Btbd8 deficiency reduces susceptibility to colitis by enhancing intestinal barrier function and suppressing inflammation.

Introduction: BTBD8 has been identified as a susceptible gene for inflammatory bowel diseases (IBD). However, the function of BTBD8 in normal development and IBD pathogenesis remains unknown. Methods: We administered drinking water with 3% dextran sodium sulfate (DSS) to wild-type (WT) and Btbd8 knockout (KO) mice for seven consecutive days to induce IBD. Subsequently, we further examined whether Btbd8 KO affects intestinal barrier and inflammation. Results: We demonstrated that Btbd8 deficiency partially protects mice from DSS-induced IBD, even though no obvious phenotypes were observed in Btbd8 KO mice. Btbd8 deletion leads to strengthened tight junctions between intestinal epithelial cells, elevated intestinal stem cell activity, and enhanced mucus layer. All these three mechanisms work together to improve the intestinal barrier integrity in Btbd8 KO mice. In addition, Btbd8 deficiency mitigates inflammation by reducing the expression of IL-1ß and IL-6 by macrophages. Discussion: Our studies validate the crucial role of Btbd8 in IBD pathogenesis, and reveal that Btbd8 deficiency may ameliorate DSS-induced IBD through improving the intestinal barrier integrity, as well as suppressing inflammatory response mediated by macrophages. These findings suggest that Btbd8 could be a promising therapeutic target for the treatment of IBD.

HDS screening with patient-derived primary cells guided individualized therapy for esophageal squamous cell carcinoma-in vivo and vitro.

Objective: To analyze and evaluate the role of the High-throughput Drug Sensitivity (HDS) screening strategy in identifying highly sensitive drugs against esophageal squamous cell carcinoma (ESCC). Methods: A total of 80 patients with progressive ESCC were randomly divided into the observation (40 cases) and the control groups (40 cases). In the observation group, primary ESCC cells were isolated from the tumor tissues with a gastroscope, and drug sensitivity screening was performed on cells derived from the 40 ESCC cases using the HDS method, followed by verification in a patient-derived tumor xenograft (PDX) mouse model. Finally, the differences in the therapeutic efficacy (levels of CEA, CYFRA21-1, SCCA after chemotherapy and the rates of overall survival, local progression, and distant metastasis at 12 months and 18 months time points after chemotherapy) were compared between the observation group (Screened drug-treated) and the control group (Paclitaxel combined with cisplatin regimen-treated). Results: Forty ESCC patients were screened for nine different high-sensitive chemotherapeutics, with the majority showing sensitivity to Bortezomib. Experiments on animal models revealed that the tumor tissue mass of PDX mice treated with the HDS-screened drug was significantly lower than that of the Paclitaxel-treated mice (p < 0.05), and the therapeutic efficacy of the observation group was better than the control group (p < 0.05). Conclusion: HDS screening technology can be beneficial in screening high-efficacy anticancer drugs for advanced-stage ESCC patients, thereby minimizing adverse drug toxicity in critically ill patients. Moreover, this study provides a new avenue for treating advanced ESCC patients with improved outcomes.

Analysis of Complications and Risk Factors Other than Bleeding before and after Endoscopic Treatment of Esophagogastric Variceal Bleeding in Patients with Liver Cirrhosis.

Objective: To identify any concomitant complications other than bleeding (COTB) before and after endoscopic treatment of esophagogastric variceal bleeding (EGVB) in liver cirrhosis patients and explore the underlying risk factors. Materials and Methods: Cirrhotic patients complicated with EGVB, who underwent interventional endoscopic treatments in our hospital from November 2017 to August 2020, were enrolled in this study. Clinical data were retrospectively analyzed for COTB at admission and within 2 years of the first endoscopic treatment. Patients were screened for potential risk factors of COTB before and after the treatment. Univariate analysis was performed to identify clinical factors of secondary complications, and statistically significant factors were included in the multivariate Cox and logistic regression analyses. Results: Of the 547 patients with cirrhosis, 361 individuals had COTB in the first endoscopic treatment. In this cohort, the top 3 prevalent incidences were portal vein thrombosis (PVT) or spongiosis, cholelithiasis, and pathogenic infections. The COTB did not occur at admission in 171 liver cirrhosis patients but happened at the follow-up. Higher Child-Pugh scores indicated potential risks of multiple concurrent complications, including bleeding. Risk factors for concomitant PVT or cavernous changes after endoscopic treatment of EGVB, pathogenic infections, and cholelithiasis could prolong the cirrhosis symptoms, while noncholestatic cirrhosis patients might have a lower risk than posthepatitis B cirrhosis patients, in the context of a higher degree of EGV and serum level of D-D and a lower blood calcium level. Conclusions: Clinical treatment and interventions can be tailored to avoid other complications during and after EGVB treatment, which can affect the outcome and prognosis of bleeding symptoms.

Generation of singlet oxygen catalyzed by the room-temperature-stable anthraquinone anion radical.

The chemical nature and the catalytic selectivity of the complex of anthraquinone and potassium tert-butoxide, AQ-KOtBu, in generating singlet oxygen (1O2) have been studied using a high-level ab initio method and density functional theory (DFT). The results suggest that the stable catalytic center of the AQ anion radical (semiquinone, [AQ˙]-) can be produced at room temperature, which is due to the strong delocalization characteristics of electrons in potassium atoms. Two experimentally observed complexes, the ground state AQ-KOtBu, i.e., C(1), and the photoexcited AQ-KOtBu, i.e., C(2), can be distinguished via the two different electronic states (π-type and σ-type) of the tert-butoxide group. More interestingly, the catalytic selectivity of AQ-KOtBu to generate 1O2 was investigated using multistate density functional theory (MSDFT), and the results suggest that only open-shell 1O2 rather than the closed-shell component can be generated. This work explores the electronic structure and the catalytic nature of AQ-KOtBu, which is of great importance for the application of AQ and its derivatives.

Effects of full-threaded headless cannulated compression screws and anatomical plates on the efficacy, safety, and prognosis of patients with triplane fractures of the distal tibia.

OBJECTIVE: To compare the clinical efficacy, safety, and prognosis of full-threaded headless cannulated compression screws (HCCSs) and anatomical plates (APs) in the treatment of triplane fractures of the distal tibia. METHODS: In this retrospective study, 74 patients with triplane fractures of the distal tibia treated in our hospital from April 2017 to March 2019 were selected as the research subjects. Among them, 38 patients receiving full-threaded HCCSs were assigned to the research group (RG), and the remaining 36 patients receiving APs were assigned to the control group (CG). The general indices, including operation, fracture healing, and ambulation times, efficacy, and complications were recorded and compared between the two groups. Visual analogue scale (VAS) was applied to assess pain, and a quality of life (QOL) survey was conducted at 6 months after surgery. RESULTS: Compared with the CG, the operation time, fracture healing time, and ambulation time of the RG were significantly shortened (P<0.05). The proportion of patients with excellent and good outcomes and Mazur Scores in the RG were higher than those in the CG (P<0.05). The frequency of complications in the RG was lower than that in the CG (P<0.05). The preoperative VAS score did not exhibit significant differences between the two groups (P<0.05), but the scores in the RG at T1 and T2 were significantly lower than those in the CG (P<0.001). The QOL score in the RG (76.17±8.57) was also significantly higher than in the CG (71.54±8.02) (P<0.05). CONCLUSION: Full-threaded HCCSs are more effective and safer than APs and can effectively improve the prognosis of patients with triplane fractures of the distal tibia.

Anemoside B4 sensitizes human colorectal cancer to fluorouracil-based chemotherapy through src-mediated cell apoptosis.

Currently, 5-Fluorouracil (5-FU) based chemotherapy is the primary option for colorectal cancer after surgery, whereas chemotherapy resistance related mortality is observed in a large proportion of patients. Anemoside B4 (AB4) is a triterpene saponin, which exhibits a considerable activity in oncotherapy. In this study, we explored the efficacy of AB4 in FU-based chemotherapy in colorectal cancer cells and the underlying molecular mechanisms. Our results indicated a significant synergistic activity of AB4 in 5-FU treated colorectal cancer cells. Furthermore, AB4 treatment eliminated colorectal cancer stem cells by promoting apoptotic cell death in 5-FU resistant colorectal cancer cells. Mechanically, AB4 activated caspase-9 pathway in 5-FU resistant colorectal cancer cells. Elevated Src activity induced cell apoptosis and cancer stem cells elimination effects in AB4 treated colorectal cancer cells. In conclusion, AB4 showed promising sensitization effect in the FU-based chemotherapy of colorectal cancer. Our study may pave a way to ameliorate FU-based chemotherapeutic efficiency in colorectal cancer.

The lupus autoantigen La/Ssb is an Xist-binding protein involved in Xist folding and cloud formation.

Using the programmable RNA-sequence binding domain of the Pumilio protein, we FLAG-tagged Xist (inactivated X chromosome specific transcript) in live mouse cells. Affinity pulldown coupled to mass spectrometry was employed to identify a list of 138 candidate Xist-binding proteins, from which, Ssb (also known as the lupus autoantigen La) was validated as a protein functionally critical for X chromosome inactivation (XCI). Extensive XCI defects were detected in Ssb knockdown cells, including chromatin compaction, death of female mouse embryonic stem cells during in vitro differentiation and chromosome-wide monoallelic gene expression pattern. Live-cell imaging of Xist RNA reveals the defining XCI defect: Xist cloud formation. Ssb is a ubiquitous and versatile RNA-binding protein with RNA chaperone and RNA helicase activities. Functional dissection of Ssb shows that the RNA chaperone domain plays critical roles in XCI. In Ssb knockdown cells, Xist transcripts are unstable and misfolded. These results show that Ssb is critically involved in XCI, possibly as a protein regulating the in-cell structure of Xist.

Predictive nursing helps improve treatment efficacy, treatment compliance, and quality of life in unstable angina pectoris patients.

OBJECTIVE: This paper aims to explore the effects of predictive nursing on the treatment efficacy in unstable angina pectoris (UAP) patients and on their treatment compliance and quality of life (QOL). METHODS: Admitted to our hospital from November 2017 to August 2019, 110 UAP patients were recruited as the study cohort and randomized into a control group (CG) and an observation group (OG). Among them, 53 patients in the CG underwent routine nursing, and the remaining 57 patients in the OG underwent additional predictive nursing in addition to the routine nursing. The patients in both groups were observed with respect to their general data, the therapeutic effects after the nursing, their clinical indicators (length of hospital stays, stable states of angina pectoris, attacks of angina pectoris), their treatment compliance after the nursing, their negative emotions before and after the nursing, their adverse reactions during the nursing, and the changes in their blood pressure (diastolic blood pressure, systolic blood pressure) and QOL indices after the nursing. RESULTS: There were no differences in the general data between the two groups (P>0.05), but the clinical indicators were better in the OG (P<0.05). After the nursing, the treatment compliance and improvement of the negative emotions were better in the OG (P<0.05), and the efficacy was also better in this group (P<0.05). The incidence of adverse reactions was lower in the OG (P<0.05), and the changes in the blood pressure indices were better in this group (P<0.05). After the nursing, the QOL in the OG was better (P<0.05). CONCLUSION: Predictive nursing is conducive to improving the efficacy, the treatment compliance, and the QOL of UAP patients.

[Detection of KRAS gene mutations in colorectal carcinoma: a study of 6 364 patients].

OBJECTIVE: To investigate the mutation rate and types of KRAS gene in colorectal carcinoma of Chinese patients, and to document the regional distribution of the mutation. METHODS: A total of 6 364 colorectal carcinoma tumor specimens were obtained from 27 provinces and autonomous regions in China from 2009 to 2013. Pyrosequencing was used to detect mutations in codons 12 and 13 of KRAS gene. The mutation types of KRAS and the difference of regional distribution were statistically analyzed. RESULTS: KRAS mutation rate in Chinese colorectal carcinoma patients was 37.43 % (2 382/6 364). Ten types of single-base mutations of KRAS codons 12 and 13 were detected, including six common types: 12GGT > GAT (14.77%), 13GGC > GAC (8.19%), 12GGT > GTT (7.89%), 12GGT > TGT (2.20%), 12GGT > AGT (2.00%), and 12GGT > GCT (1.48%). Other four less occurring mutation types (<1%) included 12GGT > CGT, 13GGC > TGC, 13GGC > CGC, and 13GGC > AGC. In addition, 8 other mutation types were identified in 13 tumor samples. The rates of KRAS mutation in patients from different regions were between 35.68% and 38.04% and no significant differences were observed (P > 0.05). CONCLUSIONS: Abundant mutation types of KRAS gene exist in colorectal cancers among Chinese patients. The six common mutation types occur with a frequency of not less than 1%. There are no significant differences of KRAS mutation rate among Chinese patients from various areas. Pyrosequencing provides a rapid and accurate method of KRAS mutation detection for clinical application.

Design, synthesis, and biological evaluation of 1,4-diaryl-1,4-dihydropyrazines as novel 11ß-HSD1 inhibitors.

The inhibition of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) has demonstrated potential for the treatment of various components of metabolic syndrome. In this study, a series of 1,4-diaryl-1,4-dihydropyrazines were designed as inhibitors of 11ß-HSD1 based on the structure-activity relationship of known 11ß-HSD1 inhibitors through docking simulations. The docking simulation results supported the initial pharmacophore hypothesis: the docking results of the known inhibitors with 11ß-HSD1 suggested a similar interaction of 1,4-diaryl-1,4-dihydropyrazines with the catalytic site of 11ß-HSD1. Twelve of these compounds were synthesized through the cyclization of N,N-dialkylanilines with anilines, and their structures were determined by (1)H-NMR, (13)C-NMR, high resolution (HR)-MS, and single-crystal X-ray diffraction. The inhibitory activities of these compounds against human 11ß-HSD1 were investigated in vitro through a scintillation proximity assay using microsomes containing 11ß-HSD1.

Synthesis of 4H-1,4-oxazines as transthyretin amyloid fibril inhibitors.

4H-1,4-oxazines were designed as transthyretin (TTR) amyloid fibril inhibitors based on an analysis of the interactions between known small molecule inhibitors and TTR by molecular docking. A series of 2,4,6-triaryl-4H-1,4-oxazines was synthesized by the cyclization of N,N-bis(phenacyl)anilines with POCl3 in pyridine. Inhibition of TTR amyloid fibril was evaluated by a fibril formation assay. The results indicate that 4H-1,4-oxazines significantly inhibit TTR amyloid fibril at a concentration of 7.2 µM.

Ag nanoparticle decorated nanoporous ZnO microrods and their enhanced photocatalytic activities.

Nanostructured Ag nanoparticles (Ag-NPs)/nanoporous ZnO micrometer-rods (n-ZnO MRs) have been synthesized by a two-step method. The n-ZnO MRs was initially prepared by solvothermal-assisted heat treatment. The rods had the diameter ranged from 90 to 150 nm and length between 0.5 and 3 µm. They were found to be porous and were composited of ZnO nanopartiles with size of about 20 nm. In the second stage, Ag-NPs with a diameter of 20-50 nm were anchored onto the surface of the as-prepared n-ZnO MRs by a photoreduction method. The Ag-NPs/n-ZnO MRs were evaluated for their ability to degrade methylene blue (MB) solution under visible to ultraviolet (UV) light irradiation. The rate of degradation of the as-prepared Ag-NPs/n-ZnO MRs was more than twice and nearly 5.6 times faster than that of using bare n-ZnO MRs under the UV and solar light irradiation, respectively. The formation of Schottky barriers in the regions between the Ag-NPs and n-ZnO MRs had improved the charge separation and consequently enhanced the efficiency of the degradation process. Moreover, the as-prepared hybrid structure exhibited high photostability, and 98% of degradation efficiency could be maintained even after being used five times. This endurance was attributed to the retardation of photocorrosion of ZnO as a result of the low concentration of surface defects in the as-prepared n-ZnO MRs. It also minimized the surface defects of the as-prepared n-ZnO MRs and consequently further inhibited the photocorrosion of ZnO when the deposited Ag-NPs were much more inclined to combine with the chemisorbed oxygen.

GSK-3ß activation mediates Nogo-66-induced inhibition of neurite outgrowth in N2a cells.

The axons of the adult mammalian brain and spinal cord fail to regenerate after injury, and it has been suggested that Nogo-66 could prevent CNS axon repair. However, the mechanism of Nogo-66 inhibiting neurite outgrowth remains unknown. Our previous results indicated that protein kinase B (PKB) is involved in the inhibition of the neurite outgrowth by Nogo-66. Glycogen synthase kinase-3ß (GSK-3ß) is implicated in many processes in the nervous system, including differentiation, specification, polarity, plasticity and axon growth. In addition, GSK-3ß is one of the most important molecules downstream of PKB. In the present study, we report on the role of GSK-3ß signaling on Nogo-66-treated mouse neuroblastoma N2a cells. Nogo-66 reduced the phosphorylation of GSK-3ß at Ser9 in N2a cells. In contrast, pretreatment with SB216763, a specific inhibitor of GSK-3ß, resulted in an amelioration of neurite outgrowth by Nogo-66, compared with the Nogo-66 alone group (P<0.05). Moreover, we performed RNA interference experiments to knock down GSK-3ß expression levels in N2a cells via transient transfection of shRNA plasmids. The inhibition of neurite outgrowth by Nogo-66 was subdued in shRNA cells, compared to the non-RNAi cells (P<0.05). Taken together, these data suggest that GSK-3ß is involved in the inhibition by Nogo-66 of neurite outgrowth in N2a cells.

[Effects of grazing on zoobenthos community in beach].

In May (spring) and October (autumn) 2005, the effects of grazing on the zoobenthos community in Chongming Dongtan wetland of Shanghai were investigated. A total of 3 transects including 90 sampling plots were set up. Transects I and II were in feeding area, and transect III was in non-pasture area. All of these three transects were set in mid-tidal zone. 13 zoobenthos species were observed, with 7 species of arthropod, 4 species of mollusk, and 2 species of annelid. In spring, there were 6, 8 and 10 species in transects I , II and III while in autumn, the species number was 6, 8 and 12, respectively. The mean abundance of zoobenthos community in all transects was higher in autumn than in spring, and transect III had the highest mean abundance and biomass both in autumn and spring. Transect III also had the highest evenness, richness and diversity, indicating that grazing could change the species distribution of zoobenthos, and affect their abundance and biomass to different degree. Grazing had made certain negative effects on the biodiversity of zoobenthos community in Chongming Dongtan wetland.