ObjectiveTo investigate the processing technology of calcined Haematitum based on the concept of quality by design（QbD） and to assess its health risk. MethodsTaking whole iron content， Fe²⁺ dissolution content and looseness as critical quality attributes（CQAs）， and calcination temperature， calcination time， spreading thickness and particle size as critical process parameters（CPPs） determined by the failure mode and effect analysis（FMEA）， the processing technology of calcined Haematitum was optimized by orthogonal test combined with analytic hierarchy process-criteria importance through intercriteria correlation（AHP-CRITIC） hybrid weighting method. The contents of heavy metals and harmful elements were determined by inductively coupled plasma mass spectrometry， and the health risk assessment was carried out by daily exposure（EXP）， target hazard quotient（THQ） and lifetime cancer risk（LCR）， and the theoretical value of the maximum limit was deduced. ResultsThe optimal processing technology for calcined Haematitum was calcination at 650 ℃， calcination time of 1 h， particle size of 0.2-0.5 cm， spreading thickness of 1 cm， and vinegar quenching for 1 time［Haematitum-vinegar（10：3）］. The contents of 5 heavy metals and harmful elements in 13 batches of calcined Haematitum were all decreased with reductions of up to 5-fold. The cumulative THQ of 2 batches of samples was>1， while the cumulative THQ of all batches of Haematitum was>1. The LCR of As in 1 batches of Haematitum was 1×10^-6-1×10^-4， and the LCR of the rest was<1×10^-6， and the LCRs of calcined Haematitum were all<1×10^-6， indicating that the carcinogenic risk of calcined Haematitum was low， but special attention should still be paid to Haematitum medicinal materials. Preliminary theoretical values of the maximum limits of Cu， As， Cd， Pb and Hg were formulated as 1 014， 25， 17， 27， 7 mg·kg^-1. ConclusionThe optimized processing technology of calcined Haematitum is stable and feasible， and the contents of heavy metals and harmful elements are reduced after processing. Preliminary theoretical values of the maximum limits of Cu， As， Cd， Pb and Hg are formulated to provide a scientific basis for the formulation of standards for the limits of harmful elements in Haematitum.

ObjectiveTo investigate the processing technology of calcined Haematitum based on the concept of quality by design（QbD） and to assess its health risk. MethodsTaking whole iron content， Fe²⁺ dissolution content and looseness as critical quality attributes（CQAs）， and calcination temperature， calcination time， spreading thickness and particle size as critical process parameters（CPPs） determined by the failure mode and effect analysis（FMEA）， the processing technology of calcined Haematitum was optimized by orthogonal test combined with analytic hierarchy process-criteria importance through intercriteria correlation（AHP-CRITIC） hybrid weighting method. The contents of heavy metals and harmful elements were determined by inductively coupled plasma mass spectrometry， and the health risk assessment was carried out by daily exposure（EXP）， target hazard quotient（THQ） and lifetime cancer risk（LCR）， and the theoretical value of the maximum limit was deduced. ResultsThe optimal processing technology for calcined Haematitum was calcination at 650 ℃， calcination time of 1 h， particle size of 0.2-0.5 cm， spreading thickness of 1 cm， and vinegar quenching for 1 time［Haematitum-vinegar（10：3）］. The contents of 5 heavy metals and harmful elements in 13 batches of calcined Haematitum were all decreased with reductions of up to 5-fold. The cumulative THQ of 2 batches of samples was>1， while the cumulative THQ of all batches of Haematitum was>1. The LCR of As in 1 batches of Haematitum was 1×10^-6-1×10^-4， and the LCR of the rest was<1×10^-6， and the LCRs of calcined Haematitum were all<1×10^-6， indicating that the carcinogenic risk of calcined Haematitum was low， but special attention should still be paid to Haematitum medicinal materials. Preliminary theoretical values of the maximum limits of Cu， As， Cd， Pb and Hg were formulated as 1 014， 25， 17， 27， 7 mg·kg^-1. ConclusionThe optimized processing technology of calcined Haematitum is stable and feasible， and the contents of heavy metals and harmful elements are reduced after processing. Preliminary theoretical values of the maximum limits of Cu， As， Cd， Pb and Hg are formulated to provide a scientific basis for the formulation of standards for the limits of harmful elements in Haematitum.

Abdominal aortic aneurysm (AAA) is a deadly condition of the aorta, carrying a significant risk of death upon rupture. Currently, there is a dearth of efficacious pharmaceutical interventions to impede the advancement of AAA and avert it from rupturing. Here, we investigated dihydromyricetin (DHM), one of the predominant bioactive flavonoids in Ampelopsis grossedentata (A. grossedentata), as a potential agent for inhibiting AAA. DHM effectively blocked the formation of AAA in angiotensin II-infused apolipoprotein E-deficient (ApoE^-/-) mice. A combination of network pharmacology and whole transcriptome sequencing analysis revealed that DHM's anti-AAA action is linked to heme oxygenase (HO)-1 (Hmox-1 for the rodent gene) and hypoxia-inducible factor (HIF)-1α in vascular smooth muscle cells (VSMCs). Remarkably, DHM caused a robust rise (∼10-fold) of HO-1 protein expression in VSMCs, thereby suppressing VSMC inflammation and oxidative stress and preserving the VSMC contractile phenotype. Intriguingly, the therapeutic effect of DHM on AAA was largely abrogated by VSMC-specific Hmox1 knockdown in mice. Mechanistically, on one hand, DHM increased the transcription of Hmox-1 by triggering the nuclear translocation and activation of HIF-1α, but not nuclear factor erythroid 2-related factor 2 (NRF2). On the other hand, molecular docking, combined with cellular thermal shift assay (CETSA), isothermal titration calorimetry (ITC), drug affinity responsive target stability (DARTS), co-immunoprecipitation (Co-IP), and site mutant experiments revealed that DHM bonded to HO-1 at Lys243 and prevented its degradation, thereby resulting in considerable HO-1 buildup. In summary, our findings suggest that naturally derived DHM has the capacity to markedly enhance HO-1 expression in VSMCs, which may hold promise as a therapeutic strategy for AAA.

Sigma-1 receptor (σ ₁R) has become a focus point of drug discovery for central nervous system (CNS) diseases. A series of novel 1-phenylethan-1-one O-(2-aminoethyl) oxime derivatives were synthesized. In vitro biological evaluation led to the identification of 1a, 14a, 15d and 16d as the most high-affinity (K _i < 4 nmol/L) and selective σ ₁R agonists. Among these, 15d, the most metabolically stable derivative exhibited high selectivity for σ ₁R in relation to σ ₂R and 52 other human targets. In addition to low CYP450 inhibition and induction, 15d also exhibited high brain permeability and excellent oral bioavailability. Importantly, 15d demonstrated effective antipsychotic potency, particularly for alleviating negative symptoms and improving cognitive impairment in experimental animal models, both of which are major challenges for schizophrenia treatment. Moreover, 15d produced no significant extrapyramidal symptoms, exhibiting superior pharmacological profiles in relation to current antipsychotic drugs. Mechanistically, 15d inhibited GSK3β and enhanced prefrontal BDNF expression and excitatory synaptic transmission in pyramidal neurons. Collectively, these in vivo proof-of-concept findings provide substantial experimental evidence to demonstrate that modulating σ ₁R represents a potential new therapeutic approach for schizophrenia. The novel chemical entity along with its favorable drug-like and pharmacological profile of 15d renders it a promising candidate for treating schizophrenia.

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba, a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba, can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

Objective To evaluate the effect of the current immunization strategy for hepatitis B virus (Hepatitis B) in blocking mother-to-infant transmission in Hubei Province, and to explore the mechanism and possible influencing factors of failure of mother-to-infant blockade. Methods A multi-stage random sampling method was used to select 2 counties or districts in Hubei Province. Through maternity hospital health handbook, neonatal health record or hospital medical record system, hepatitis B virus (HBV) surface antigen (HBsAg)-positive pregnant women in 2012-2018 years were included to retrospectively investigate their delivery status and the HBV infection status of their children. Results Among the 302 newborns, 32 were positive for HBsAg, and the success rate of blockade of mother-to-infant transmission of hepatitis B was 89.45%. Further analysis showed that 68.21% (206 / 302) of newborns were delivered in township hospitals, 66.23% (200 / 302) were delivered by caesarean section and 41.72% (126 / 302) were breastfed, while 16.89% (51/302) were positive for hepatitis B virus e antigen (HBeAg), and 41.06% (124/302) were positive for anti-HBe. The vaccination rate of hepatitis B immunoglobulin (HBIG) during pregnancy was 3.31% (10/302), and the newborn HBIG vaccination rate was 94.37% (285/302). There were 84.11% (254/302) of pregnant women taking protective measures in daily life. Logistic regression analysis showed that township hospitals (OR=2.82, P<0.05), HBeAg positivity during pregnancy (OR=8.68, P<0.05), and HBIG vaccination during pregnancy (OR=12.62 , P<0.05) were risk factors for failure of mother-to-infant blockade, while anti-HBe positivity during pregnancy (OR=0.22, P<0.05), vaccination of newborns with HBIG (OR=0.20, P<0.05), and protective measures taken in daily life (OR=0.28, P<0.05) were protective factors for mother-to-infant interruption. Conclusion Deliveries in township hospitals and HBeAg-positivity during pregnancy are more likely to fail in blocking of mother-to-infant transmission of hepatitis B. HBIG vaccination during pregnancy does not reduce the risk of blockade failure. Neonatal HBIG vaccination, anti-HBe positivity during pregnancy, and protective measures in daily life can reduce the risk of blockade failure of mother-to-infant transmission of hepatitis B.

Objective: To investigate the mechanism of moxibustion in the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D), by observing the effects of moxibustion at Tianshu (ST25) and Shangjuxu (ST37) on microRNA-133b (miRNA-133b), pituitary homeobox family factor 3 (Pitx3)/tyrosine hydroxylase (TH), and neurotransmitters in the brain tissue of IBS-D rats. Methods: Healthy Sprague-Dawley rats were randomly divided into a normal group, a model group, a moxibustion group, and a Western medicine group, with 12 rats in each group. Except for the normal group, the IBS-D rat model was established by mother-offspring separation and acetic acid enema combined with restraint stress stimulation in all the other groups. No intervention was performed in the normal and model groups. Mild moxibustion was applied to both Tianshu (ST25) and Shangjuxu (ST37) in the moxibustion group. Rifaximin was given by gavage in the Western medicine group. The physical status of rats in each group was observed at different periods. After the intervention, hematoxylin- eosin staining was performed to observe the histopathological morphology of rat colon; enzyme-linked immunosorbent assay was used to measure the levels of dopamine (DA), noradrenaline (NE), and 5-hydroxytryptamine (5-HT) in plasma, colon, and midbrain tissue of rats; the relative expression levels of miRNA-133b, Pitx3 mRNA, and TH mRNA in the midbrain tissue were measured by real-time fluorescence quantitative polymerase chain reaction, and the relative expression levels of Pitx3 and TH proteins in the midbrain tissue were measured by Western blotting and immunofluorescence. Results: The body weights of rats among groups and at different time points were statistically different (P<0.01). The body weight of the normal group was higher than that of the other groups over time (P<0.01). After modeling, the minimum volume threshold of abdominal withdrawal reflex (AWR) was significantly lower (P<0.01) and the loose stool rate was significantly higher (P<0.01) in the model, moxibustion, and Western medicine groups compared with the normal group; the miRNA-133b expression in the midbrain tissue was significantly lower (P<0.01), the expression levels of Pitx3 and TH in the midbrain tissue were significantly higher (P<0.01), and the levels of DA, NE, and 5-HT in plasma, colon and midbrain tissue were significantly higher (P<0.01). After the intervention, the minimum volume threshold of AWR was significantly higher (P<0.01), the loose stool rate was significantly lower (P<0.01), the miRNA-133b expression was significantly increased (P<0.01 or P<0.05) and the expression levels of Pitx3 and TH were significantly decreased (P<0.01) in the midbrain tissue, the levels of DA, NE, and 5-HT in plasma, colon, and midbrain tissue were significantly reduced (P<0.01) in the moxibustion and Western medicine groups compared with the model group; the levels of 5-HT in the colon and midbrain tissue of the moxibustion group were significantly lower than those in the Western medicine group (P<0.05), and there was no statistical difference compared with the remaining groups (P>0.05). Linear correlation analysis showed that miRNA-133b was negatively correlated with Pitx3 (r<0, P<0.01); Pitx3 with TH, TH with DA, and NE with 5-HT were positively correlated (r>0, P<0.01).Conclusion: Moxibustion at Tianshu (ST25) and Shangjuxu (ST37) improves diarrhea symptoms and visceral hypersensitivity in IBS-D rats. The mechanism may be related to up-regulating miRNA-133b, inhibiting Pitx3/TH, and reducing neurotransmitter expression levels in the midbrain tissue.

Objective:To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) for the elderly patients (80 years or older) with choledocholithiasis.Methods:A retrospective study was conducted on 742 cases of choledocholithiasis who underwent ERCP at Nanjing Drum Tower Hospital Affiliated to Nanjing University Medical School from January 2014 to December 2017. The patients were divided into two groups: 196 patients aged 80 or above (the very elderly group) and 546 patients aged 60 or below (the non-elderly group). The baseline data including gender, number and size of stones of the two groups were matched using the 1∶1 propensity score matching, and the covariate equalization samples between the two groups were obtained and 196 pairs of patients were successfully matched. The treatment success rate, complication incidence, hospitalization time and cost were analyzed.Results:Comorbidities in patients of the elderly group were significantly more than those in the non-elderly group [93.4% (183/196) VS 76.5% (150/196), P<0.001]. The success rates of treatment were 96.4% (189/196) and 96.9% (190/196), respectively ( P=0.778). The incidence of postoperative complications were 8.7% (17/196) in the elderly group and 6.6% (13/196) in the non-elderly group ( P=0.447). The mean hospitalization time and the mean hospitalization cost of the elderly group and the non-elderly group were 8.20 days, 23 624.06 Yuan and 8.03 days, 22 249.64 Yuan, respectively (all P>0.05). Conclusion:ERCP is effective and safe, and can be used as the first choice for senile patients with choledocholithiasis.

Objective:To observe the effects of low intensity pulsed ultrasound(LIPUS) on the osteogenic differentiation of rat bone marrow mesenchymal stem cells(BMSCs) on titanium surface.Methods:BMSCs from Wistar rat bone marrow were respectively cultured on the flat titanium surface and the large grain blast acid etched(SLA) titanium surface,and induced by mineralization medium.Then,the cells were interfered by LIPUS and a control condition.Alkaline phosphatase(ALP) were quantitative determinated after 3 and 7 d mineralization induction respectively,ALP staining were observed after 14 d induction.Alizarin red staining were observed after 21 d mineralization induction.Osteogenic related protein and gene expressions were detected after mineralization induction.Results:ALP in culture medium of LIPUS group was higher than that of the control group after 3 d and 7 d mineralization induction(P＜0.05).LIPUS group showed stronger ALP staining and alizarin staining,and more mineralized nodules than control group.The expression of osteogenic related proteins,including Runx2,BMP2,OPN in LIPUS group increased.Osteogenic related genes expression,including ALP,Runx2,BMP2,OPN,OCN and Col-1 of the LIPUS group increased.Conclusion:The osteogenic differentiation of BMSCs on the fiat titanium surface or SLA titanium surface can be promoted by LIPUS.

Objective To establish a scientific and comprehensive quality of life ( QOL ) evaluation index system for the elderly living alone. Methods Based on the literature review, we organized theoretical analysis, in-depth interview with the old people living alone, experts group discussion;according to the principle of constructing index system, the QOL evaluation index system framework of the elderly living alone was initially constructed. Then 15 experts were consulted by two-round Delphi method. Each of the index was weighed by matrix dual comparison method. Results The QOL evaluation index system of the elderly living alone was established including 4 primary indexes, 9 secondary indexes and 32 tertiary indexes. Conclusions The index system can provide reference for the research of the QOL scale of the elderly living alone and the guidance for evaluation and enhancement of the QOL of the elderly living alone.