VX-765 Alleviates Circadian Rhythm Disorder in a Rodent Model of Traumatic Brain Injury Plus Hemorrhagic Shock and Resuscitation.

Severe traumatic brain injury (TBI) can result in persistent complications, including circadian rhythm disorder, that substantially affect not only the injured people, but also the mood and social interactions with the family and the community. Pyroptosis in GFAP-positive astrocytes plays a vital role in inflammatory changes post-TBI. We determined whether VX-765, a low molecular weight caspase-1 inhibitor, has potential therapeutic value against astrocytic inflammation and pyroptosis in a rodent model of TBI plus hemorrhagic shock and resuscitation (HSR). A weight-drop plus bleeding and refusion model was used to establish traumatic exposure in rats. VX-765 (50 mg/kg) was injected via the femoral vein after resuscitation. Wheel-running activity was assessed, brain magnetic resonance images were evaluated, the expression of pyroptosis-associated molecules including cleaved caspase-1, gasdermin D (GSDMD), and interleukin-18 (IL-18) in astrocytes in the region of anterior hypothalamus, were explored 30 days post-trauma. VX-765-treated rats had significant improvement in circadian rhythm disorder, decreased mean diffusivity (MD) and mean kurtosis (MK), increased fractional anisotropy (FA), an elevated number and branches of astrocytes, and lower cleaved caspase-1, GSDMD, and IL-18 expression in astrocytes than TBI + HSR-treated rats. These results demonstrated that inhibition of pyroptosis-associated astrocytic activations in the anterior hypothalamus using VX-765 may ameliorate circadian rhythm disorder after trauma. In conclusion, we suggest that interventions targeting caspase-1-induced astrocytic pyroptosis by VX-765 are promising strategies to alleviate circadian rhythm disorder post-TBI.

PDGFBB facilitates tumorigenesis and malignancy of lung adenocarcinoma associated with PI3K-AKT/MAPK signaling.

Lung adenocarcinoma (LUAD) remains one of the most aggressive tumors and the efficacy of conventional treatment has been bleak. Nowadays, gene-targeted therapy has become a new favorite in tumor therapy. Herein, we investigated the effect of platelet derived growth factor BB (PDGFBB) on LUAD. Firstly, PDGFBB was upregulated in LUAD patients and closely linked with poor survival. Furthermore, the expression of PDGFBB and PDGFRα/ß in LUAD cells was higher than that in normal lung cells. By loss-of-function with herpes simplex virus (HSV)-PDGFi-shRNA, we found that PDGFBB knockdown caused a significant decrease in proliferation and migration, but evoked apoptosis of LUAD cells in vitro. Conversely, exogenous PDGFBB held adverse effect. Additionally, A549 cells with PDGFBB knockdown had a low probability of tumorigenesis in vivo. Moreover, PDGFBB knockdown restrained the growth of xenografts derived from normal A549 cells. Mechanistically, PDGFBB knockdown suppressed PI3K/AKT and Ras/MAPK signaling, while PDGFBB was the opposite. Therefore, we concluded that PDGFBB might facilitate the tumorigenesis and malignancy of LUAD through its functional downstream nodes-PI3K/AKT and Ras/MAPK signaling, which supported that PDGFBB could serve as a rational therapeutic target for LUAD.

University MOOC should be added with farmer interested sections and provide individualized service to adapt to farmer training.

Vegetables represent an important agricultural industry in China. New farmers and new technologies for vegetable production have emerged in recent years, which makes farmer training very necessary. On the other hand, massive open online courses (MOOCs) are currently widely used in universities. The purpose of this study is to investigate the importance of different sections of a university MOOC focused on olericulture to farmers with different demographic characteristics and provide a basis to improve university MOOCs for farmer training. The survey results suggest that the age, education level, gender, farmer scale, facility type and profit of farmer learners are important factors determining evaluations of the importance of different MOOC sections, indicating that services customized to different farmer populations are necessary. Among different sections of MOOC "Olericulture", farmers with younger age, higher education, larger farm, more advanced facility and more profit were more interesting in sections include cultural, social and theoretical knowledge, and less interesting in practical skill sections. Based on the survey, eight new sections including one marketing subsection (new agricultural supplies and market news), one social subsection (laws and regulations), two practical subsections (practice videos, photos and videos from other farms), and three comprehensive subsections (discussion of practical issues, mechanization, and smart olericulture) were added to the original MOOC, and the results indicate that this improvement is efficient in enhancing the importance evaluations and profits of all farmer learners, especially among those with high education levels.

AGR2 and FOXA1 as prognostic markers in ER-positive breast cancer.

BACKGROUND: The prognostic role of either forkhead box A1 (FOXA1) or anterior gradient 2 (AGR2) in breast cancer has been found separately. Considering that there were interplays between them depending on ER status, we aimed to assess the statistical interaction between AGR2 and FOXA1 on breast cancer prognosis and examine the prognostic role of the combination of them by ER status. METHODS: AGR2 and FOXA1 expression in tumor tissues were evaluated with tissue microarrays by immunohistochemistry in 915 breast cancer patients with follow up data. The expression levels of these two markers were treated as binary variables, and many different cutoff values were tried for each marker. Survival and Cox proportional hazard analyses were used to evaluate the relationship between AGR2, FOXA1 and prognosis, and the statistical interaction between them on the prognosis was assessed on multiplicative scale. RESULTS: Statistical interaction between AGR2 and FOXA1 on the PFS was significant with all the cutoff points in ER-positive breast cancer patients but not ER-negative ones. Among ER-positive patients, the poor prognostic role of the high level of FOXA1 was significant only in patients with the low level of AGR2, and vice versa. When AGR2 and FOXA1 were considered together, patients with low levels of both markers had significantly longer PFS compared with all other groups. CONCLUSIONS: There was a statistical interaction between AGR2 and FOXA1 on the prognosis of ER-positive breast cancer. The combination of AGR2 and FOXA1 was a more useful marker for the prognosis of ER-positive breast cancer patients.

Combined low levels of H4K16ac and H4K20me3 predicts poor prognosis in breast cancer.

BACKGROUND: Results of previous studies about the prognostic roles of histone H4 lysine 16 acetylation (H4K16ac) and histone H4 lysine 20 trimethylation (H4K20me3) in breast cancer were inconsistent. Cellular experiments revealed the interplays between H4K16ac and H4K20me3, but no population study explored the interaction between them on the prognosis. METHODS: H4K16ac and H4K20me3 levels in tumors were evaluated by immunohistochemistry for 958 breast cancer patients. Hazard ratios for overall survival (OS) and progression-free survival (PFS) were estimated using Cox regression models. Interaction was assessed on multiplicative scale. Concordance index (C-index) was calculated to verify the predictive performance. RESULTS: The prognostic roles of the low level of H4K16ac or H4K20me3 were significant only in patients with the low level of another marker and their interactions were significant. Moreover, compared with joint high levels of both them, only the combined low levels of both them was associated with a poor prognosis but not the low level of single one. The C-index of the clinicopathological model combined the joint expression of H4K16ac and H4K20me3 [0.739 for OS; 0.672 for PFS] was significantly larger than that of the single clinicopathological model [0.699 for OS, P < 0.001; 0.642 for PFS, P = 0.003] or the model combined with the single H4K16ac [0.712 for OS, P < 0.001; 0.646 for PFS, P < 0.001] or H4K20me3 [0.724 for OS, P = 0.031; 0.662 for PFS, P = 0.006]. CONCLUSIONS: There was an interaction between H4K16ac and H4K20me3 on the prognosis of breast cancer and the combination of them was a superior prognostic marker compared to the single one.

Comprehensive chemical profiling of two Dendrobium species and identification of anti-hepatoma active constituents from Dendrobium chrysotoxum by network pharmacology.

BACKGROUND: Dendrobium nobile and Dendrobium chrysotoxum are important species of the genus Dendrobium and have great economic and medicinal value. However, the medicinal properties of these two plants remain poorly understood. This study aimed to investigate the medical properties of D. nobile and D. chrysotoxum by conducting a comprehensive chemical profiling of the two plants. Additionally, active compounds and predictive targets for anti-hepatoma activity in D. chrysotoxum extracts were identified using Network Pharmacology. RESULTS: Chemical profiling showed that altogether 65 phytochemicals were identified from D. nobile and D. chrysotoxum, with major classes as alkaloids, terpenoids, flavonoids, bibenzyls and phenanthrenes. About 18 compounds were identified as the important differential metabolites in D. nobile and D. chrysotoxum. Furtherly, CCK-8 results showed that the extracts of stems and leaves of D. nobile and D. chrysotoxum could inhibit the growth of Huh-7 cells, and the anti-hepatoma activity of extracts were dose-dependent. Among the extracts, the extract of D. chrysotoxum showed significant anti-hepatoma activity. In order to find the potential mechanism of anti-hepatoma activity of D. chrysotoxum, five key compounds and nine key targets were obtained through constructing and analyzing the compound-target-pathway network. The five key compounds were chrysotobibenzyl, chrysotoxin, moscatilin, gigantol and chrysotoxene. Nine key targets, including GAPDH, EGFR, ESR1, HRAS, SRC, CCND1, HIF1A, ERBB2 and MTOR, could be considered as the core targets of the anti-hepatoma activity of D. chrysotoxum. CONCLUSIONS: In this study, the chemical composition difference and anti-hepatoma activity of stems and leaves of D. nobile and D. chrysotoxum were compared, and the potential anti-hepatoma mechanism of D. chrysotoxum was revealed in a multi-target and multi-pathway manner.

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Endoscopy is a common tool for the diagnosis and treatment of gastrointestinal disorders in children. The presence of bubbles in the gastrointestinal tract is one of the important factors affecting the clarity of endoscopic visual field, and the application of defoamers can significantly reduce bubbles in the gastrointestinal tract, improve the quality of gastrointestinal preparation, and further increase disease detection rate. Various studies have been conducted on gastrointestinal preparation before endoscopy in children, but there still lacks a uniform protocol for the application of defoamers. This article summarizes the use of defoamers in children before digestive endoscopy and related research advances and points out that existing studies on defoamers have a small sample size and that there are still controversies over the selection and timing of administration, so as to provide a reference for in-depth research on defoamers in the future.

Two new norcassane-type diterpenoids from Mezonevron sinense Hemsl.

Two new norcassane-type diterpenoids, named 6ß-hydroxy-bisnorcass-13-en-12-one (1) and 6ß-hydroxy-bisnorcassan-12-one (2), were isolated from the seeds of Mezonevron sinense Hemsl. The structures of compounds 1-2 were determined by extensive spectroscopic analysis. Two compounds exhibited immunosuppressive activity with the IC50 values of 19.35 ± 0.87 µM and 18.69 ± 0.88 µM in the ConA induced T cell model and 65.04 ± 0.83 µM and 48.06 ± 0.76 µM in LPS induced B cell model, respectively.

CORM-3 alleviates the intestinal injury in a rodent model of hemorrhage shock and resuscitation: roles of GFAP-positive glia.

Hemorrhagic shock and resuscitation (HSR) can induce severe intestinal damages, thereby leading to sepsis and long-term complications including dysbacteriosis and pulmonary injury. The NOD-like receptor protein 3 (NLRP3) inflammasome facilitates inflammation-associated cell recruitment in the gastrointestinal tract, and participates in many inflammatory bowel diseases. Previous studies have shown that exogenous carbon monoxide (CO) exerts neuroprotective effects against pyroptosis after HSR. We aimed to investigate whether carbon monoxide-releasing molecules-3 (CORM-3), an exogenous CO compound, could attenuate HSR-induced intestinal injury and the potential underlying mechanism.Rats were subjected to a HSR model by bleeding and re-infusion. Following resuscitation, 4 mg/kg of CORM-3 was administered intravenously into femoral vein. At 24 h and 7 d after HSR modeling, the pathological changes in intestinal tissues were evaluated by H&E staining. The intestinal pyroptosis, glial fibrillary acidic protein (GFAP)-positive glial pyroptosis, DAO (diamine oxidase) content, intestine tight junction proteins including zonula occludens-1 (ZO-1) and claudin-1 were further detected by immunofluorescence, western blot and chemical assays at 7 d after HSR. CORM-3 administration led to significantly mitigated HSR-induced intestinal injury, aggravation of intestinal pyroptosis indicated by cleaved caspase-1, IL-1ß and IL-18, upregulation of GFAP-positive glial pyroptosis, decreased intensity of ZO-1 and claudin-1 in the jejunum, and increased of DAO in the serum. Nigericin, an agonist of NLRP3, significantly reversed the protective effects of CORM-3. CORM-3 alleviates the intestinal barrier dysfunction in a rodent model of HSR, and the potential mechanism may be associated with inhibition of NLRP3-associated pyroptosis. CORM-3 administration could be a promising therapeutic strategy for intestinal injury after hemorrhagic shock.

Assessment of nucleus accumbens impairment in a rat model of postoperative cognitive dysfunction using diffusion tensor imaging.

BACKGROUND: Postoperative cognitive dysfunction (POCD) often occurs in elderly patients, causing depression and other symptoms. Nucleus accumbens (NAc) is involved in depression. We investigate the diffusion tensor imaging (DTI) parameters of NAc in a POCD model of depression. METHODS: Twenty-month-old male Sprague-Dawley (SD) rats were randomly divided into the POCD and Sham groups. The POCD group underwent exploratory laparotomy to establish a POCD depression model, while the Sham group underwent a sham operation. The fractional anisotropy (FA) and mean diffusivity (MD) values of the bilateral NAc, behavioural changes of forced swimming test and sucrose preference rate, and pathological changes of glial fibrillary acidic protein (GFAP) fluorescent intensity were observed at 15 days (D15 ) and 30 days (D30 ) after the operation. RESULTS: The FA value of the bilateral NAc area in the POCD group was lower than that in the Sham group at the two time periods after the operation (P < 0.05). However, the MD value at D30 was higher in the POCD group than in the Sham group (P < 0.05). The FA value in the POCD group was lower at D30 than at D15 (P < 0.05). The floating time was prolonged while the sucrose preference rate was decreased in the POCD group compared with the Sham group (P < 0.05). The floating time in the POCD group was longer at D30 than at D15 . However, the sucrose preference rate in the POCD was lower at D30 than at D15 . The GFAP fluorescent intensity in the bilateral NAc region in the POCD group was higher than in the Sham group (P < 0.05). CONCLUSION: Microstructural changes of the NAc area are associated with POCD related depression. In addition, FA and MD were demonstrated to be effective in diagnosing and monitoring postoperative depression and its severity.

Abdominal surgery plus sevoflurane exposure induces abnormal emotional changes and cognitive dysfunction in aged rats.

BACKGROUND: Cognitive impairment, which includes perioperative psychological distress and cognitive dysfunction, can be determined by preoperative and post-operative neuropsychological tests. Several mechanisms have been proposed regarding the two-way communication between the immune system and the brain after surgery. We aimed to understand the mechanisms underlying perioperative neurocognitive disorders (PND) in elderly rats using an experimental abdominal surgery model. METHODS: 24-month-old SD rats were exposed to the abdominal surgery model (AEL) under 3% anesthesia. On day 15 and day 30 post-surgery, fractional anisotropy (FA) using diffusion kurtosis imaging (DKI) was measured. From day 25 to day 30 post-surgery, behavioral tests, including open field test (OFT), Morris water maze (MWM), novel object recognition (NOR), force swimming test (FST), and elevated plus maze (EPM), were performed. Then, the rats were euthanized to perform pathological analysis and western blot measurement. RESULTS: The rats exposed to AEL surgical treatment demonstrated significantly decreased time crossing the platform in the MWM, decreased recognition index in the NOR, reduced time in the open arm in the EPM, increased immobility time in the FST, and increased number of crossings in the OFT. Aged rats, after AEL exposure, further demonstrated decreased FA in the mPFC, nucleus accumbens (NAc), and hippocampus, together with reduced MAP2 intensity, attenuation of GAD65, VGlut2, CHAT, and phosphorylated P38MAPK expression, and increased reactive astrocytes and microglia. CONCLUSIONS: In this study, the aged rats exposed to abdominal surgery demonstrated both emotional changes and cognitive dysfunction, which may be associated with neuronal degeneration and reduced phosphorylated P38MAPK.

The insulin long-acting chitosan - Polyethyleneimine nanoparticles to treat the type 2 diabetes mellitus and prevent the associated complications.

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder, which is ultimately treated by the insulin (INS). However, the subcutaneous (s. c.) injection of insulin solution faces the problems of pain and unsatisfactory patient compliance. In this study, the long-acting formulations of insulin are propsed to treat the T2DM and prevent the associated complications. The chitosan (CS) and/or branched polyethyleneimine (bPEI) nanoparticles (bPEI-INS NPs, CS-bPEI-INS NPs) were constructed to load insulin. The long -acting nanoparticles successfully achieved the sustained release of the INS in vitro and in vivo. After s. c. administration, the CS-bPEI-INS NPs greatly improved the INS bioavailability. As a result, the CS-bPEI-INS NPs produced sustained glucose-lowering effects, promising short-term and long-term hypoglycemic efficacy in the T2DM model. Furthermore, the treatment of the CS-bPEI-INS NPs greatly protected the islet in the pancreas and prevented the associated complications of the T2DM, such as cardiac fibrosis in the myocardial interstitium and the perivascular area. In a word, the CS-bPEI-INS NPs was an encouraging long-acting formulation of insulin and had great potential in the treatment of T2DM.

Morphological characteristics, anatomical structure, and dynamic change of ascorbic acid under different storage conditions of celery.

Ascorbic acid (AsA) is a crucial antioxidant in vegetables. Celery (Apium graveolens L.) is a vegetable of Apiaceae and is rich in AsA. Till now, the effects of different storage conditions on celery morphological characteristics, anatomical features, and antioxidant accumulation are unclear. Here, the celery cvs. 'Sijixiaoxiangqin' and 'Liuhehuangxinqin' were selected as experimental materials, and the two celery plants grown for 65 days were harvested from soils and stored in light at room temperature (25 °C), darkness at low temperature (4 °C), and darkness at room temperature (25 °C) for 0, 6, 24, 30, 48, and 54 h, respectively. The results showed that celery in darkness had better water retention capacity than celery in light. Morphological changes in celery mesophyll, leaf veins, and petioles were the least in darkness at low temperature (4 °C). The weight loss rate and wilting degree in darkness at low temperature (4 °C) were the lowest, and the AsA content remained at a high level. The expression patterns of GDP-D-mannose pyrophosphorylase (AgGMP) and L-galactose dehydrogenase (AgGalDH) were similar to the change of AsA content. The results indicated that low temperature and dark was the optimized storage condition for 'Sijixiaoxiangqin' and 'Liuhehuangxinqin' celery. AgGMP and AgGalDH genes may play an important role in the accumulation of AsA in celery. This paper will provide potential references for prolonging the shelf life of celery and other horticultural crops.

Deep learning-based de novo drug design: principles, tools and practice / 药学学报

Design of structurally-novel drug molecules with deep learning can overcome the technical bottleneck of classical computer-aided drug design. It has become the frontier of new technique research on drug design, and has shown great potential in drug research and development practice. This review starts from the basic principles of deep learning-driven de novo drug design, goes on with the brief introduction to deep molecular generation techniques as well as computational tools and the analysis on representative successful cases, and eventually provides our perspective for future direction and application prospect about this technique. This review will provide ideas on new technique research and references for new drug research and development practice to which this technique is applied.

Analysis of endoscopic characteristics in 93 cases of early gastric cancer and precancerous lesions after Helicobacter pylori eradication / 中华消化杂志

Objective:To analyze the endoscopic characteristics of early gastric cancer and precancerous lesions after Helicobacter pylori ( H. pylori) eradication. Methods:From May 2019 to June 2022, at Shanghai Sixth People′s Hospital affiliated to Shanghai Jiaotong University School of Medicine, the medical data of patients diagnosed with differentiated early gastric cancer and precancerous lesions were collected. A total of 93 patients with early gastric cancer and precancerous lesions who had previous history of H. pylori infection and had undergone standardized eradication treatment were selected, and their endoscopic characteristics were retrospectively analyzed. Independent sample t-test, chi-square test, and Fisher′s exact test were used for statistical analysis. Results:Among 93 patients with early gastric cancer and precancerous lesions after H. pylori eradication, there were 56 males and 37 females, with an average age of (66.9±8.2) years old. The time after H. pylori eradication was 3.4 years (range 1.0 to 7.0 years). A total of 109 early gastric cancer and precancerous lesions were found, including 79 patients with single lesion and 14 patients with multiple lesions (30 lesions). There were 60 cases with 73 lesions in the early gastric cancer group and 33 cases with 36 lesions in the precancerous group. Among 93 patients, 89 cases (95.7%) were diagnosed with atrophy level above C-2 according to Kimura-Takemoto classification under endoscopy. The long diameter of 109 lesions was (1.38±0.70) cm and the short diameter was (1.04±0.53) cm. A total of 80 lesions (73.4%) were located in the lower 1/3 part of the stomach, and 53 lesions (48.6%) were located in the lesser curvature. A total of 106 lesions (97.2%) were superficial type (0-Ⅱ) under the endoscopy. The long diameter and short diameter in the early gastric cancer group after H. pylori eradication were both greater than those in the precancerous lesion group ((1.54±0.78) cm vs. (1.06±0.35) cm, (1.16±0.58) cm vs. (0.78±0.33) cm), and the differences were statistically significant ( t=3.53 and 3.73, both P<0.001). There was statistically significant difference in the morphological types between early gastric cancer group after H. pylori eradication and precancerous lesion group ( χ2=11.01, P=0.012). The main morphological type of early gastric cancer after H. pylori eradication was superficial depression type (0-Ⅱc), accounting for 45.2% (33/73), while the precancerous lesions were mainly superficial protruded and flat type, both accounting for 38.9% (14/36). Conclusions:After H. pylori eradication, the endoscopic atrophy range of early gastric cancer and precancerous lesions is mostly above C-2. And the lesions are mostly located in the middle and lower 1/3 part of the stomach, long diameter of lesions <20 mm. The main morphological type is superficial type, especially superficial depression type.

Volumetric measurement to diagnose syndesmotic injury in Danis-Weber B type ankle fractures / 国际外科学杂志

Objective:To investigate the change of syndesmotic volume via CT scan in Danis-Weber B type ankle fracture, aiming to provide a non-invasive diagnostic method for Danis-Weber B type ankle fracture combined with syndesmotic injury.Methods:Retrospective analysis was performed on 48 patients with Danis-Weber B type ankle fractures in Shanghai Sixth People′s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from January 2018 to March 2022, including 30 males and 18 females, aging (43.71±19.41) years. Ankle CT scans and three-dimensional reconstructions were performed before surgery and at the last follow-up, measuring the syndesmotic volume between the tibiotalar joint and 1, 3 and 5 cm above the ankle and compared with each other. Intraoperative exploration was used as the gold standard for the syndesmotic injury. Based on the results of exploration of the syndesmotic injury, patients were divided into simple ankle fracture group (fracture group, 25 cases) and ankle fracture combined with syndesmotic injury group (fracture + ligament group, 23 cases). The sensitivity and specificity of this diagnostic method were statistically evaluated. The assessments at the last follow-up were performed to value the clinical effect of surgery. The metric data conforming to the normal distribution were expressed as mean ± standard deviation ( ± s), and the t-tests were used for comparison between groups. The measurement data of skewed distribution were expressed as quartile M( Q1, Q3), and nonparametric tests were used for intergroup comparison. Counting data were expressed as number of cases and percentage (%), and Chi-square test were used for intergroup comparison. Results:In the fracture group, there were no statistically significant differences of the syndesmotic volume at 1, 3, and 5 cm above the ankle joint before surgery and at the last follow-up ( P=0.219, 0.269, 0.103). On the contrary, the volume above were statistically significant in the fracture + ligament group ( P<0.001). There were statistically significant differences in syndesmotic volume between the two groups at 1, 3, and 5 cm above the ankle joint preoperatively ( P=0.005, 0.004, 0.038). By contrast, there were no statistical differences between the two groups postoperatively ( P=0.082, 0.155, 0.249). For the sensitivity and specificity of Danis-Weber B type ankle fractures combined with syndesmotic injury, they were 92% and 67% at 1 cm above the ankle joint, 69% and 87% at 3 cm above the ankle joint, and 62% and 87% at 5 cm above the ankle joint, respectively. The last follow-up clinical function score indicated a good surgical outcome. Conclusions:Volumetric measurement via CT scan is one of the diagnostic methods for evaluating Danis-Weber B type ankle fracture combined with syndesmotic injurys. Open resection internal fixation combined with elastic fixation of the ankle fracture combined with syndesmotic injurys can significantly reduce the lower tibiofibular volume, and the efficacy is definite.

Discovery and druggability evaluation of pyrrolamide-type GyrB/ParE inhibitor against drug-resistant bacterial infection

The bacterial ATP-competitive GyrB/ParE subunits of type II topoisomerase are important anti-bacterial targets to treat super drug-resistant bacterial infections. Herein we discovered novel pyrrolamide-type GyrB/ParE inhibitors based on the structural modifications of the candidate AZD5099 that was withdrawn from the clinical trials due to safety liabilities such as mitochondrial toxicity. The hydroxyisopropyl pyridazine compound 28 had a significant inhibitory effect on Gyrase (GyrB, IC50 = 49 nmol/L) and a modest inhibitory effect on Topo IV (ParE, IC50 = 1.513 μmol/L) of Staphylococcus aureus. It also had significant antibacterial activities on susceptible and resistant Gram-positive bacteria with a minimum inhibitory concentration (MIC) of less than 0.03 μg/mL, which showed a time-dependent bactericidal effect and low frequencies of spontaneous resistance against S. aureus. Compound 28 had better protective effects than the positive control drugs such as DS-2969 ( 5) and AZD5099 ( 6) in mouse models of sepsis induced by methicillin-resistant Staphylococcus aureus (MRSA) infection. It also showed better bactericidal activities than clinically used vancomycin in the mouse thigh MRSA infection models. Moreover, compound 28 has much lower mitochondrial toxicity than AZD5099 ( 6) as well as excellent therapeutic indexes and pharmacokinetic properties. At present, compound 28 has been evaluated as a pre-clinical drug candidate for the treatment of drug-resistant Gram-positive bacterial infection. On the other hand, compound 28 also has good inhibitory activities against stubborn Gram-negative bacteria such as Escherichia coli (MIC = 1 μg/mL), which is comparable with the most potent pyrrolamide-type GyrB/ParE inhibitors reported recently. In addition, the structure-activity relationships of the compounds were also studied.

Study on the present situation of narcotic drugs equipment and management in 251 primary healthcare institutions from Qiandongnan prefecture / 中国药房

OBJECTIVE To investigate the present equipment and management situation of narcotic drugs in primary healthcare institutions from Qiandongnan prefecture of Guizhou province. METHODS The questionnaire survey was conducted among pharmacy department heads and medical staff from primary healthcare institutions in Qiandongnan prefecture of Guizhou province. Descriptive statistical analysis was conducted on the survey results. RESULTS Of 251 healthcare institutions in this survey， 29 healthcare institutions were equipped with narcotic drugs， accounting for 11.55%. The reasons for the narcotic drugs unequipped were mainly as follows: insufficient attention， no storage conditions for narcotic drugs， complex program of narcotic drug management， small amount usage and so on. Among the 29 primary healthcare institutions equipped with narcotic drugs， all of them did not monitor patient usage， accounting for 100%； 29 healthcare institutions did not implement a return visit or follow-up every 3 months， accounting for 100%. CONCLUSIONS The health administration departments should strengthen the administration of narcotic drugs in primary healthcare institutions. At the same time， training on standardized management and clinical rational application of narcotic drugs for medical staff in primary healthcare institutions should be enhanced by the health administrative department.

Recent research on the application of defoamers in children undergoing digestive endoscopy / 中国当代儿科杂志

Endoscopy is a common tool for the diagnosis and treatment of gastrointestinal disorders in children. The presence of bubbles in the gastrointestinal tract is one of the important factors affecting the clarity of endoscopic visual field, and the application of defoamers can significantly reduce bubbles in the gastrointestinal tract, improve the quality of gastrointestinal preparation, and further increase disease detection rate. Various studies have been conducted on gastrointestinal preparation before endoscopy in children, but there still lacks a uniform protocol for the application of defoamers. This article summarizes the use of defoamers in children before digestive endoscopy and related research advances and points out that existing studies on defoamers have a small sample size and that there are still controversies over the selection and timing of administration, so as to provide a reference for in-depth research on defoamers in the future.

Differential hydroxylation efficiency of the two non-heme carotene hydroxylases: DcBCH1, rather than DcBCH2, plays a major role in carrot taproot.

Carotene hydroxylase plays an important role in catalyzing the hydroxylation of carotene to xanthopylls, including two types: non-heme carotene hydroxylase (BCH type) and heme-containing cytochrome P450 hydroxylase (P450 type). Two BCH-encoding genes were annotated in the carrot genome. However, the role of BCHs and whether there are functional interactions between the duplicated BCHs in carrot remains unclear. In this study, two BCH encoding genes, DcBCH1 and DcBCH2, were cloned from carrot. The relative expression level of DcBCH1 was much higher than that of DcBCH2 in carrot taproots with different carotene accumulation levels. Overexpression of DcBCH1 in 'KRD' (high carotene accumulated) carrot changed the taproot color from orange to yellow, accompanied by substantial reductions in α-carotene and ß-carotene. There was no obvious change in taproot color between transgenic 'KRD' carrot overexpressing DcBCH2 and control carrot. Simultaneously, the content of α-carotene in the taproot of DcBCH2-overexpressing carrot decreased, but the content of ß-carotene did not change significantly in comparison with control carrot. Using the CRISPR/Cas9 system to knock out DcBCH1 in 'KRD' carrot lightened the taproot color from orange to pink-orange; the content of α-carotene in the taproot increased slightly, while the ß-carotene content was still significantly decreased, compared with control carrot. In DcBCH1-knockout carrot, the transcript level of DcBCH2 was significantly increased. These results indicated that in carrot taproot, DcBCH1 played the main function of BCH enzyme, which could hydroxylate α-carotene and ß-carotene; DcBCH1 and DcBCH2 had functional redundancy, and these two DcBCHs could partially compensate for each other.