Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Objective:To explore the effect of bismuth containing triple therapy on serum gastrin (Gas), transforming growth factor-α (TGF-α), and high-sensitivity C-reactive protein (hs-CRP) levels in children with Helicobacter pylori (Hp) positive peptic ulcers.Methods:A total of 96 children with Hp positive peptic ulcers admitted to the Second Hospital of Jiaxing from January 2020 to December 2021 were selected as the study subjects. They were randomly divided into two groups using the remainder of a random number table. The control group (48 cases) received treatment with omeprazole, clarithromycin, and amoxicillin, while the observation group (48 cases) received treatment with bismuth containing triple therapy (amoxicillin+ metronidazole+ bismuth potassium citrate). After 10 days of treatment, the clinical efficacy of the two groups was evaluated The improvement time of clinical symptoms, Hp conversion rate, serum indicators (Gas, TGF-α, hs-CRP) before and after treatment, and incidence of adverse reactions were observed.Results:The total effective rate and Hp conversion rate of the observation group were significantly higher than those of the control group [95.83%(46/48) vs 81.25%(39/48), 97.92%(47/48) vs 83.33%(40/48), P<0.05]. The improvement time of upper abdominal pain, heartburn, and acid reflux symptoms was significantly shorter than that of the control group (all P<0.05). After 10 days of treatment, the serum Gas and hs-CRP levels in both groups significantly decreased compared to before treatment (all P<0.05), and the observation group was lower than the control group after treatment ( P<0.05); The levels of TGF-α in both groups increased compared to before treatment (all P<0.05), and the observation group was higher than the control group after treatment ( P<0.05). There was no statistically significant difference in the incidence of adverse reactions between the two groups [4.17%(2/48) vs 2.08%(1/48), P>0.05]. Conclusions:The triple therapy with bismuth containing agents has a better therapeutic effect on children with Hp positive peptic ulcers, and can promote ulcer mucosal repair by improving inflammatory response, with good safety.

Objective:To observe the projections from tyrosine hydroxylase(TH)positive neurons in locus coerule-us(LC)to tachykinin-1(TAC1)neurons in paraventricular nucleus of the thalamus(PVT),and morphologically determine whether they are involved in transmission and modulation of nociceptive information.Methods:TAC1-ires-Cre mice were hybridized with Rosa26:CAG-LSL-tdTomato(Ai9)mice.And spared nerve injury(SNI)induced neu-ropathic pain model was established with TAC1-ires-Cre::Ai9 mice to observe the colocalization of TAC1 and Fos and the close appositions between TAC1/FOS double-labeled neurons and TH positive axonal terminals.The distribution of the TH positive neurons and FG retrogradely labeled neurons were observed in the LC after Fluorogold(FG)was injec-ted into the PVT.Finally,the coexistences of TH positive neurons and RV labeled neurons in the LC were observed after injection of RV-mediated retrograde tracing system.Results:TAC1 positive neurons were shown with red fluores-cence in TAC1-ires-Cre::Ai9 mice.TAC1/FOS double-labeled neurons were found in the PVT of the SNI model.Some TAC1/FOS double labeled neurons made close appositions with TH positive axonal terminals.FG retrogradely labeled neurons were observed in the LC after FG injected into the PVT,and some of the FG labeled neurons coexisted with TH positive neurons.Using RV retrograde transsynaptic tracing virus,the results showed that presynaptic neurons of TAC1 positive neurons in the PVT were found in the LC,and most of the presynaptic neurons were TH positive neu-rons.Conclusion:TH positive neurons in the LC project to TAC1 positive neurons of the PVT,forming LCTH+-PVTTAC1+neural circuit,which were activated by nociceptive information.It demonstrates that this pathway plays a role in pain transmission or regulation.

Objective:To investigate the regulatory effect of vitamin D on the HMGB1/RAGE pathway and adipokine levels in a mouse model of obesity and asthma.Methods:This study was conducted at the Experimental Center of the Second Affiliated Hospital of Jiaxing University and the laboratory of Jiaxing University from February to September 2023. Thirty mice were marked with digital ear numbers and were randomly divided into five groups, with six mice in each group: Group Ⅰ (normal control group), Group Ⅱ (asthma group), Group Ⅲ (obesity and asthma group), Group Ⅳ (asthma + vitamin D group), and Group V (obesity and asthma + vitamin D group). An obesity mouse model was induced using a high-fat diet, while an asthma mouse model was induced through sensitization via intraperitoneal injection of ovalbumin and aerosol inhalation. The vitamin D intervention consisted of continuous intragastric administration of vitamin D (1 mL/d) for 2 weeks. Blood levels of interleukin-4, interleukin-6, interleukin-10, adiponectin, and leptin were determined using the enzyme-linked immunosorbent assay method. The expression of genes encoding high mobility group protein B1 (HMGB1) and the receptor for advanced glycation end products (RAGE) was detected using a quantitative reverse transcription polymerase chain reaction. All the obtained results were statistically analyzed using SPSS software.Results:The white blood cell count in bronchoalveolar lavage fluid (BALF) of Group Ⅱ was (1.34 ± 0.48) × 10 5/L, which was significantly lower than (4.07 ± 0.14) × 10 5/L in Group Ⅳ ( t = -18.28, P < 0.001). The white blood cell count in BALF in Group Ⅲ was (9.61 ± 0.91) × 10 5/L, which was significantly higher than (4.89 ± 0.38) × 10 5/L in Group V ( t = 11.75, P < 0.001). The percentage of eosinophils in BALF of Group II was (28.75 ± 1.94)%, which was significantly higher than (11.51 ± 1.99)% in Group Ⅳ ( t = 15.20, P < 0.001). The percentage of eosinophils in BALF of Group V was (12.50 ± 1.42)%, which was significantly lower than (29.80 ± 1.96)% in Group Ⅲ ( t = 17.74, P < 0.001). The ELISA results demonstrated that serum levels of interleukin-4, interleukin-6, interleukin-17, interleukin-1β, immunoglobulin E, and tumor necrosis factor-α in Group V were significantly lower than those in Group Ⅲ ( t = 15.24, 9.65, 2.26, 5.83, 10.86, 2.50, all P < 0.001). The serum level of interleukin-10 in Group Ⅲ was (4.97 ± 0.25) pg/mL, which was significantly lower than (8.84 ± 0.64) pg/mL in Group V ( t = -13.89, P < 0.001). The serum level of adiponectin in Group V was (1.95 ± 0.85) mg/L, which was significantly higher than (1.15 ± 0.13) mg/L in Group Ⅲ ( t = -12.67, P < 0.001). The HMGB1 expression level in lung tissue of Group Ⅳ was 1.42 ± 0.09, which was significantly lower than 1.91 ± 0.16 in Group Ⅱ ( t = 6.55, P < 0.001). The expression level of RAGE mRNA in lung tissue in Group Ⅳ was 1.35 ± 0.11, which was significantly lower than 1.55 ± 0.152 in Group Ⅱ ( t = 4.19, P < 0.05). The expression level of HMGB1 in lung tissue in Group V was 1.51 ± 0.10, which was significantly lower than 2.44 ± 0.10 in Group Ⅲ ( t = 1.02, P < 0.001). Conclusion:Vitamin D may alleviate lung injury by up-regulating the expression of HMGB1 and RAGE in a mouse model of obesity and asthma. This provides a new concept and method for the treatment and prevention of obesity and asthma.

Objective To investigate the mechanism of fibroblast growth factor(FGF)21 in liver lipid deposition.Methods HepG2 cells were divided into control group and induction group.Fatty liver cell model was constructed using oleic acid and palmitic acid in induction group.Lipid deposition under the microscope was observed between two groups by oil red O staining,and the protein expression of FGF21 and glutathione peroxidase 4(GPX4)in two groups were detected.FGF21 lentivirus-infected fatty liver cells were used as interference group,and scramble lentivirus-infected fatty liver cells were used as non-interference group.The expression level of FGF21 mRNA,lipid deposition and expression level of GPX4 protein were compared between two groups.Results Compared with control group,induction group had significant lipid deposition,significantly increased expression level of FGF21 protein,and significantly decreased expression level of GPX4 protein(P＜0.05).After the interference of FGF21 lentivirus,expression level of FGF21 mRNA was significantly decreased,lipid droplets were decreased,lipid deposition was significantly improved,and GPX4 protein expression level was significantly increased in interference group(P＜0.05).Conclusion FGF21 may promote liver lipid formation by inhibiting lipid peroxidation.

Objective: To investigate the mechanism of vascular endothelial growth factor(VEGF) inducing tolerogenic dendritic cells(DCs) in oral squamous cell carcinoma (OSCC). Methods: The DCs were divided into four groups: Control group (DC), VEGF group (VEGF added into DC), Co-culture group (DC co-cultured with SCC7) and Anti-VEGF group (anti-VEGF antibody added into DC co-cultured with SCC7). Flow cytometry (FCM) was used to detect DC surface markers. To detect the effect of DC on proliferation activity of T lymphocyte, the experiment included five groups: Nc group (T lymphocyte), Control group (T lymphocyte added into DC), VEGF group (T lymphocyte + DC + VEGF), Co-culture group (T lymphocyte + DC + supernatant of SCC7) and Anti-VEGF group (T lymphocyte + DC + supernatant of SCC7 + anti-VEGF antibody). Subsequently, the mixed lymphocyte reaction(MLR) was conducted. The expression levels of indole-2, 3-doxygenase(IDO)and programmed cell death 1 ligand 1(PD-L1)in DC were detected by western blot, real time PCR and FCM respectively. For the cytotoxic lymphocyte (CTL) assay, SCC7 cells and CTLs were mixed and CTL-mediated SCC7 cells cytotoxicity was tested. The experiment included four groups: Control group (T lymphocyte + DC), IDO inhibition group (T lymphocyte + DC + IDO inhibitor), Anti-PD-L1 antibody group (T lymphocyte + DC + anti-PD-L1 antibody) and Combination group (T lymphocyte + DC + IDO inhibitor + anti-PD-L1 antibody). The SCC7 tumor-bearing mice treated with IDO inhibitor and the anti-PD-L1 antibody were sacrificed and the tumor inhibition rate and the spleen index were determined. Results: Compared with Control group, exogenous VEGF or SCC7 co-culture inhibited the relative number of DC expressing CD11C, CD80, CD86, CD40 and MHC Ⅱ. The positive DCs were increased in the Anti-VEGF group compared with VEGF or Co-culture group. In VEGF or Co-culture group, the number of T cells stimulated by SCC7-pulsed DCs was decreased compared with Control group. However, the ability of Anti-VEGF group to induce T cell proliferation was significantly increased compared with VEGF or Co-culture group. Significantly increased expression of IDO and PD-L1 were observed in VEGF and Co-culture group. However, this was partially reversed by addition of anti-VEGF antibody into the co-culture system. Compared with Control group, the expressions of CD11C and CD86 in DC in both the IDO inhibition group and Anti-PD-L1 antibody group were increased, and were significantly higher in the Combination group compared with the single drug groups. The similar results were exhibited in MLR and CTL assay. In vivo, the results revealed that the tumors obtained from the mice in three experimental groups were smaller than those in the control group. Furthermore, the tumor volume of the Combination group was the smallest. The spleen index of each group was calculated and the results showed the spleen index of the three experimental groups was significantly higher than that of Control group. Conclusion VEGF in OSCC micro-environment inhibits the maturation and function of DC that are transformed into tolerogenic DC by high expression of IDO and PD-L1.

Objective:To investigate the association between dietary intake and physical activity category and their combined effects on all-cause and cause-specific mortality risk in patients with type 2 diabetes mellitus (T2DM).Methods:Between December 2013 and December 2021, a prospective cohort study was conducted on 19 863 T2DM patients in Changshu City, Qingjiangpu District (formerly Qinghe District), and Huai'an District, included in the national basic health service management. Information on deaths and underlying causes of death was obtained from the Jiangsu Provincial CDC and Prevention Death Surveillance System. Cox proportional hazards models were used to estimate the intensity of associations between dietary intake, physical activity, and their combined effects with all-cause and cause-specific mortality in patients with T2DM.Results:As of December 31, 2021, the research subjects had been followed up for 150 283 person-years, with a median follow-up time of 8.15 years. During the follow-up period, 3 293 people died, including 1 124 deaths from cardiovascular disease (CVD) and 875 deaths from cancer. Cox regression analysis showed that compared with the population of 0-1 recommended food group, those having more than five recommended food groups had a 19% lower risk of all-cause mortality [hazard ratio ( HR)=0.81, 95% CI: 0.70-0.94] and a 33% lower risk of all-cause mortality ( HR=0.67, 95% CI: 0.52-0.87). Compared with the T2DM population in the physical activity Q1 group, the risk of all-cause mortality, CVD mortality, and cancer mortality among the physical activity Q4 group reduced by 50% ( HR=0.50, 95% CI: 0.45-0.56), 50% ( HR=0.50, 95% CI: 0.41-0.61), and 27% ( HR=0.73, 95% CI: 0.60-0.88), respectively. The combined effect showed that compared with the population in the intake of food categories 0-2 and low physical activity groups, the risk of all-cause, CVD mortality, and cancer mortality in the intake of food categories 4-9 and high physical activity groups reduced by 55% ( HR=0.45, 95% CI: 0.38-0.53), 56% ( HR=0.44, 95% CI: 0.32-0.59), and 40% ( HR=0.60, 95% CI: 0.44-0.82), respectively. Conclusion:Type of dietary intake, physical activity, and their combined effects are associated with a reduced mortality risk in patients with T2DM.

Astrocytes are increasingly recognized to play an active role in learning and memory, but whether neural inputs can trigger event-specific astrocytic Ca²⁺ dynamics in real time to participate in working memory remains unclear due to the difficulties in directly monitoring astrocytic Ca²⁺ dynamics in animals performing tasks. Here, using fiber photometry, we showed that population astrocytic Ca²⁺ dynamics in the hippocampus were gated by sensory inputs (centered at the turning point of the T-maze) and modified by the reward delivery during the encoding and retrieval phases. Notably, there was a strong inter-locked and antagonistic relationship between the astrocytic and neuronal Ca²⁺ dynamics with a 3-s phase difference. Furthermore, there was a robust synchronization of astrocytic Ca²⁺ at the population level among the hippocampus, medial prefrontal cortex, and striatum. The inter-locked, bidirectional communication between astrocytes and neurons at the population level may contribute to the modulation of information processing in working memory.
Animals ; Astrocytes ; Hippocampus/physiology* ; Humans ; Memory, Short-Term/physiology* ; Mice ; Neurons/physiology* ; Population Dynamics

Objective:To summarize the experience of Bipartition osteotomy combined with craniofacial bone remodeling in the treatment of orbital hypertelorism and midfacial dysplasia.Methods:A retrospective analysis was done by the clinical data of two patients with orbital hypertelorism with maxillofacial malformation treated in the Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine in July 2005 and August 2018. The Bipartition osteotomy via intracranial approach were applied for the two patients, one male and one female. The two patients aged 17 and 19, were suffered from degree Ⅰ orbital hypertelorism [interorbital distance(IOD) 32 mm and 34 mm]. With a frontal bone fenestration, the Monobloc osteotomy was done firstly to dislocate the cranio-orbital-maxilla bone graft, then the Bipartition osteotomy was performed according to the preoperative design through 3D computer aided design(CAD) and a V-shape bone graft was removed from the interorbital bone graft to split the hard palate longitudinally along the midline. After all, the whole facial bone was separated to two blocks: bilateral orbital-maxillary segments. Finally the midface had been remodeled by the bilateral orbital-maxillary segments which rotated and fixed internally. Self-rib nasal augmentation was done later. Patents’ complications, eye movement, visual acuity, olfactory sensation, nasal shape, IOD were measured through CT scan and the appearances were observed in the postoperative follow-up to determine the degree of improvement.Results:15 mm in width of interorbital bone was resected in both of the two patients, respectively. Postoperative IOD reduced by 17 mm, 19 mm, respectively. Mild cerebrospinal fluid leakage occurred in both patients after operation. They recovered after 5, 8 days of pillow-free horizontal position, respectively. The male patient developed local skin infection at the coronal incision and recovered after dressing change for 1 week. One week after operation, the female patient’s nose tip was partially broken near the nasal columella, and recovered after debridement and repairment. Follow up for 4-11 months showed that the eye movement, visual acuity, normal convergence and olfactory sensation were normal and no diplopia of 2 patients. The nasal appearances and orbital hypertelorisum of them were corrected obviously by follow-up after 4 months, but the nasal morphology and epicanthus still need further improvement.Conclusions:The Bipartition osteotomy can effectively treat the orbital hypertelorisum through the internal rotation fixation of bilateral orbital-maxillary segments, that makes the high arch palate lower and the occlusal plane of the upper jaw flattened.

Objective:To summarize the experience of Bipartition osteotomy combined with craniofacial bone remodeling in the treatment of orbital hypertelorism and midfacial dysplasia.Methods:A retrospective analysis was done by the clinical data of two patients with orbital hypertelorism with maxillofacial malformation treated in the Shanghai Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine in July 2005 and August 2018. The Bipartition osteotomy via intracranial approach were applied for the two patients, one male and one female. The two patients aged 17 and 19, were suffered from degree Ⅰ orbital hypertelorism [interorbital distance(IOD) 32 mm and 34 mm]. With a frontal bone fenestration, the Monobloc osteotomy was done firstly to dislocate the cranio-orbital-maxilla bone graft, then the Bipartition osteotomy was performed according to the preoperative design through 3D computer aided design(CAD) and a V-shape bone graft was removed from the interorbital bone graft to split the hard palate longitudinally along the midline. After all, the whole facial bone was separated to two blocks: bilateral orbital-maxillary segments. Finally the midface had been remodeled by the bilateral orbital-maxillary segments which rotated and fixed internally. Self-rib nasal augmentation was done later. Patents’ complications, eye movement, visual acuity, olfactory sensation, nasal shape, IOD were measured through CT scan and the appearances were observed in the postoperative follow-up to determine the degree of improvement.Results:15 mm in width of interorbital bone was resected in both of the two patients, respectively. Postoperative IOD reduced by 17 mm, 19 mm, respectively. Mild cerebrospinal fluid leakage occurred in both patients after operation. They recovered after 5, 8 days of pillow-free horizontal position, respectively. The male patient developed local skin infection at the coronal incision and recovered after dressing change for 1 week. One week after operation, the female patient’s nose tip was partially broken near the nasal columella, and recovered after debridement and repairment. Follow up for 4-11 months showed that the eye movement, visual acuity, normal convergence and olfactory sensation were normal and no diplopia of 2 patients. The nasal appearances and orbital hypertelorisum of them were corrected obviously by follow-up after 4 months, but the nasal morphology and epicanthus still need further improvement.Conclusions:The Bipartition osteotomy can effectively treat the orbital hypertelorisum through the internal rotation fixation of bilateral orbital-maxillary segments, that makes the high arch palate lower and the occlusal plane of the upper jaw flattened.