays were conducted to assess oxidative stress markers in intestinal tissue,including nitric oxide synthase(NOS),malondialdehyde(MDA),superoxide dismutase(SOD),and glutathione peroxidase(GSH-Px).Western blot was used to determine the protein expression levels of endogenous antioxidant pathway components:nuclear factor erythroid 2-related factor 2(Nrf2),heme oxygenase-1(HO-1),and NAD(P)H:quinone oxidoreductase 1(NQO1).Results:HE staining showed no significant histological changes in the intestinal tissues of the normal control group,with a mucosal injury score of 0.The model and treatment groups exhibited varying degrees of villous disorganization and tissue edema,with injury scores of 4.69±0.62,3.36±0.41,2.29±0.22,and 1.53±0.14 in the model,low-,medium-,and high-dose groups,respectively(all P＜0.05 vs.model group).Compared with the normal control group,the other groups showed significantly increased levels of D-lactic acid and endotoxin in the blood(all P＜0.05);elevated expression of MUC2 and MUC3,reduced HD5 expression(all P＜0.05);increased NOS and MDA levels,decreased SOD and GSH-Px levels(all P＜0.05);downregulated expression of Nrf2,HO-1,and NQO1 proteins in intestinal tissues(all P＜0.05).These changes were significantly attenuated in the Danshen-treated groups in a dose-dependent manner(all P＜0.05).Conclusion:Danshen injection can alleviate intestinal mucosal injury in AIO rats,possibly by activating the Nrf2/HO-1/NQO1 signaling pathway and reducing oxidative stress,thereby enhancing the intestinal mucosal barrier function.

Heme, which exists widely in living organisms, is a porphyrin compound with a variety of physiological functions. Bacillus amyloliquefaciens is an important industrial strain with the characteristics of easy cultivation and strong ability for expression and secretion of proteins. In order to screen the optimal starting strain for heme synthesis, the laboratory preserved strains were screened with and without addition of 5-aminolevulinic acid (ALA). There was no significant difference in the heme production of strains BA, BAΔ6 and BAΔ6ΔsigF. However, upon addition of ALA, the heme titer and specific heme production of strain BAΔ6ΔsigF were the highest, reaching 200.77 μmol/L and 615.70 μmol/(L·g DCW), respectively. Subsequently, the hemX gene (encoding the cytochrome assembly protein HemX) of strain BAΔ6ΔsigF was knocked out to explore its role in heme synthesis. It was found that the fermentation broth of the knockout strain turned red, while the growth was not significantly affected. The highest ALA concentration in flask fermentation reached 82.13 mg/L at 12 h, which was slightly higher than that of the control 75.11 mg/L. When ALA was not added, the heme titer and specific heme production were 1.99 times and 1.45 times that of the control, respectively. After adding ALA, the heme titer and specific heme production were 2.08 times and 1.72 times higher than that of the control, respectively. Real-time quantitative fluorescent PCR showed that the expressions of hemA, hemL, hemB, hemC, hemD, and hemQ genes at transcription level were up-regulated. We demonstrated that deletion of hemX gene can improve the production of heme, which may facilitate future development of heme-producing strain.
Gene Deletion ; Bacillus amyloliquefaciens/metabolism* ; Aminolevulinic Acid/metabolism* ; Heme/metabolism* ; Fermentation

Objective: To investigate the clinical efficacy of laparoscopic subtotal colonic bypass plus colostomy with antiperistaltic cecoproctostomy (SCBCAC) in the treatment of senile slow transit constipation. Methods: A retrospective cohort study was performed. Clinical data of 30 colonic slow transit constipation patients aged ≥70 years old undergoing laparoscopic SCBCAC from July 2012 to October 2016 (bypass plus colostomy group), and 28 patients undergoing laparoscopic subtotal colonic bypass with antiperistaltic cecoproctostomy (SCBAC) from February 2009 to June 2012 (bypass group) at our institute were collected. Efficacy was compared between the two procedures. Inclusion criteria: (1) meeting the Rome III diagnosis criteria for constipation; (2) confirmed diagnosis of slow transit constipation; (3) age ≥ 70 years old; (4) receiving non-surgical treatment for more than 5 years, and Wexner constipation score > 15; (5) follow-up for more than 2 years. Those with psychiatric symptoms or previous psychiatric history, obvious signs of outlet obstructive constipation, organic diseases of the colon and life-threatening cardiovascular diseases or cancer were excluded. In the bypass plus colostomy group, laparoscopy was performed via five trocars. The ileocecal junction and the ascending colon were mobilized and the ileocecal junction was pulled down to the pelvic inlet. The ascending colon was transected and the appendix was excised. The lateral peritoneum of the sigmoid colon and the rectal mesentery were dissected and the upper rectum was transected. The avil of a circular stapler was placed in the bottom of the cecum. The shaft of the stapler was placed in the rectum via the anal canal to complete end-to-side anastomosis (end rectum to lateral cecum). The end of the rectal-sigmoid colon was used for colostomy via an extraperitoneal approach to complete the operation. The following efficacy indexes were collected before surgery and 3, 6, 12, and 24 months after surgery: the number of daily bowel movements, the Wexner incontinence scale (WIS, 0-20, the lower the better), the Wexner constipation scale (WCS, 0-30, the lower the better), the gastrointestinal quality of life index (GIQLI, 0-144, the higher score, the better), abdominal pain intensity indicated by the numerical rating scale (NRS, 0-10, the lower score, the better), and the abdominal bloating score (ABS, 0-4, the lower score, the better). The complications defined as Clavien-Dindo class II or above were observed and recorded. Results: No significant differences in preoperative WCS, WIS, GIQLI, NRS, and ABS were observed between bypass plus colostomy group and bypass group (all P>0.05). All the patients successfully underwent laparoscopic surgery and no patient in either group experienced postoperative fecal incontinence. WCS and GIQLI were significantly improved (all P<0.001) at 3, 6, 12, and 24 months after surgery in both groups. At 12 months after surgery, the number of bowel movements was significantly less in bypass plus colostomy group than that in bypass group [(2.4±0.7) times vs. (3.4±1.2) times, t=4.048, P<0.001]. At 3, 6, 12 and 24 months after surgery, the improvement of GIQLI in bypass plus colostomy group was significantly better than that in bypass group (all P<0.001). At 24 months after surgery, GIQLI in bypass plus colostomy group and bypass group was 122.3±5.3 and 92.8±16.6, respectively, with a significant difference (t=9.276, P<0.001). At 12 and 24 months after surgery, NRS in bypass plus colostomy group was significantly better than that in bypass group (both P<0.001). At 24 months after surgery, NRS in bypass plus colostomy group was 0.9±0.7, while that in bypass group was 3.7±2.7. There was a significant difference between two groups (t=5.585, P<0.001). At 6, 12 and 24 months after surgery, the improvement of ABS in bypass plus colostomy group was also significantly better than that in bypass group. At 24 months after surgery, ABS in bypass plus colostomy group was 0.6±0.6, while that in bypass group was 2.5±1.0, with a significant difference between two groups (t=8.797, P<0.001). At 1 year after surgery, barium enema examination was performed in all the patients of both groups. The barium emptying time was (21.2±3.8) hours and (95.8±86.2) hours in bypass plus colostomy group and bypass group respectively. The former group was significantly better than the latter group (t=4.740, P<0.001). Conclusions Laparoscopic SCBCAC is an effective and safe procedure for the treatment of senile slow transit constipation and can significantly improve prognosis. Its clinical efficacy is better than laparoscopic SCBAC.

Objective To explore the value of ultra-large pitch Turbo Flash scan mode in the diagnosis of tracheal foreign body in infants.Methods The imaging data of 60 infants with foreign body in trachea confirmed by bronchus endoscopy were analyzed retrospectively. The 60 infants were equally divided into 2 groups according to the scanning time.For group A,the routine scan with the mode of CARE Dose 4D/CARE kV and pitch as 1.9 was performed.For group B,the scan with ultra-large pitch Turbo Flash model was performed.The scanning time,volume CT dose index (CTDIvol)and dose length product (DLP)of each patient were recorded in both groups and statistically analyzed.Results The scanning time,DLP and CTDIvol of group A and group B were statistically significant.CTDIvol and DLP of group B were significantly lower than those of group A (P＜0.05).The diagnostic accuracy of group A and B were 100%(30/30),respectively (P＞0.05).The foreign body display of group A and B were 100% (30/30),respectively (P＞0.05).Conclusion Ultra-large pitch Turbo Flash can be used to detect tracheal foreign body in infants.It can significantly reduce radiation dose,shorten examination time and obtain satisfactory image quality.

Objective To investigate the clinical efficacy of laparoscopic subtotal colonic bypass plus colostomy with antiperistaltic cecoproctostomy (SCBCAC) in the treatment of senile slow transit constipation. Methods A retrospective cohort study was performed. Clinical data of 30 colonic slow transit constipation patients aged ≥70 years old undergoing laparoscopic SCBCAC from July 2012 to October 2016 (bypass plus colostomy group), and 28 patients undergoing laparoscopic subtotal colonic bypass with antiperistaltic cecoproctostomy (SCBAC) from February 2009 to June 2012 (bypass group) at our institute were collected. Efficacy was compared between the two procedures. Inclusion criteria: (1) meeting the Rome III diagnosis criteria for constipation; (2) confirmed diagnosis of slow transit constipation;(3) age≥70 years old; (4) receiving non?surgical treatment for more than 5 years, and Wexner constipation score> 15; (5) follow?up for more than 2 years. Those with psychiatric symptoms or previous psychiatric history, obvious signs of outlet obstructive constipation, organic diseases of the colon and life?threatening cardiovascular diseases or cancer were excluded. In the bypass plus colostomy group, laparoscopy was performed via five trocars. The ileocecal junction and the ascending colon were mobilized and the ileocecal junction was pulled down to the pelvic inlet. The ascending colon was transected and the appendix was excised. The lateral peritoneum of the sigmoid colon and the rectal mesentery were dissected and the upper rectum was transected. The avil of a circular stapler was placed in the bottom of the cecum. The shaft of the stapler was placed in the rectum via the anal canal to complete end?to?side anastomosis (end rectum to lateral cecum). The end of the rectal?sigmoid colon was used for colostomy via an extraperitoneal approach to complete the operation. The following efficacy indexes were collected before surgery and 3, 6, 12, and 24 months after surgery: the number of daily bowel movements, the Wexner incontinence scale (WIS, 0?20, the lower the better), the Wexner constipation scale (WCS, 0?30, the lower the better), the gastrointestinal quality of life index (GIQLI, 0?144, the higher score, the better), abdominal pain intensity indicated by the numerical rating scale (NRS, 0?10, the lower score, the better), and the abdominal bloating score (ABS, 0?4, the lower score, the better). The complications defined as Clavien?Dindo class II or above were observed and recorded. Results No significant differences in preoperative WCS, WIS, GIQLI, NRS, and ABS were observed between bypass plus colostomy group and bypass group (all P>0.05). All the patients successfully underwent laparoscopic surgery and no patient in either group experienced postoperative fecal incontinence. WCS and GIQLI were significantly improved (all P<0.001) at 3, 6, 12, and 24 months after surgery in both groups. At 12 months after surgery, the number of bowel movements was significantly less in bypass plus colostomy group than that in bypass group [(2.4±0.7) times vs. (3.4±1.2) times, t=4.048, P<0.001]. At 3, 6, 12 and 24 months after surgery, the improvement of GIQLI in bypass plus colostomy group was significantly better than that in bypass group (all P<0.001). At 24 months after surgery, GIQLI in bypass plus colostomy group and bypass group was 122.3 ± 5.3 and 92.8 ± 16.6, respectively, with a significant difference (t=9.276, P<0.001). At 12 and 24 months after surgery, NRS in bypass plus colostomy group was significantly better than that in bypass group (both P<0.001). At 24 months after surgery, NRS in bypass plus colostomy group was 0.9±0.7, while that in bypass group was 3.7±2.7. There was a significant difference between two groups (t=5.585, P<0.001). At 6, 12 and 24 months after surgery, the improvement of ABS in bypass plus colostomy group was also significantly better than that in bypass group. At 24 months after surgery, ABS in bypass plus colostomy group was 0.6±0.6, while that in bypass group was 2.5±1.0, with a significant difference between two groups (t=8.797, P<0.001). At 1 year after surgery, barium enema examination was performed in all the patients of both groups. The barium emptying time was (21.2 ± 3.8) hours and (95.8 ± 86.2) hours in bypass plus colostomy group and bypass group respectively. The former group was significantly better than the latter group (t=4.740, P<0.001). Conclusions Laparoscopic SCBCAC is an effective and safe procedure for the treatment of senile slow transit constipation and can significantly improve prognosis. Its clinical efficacy is better than laparoscopic SCBAC.

Objective To investigate the clinical efficacy of laparoscopic subtotal colonic bypass plus colostomy with antiperistaltic cecoproctostomy (SCBCAC) in the treatment of senile slow transit constipation. Methods A retrospective cohort study was performed. Clinical data of 30 colonic slow transit constipation patients aged ≥70 years old undergoing laparoscopic SCBCAC from July 2012 to October 2016 (bypass plus colostomy group), and 28 patients undergoing laparoscopic subtotal colonic bypass with antiperistaltic cecoproctostomy (SCBAC) from February 2009 to June 2012 (bypass group) at our institute were collected. Efficacy was compared between the two procedures. Inclusion criteria: (1) meeting the Rome III diagnosis criteria for constipation; (2) confirmed diagnosis of slow transit constipation;(3) age≥70 years old; (4) receiving non?surgical treatment for more than 5 years, and Wexner constipation score> 15; (5) follow?up for more than 2 years. Those with psychiatric symptoms or previous psychiatric history, obvious signs of outlet obstructive constipation, organic diseases of the colon and life?threatening cardiovascular diseases or cancer were excluded. In the bypass plus colostomy group, laparoscopy was performed via five trocars. The ileocecal junction and the ascending colon were mobilized and the ileocecal junction was pulled down to the pelvic inlet. The ascending colon was transected and the appendix was excised. The lateral peritoneum of the sigmoid colon and the rectal mesentery were dissected and the upper rectum was transected. The avil of a circular stapler was placed in the bottom of the cecum. The shaft of the stapler was placed in the rectum via the anal canal to complete end?to?side anastomosis (end rectum to lateral cecum). The end of the rectal?sigmoid colon was used for colostomy via an extraperitoneal approach to complete the operation. The following efficacy indexes were collected before surgery and 3, 6, 12, and 24 months after surgery: the number of daily bowel movements, the Wexner incontinence scale (WIS, 0?20, the lower the better), the Wexner constipation scale (WCS, 0?30, the lower the better), the gastrointestinal quality of life index (GIQLI, 0?144, the higher score, the better), abdominal pain intensity indicated by the numerical rating scale (NRS, 0?10, the lower score, the better), and the abdominal bloating score (ABS, 0?4, the lower score, the better). The complications defined as Clavien?Dindo class II or above were observed and recorded. Results No significant differences in preoperative WCS, WIS, GIQLI, NRS, and ABS were observed between bypass plus colostomy group and bypass group (all P>0.05). All the patients successfully underwent laparoscopic surgery and no patient in either group experienced postoperative fecal incontinence. WCS and GIQLI were significantly improved (all P<0.001) at 3, 6, 12, and 24 months after surgery in both groups. At 12 months after surgery, the number of bowel movements was significantly less in bypass plus colostomy group than that in bypass group [(2.4±0.7) times vs. (3.4±1.2) times, t=4.048, P<0.001]. At 3, 6, 12 and 24 months after surgery, the improvement of GIQLI in bypass plus colostomy group was significantly better than that in bypass group (all P<0.001). At 24 months after surgery, GIQLI in bypass plus colostomy group and bypass group was 122.3 ± 5.3 and 92.8 ± 16.6, respectively, with a significant difference (t=9.276, P<0.001). At 12 and 24 months after surgery, NRS in bypass plus colostomy group was significantly better than that in bypass group (both P<0.001). At 24 months after surgery, NRS in bypass plus colostomy group was 0.9±0.7, while that in bypass group was 3.7±2.7. There was a significant difference between two groups (t=5.585, P<0.001). At 6, 12 and 24 months after surgery, the improvement of ABS in bypass plus colostomy group was also significantly better than that in bypass group. At 24 months after surgery, ABS in bypass plus colostomy group was 0.6±0.6, while that in bypass group was 2.5±1.0, with a significant difference between two groups (t=8.797, P<0.001). At 1 year after surgery, barium enema examination was performed in all the patients of both groups. The barium emptying time was (21.2 ± 3.8) hours and (95.8 ± 86.2) hours in bypass plus colostomy group and bypass group respectively. The former group was significantly better than the latter group (t=4.740, P<0.001). Conclusions Laparoscopic SCBCAC is an effective and safe procedure for the treatment of senile slow transit constipation and can significantly improve prognosis. Its clinical efficacy is better than laparoscopic SCBAC.

Objective: To explore the role of calcium/calmodulin-dependent protein kinase-II δ (CaMK-II δ) in doxorubicin (DOX) induced cardio-toxicity in experimental rats.
Methods:①The rat’s cardiomyocytes were treated by DOX and the cell proliferation, protein expression and activity of CaMK-II δ were examined.②CaMK-II δ gene was knocked out by CRISPR method, the changes of DOX induced cell apoptosis and NF-κb activity and miR-146a expression were detected.
Results: DOX could inhibit cardiomyocyte proliferation, the protein expression level of CaMK-II δ was similar and the activity was increased. CRISPR method may effectively knock out CaMK-II δ gene. Compared with normal cells, the cells from CaMK-II δ knocked out rats had decreased sensitivity to DOX induction, suppressed NF-κb activation and miR-146a up-regulation.
Conclusion: CaMK-II δ participated in DOX induced cardio-toxicity in experimental rats and NF-κb and miR-146a were involved in this process.