Alzheimer's disease (AD) poses one of the most urgent medical challenges in the 21st century as it affects millions of people. Unfortunately, the etiopathogenesis of AD is not yet fully understood and the current pharmacotherapy options are somewhat limited. Here, we report a novel inhibitor, Compound 44, for targeting cholinesterases, amyloid-β (Aβ) aggregation, and glycogen synthase kinase 3β (GSK-3β) simultaneously with the aim of achieving symptomatic relief and disease modification in AD therapy. We found that Compound 44 had good inhibitory effects on all intended targets with IC₅₀s of submicromolar or better, significant neuroprotective effects in cell models, and beneficial improvement of cognitive deficits in the triple transgenic AD (3 × Tg AD) mouse model. Moreover, we showed that Compound 44 acts as an autophagy regulator by inducing nuclear translocation of transcription factor EB through GSK-3β inhibition, enhancing the biogenesis of lysosomes and elevating autophagic flux, thus ameliorating the amyloid burden and tauopathy, as well as mitigating the disease phenotype. Our results suggest that triple-target inhibition via Compound 44 could be a promising strategy that may lead to the development of effective therapeutic approaches for AD.
Animals ; Alzheimer Disease/genetics* ; Mice, Transgenic ; Glycogen Synthase Kinase 3 beta/metabolism* ; Disease Models, Animal ; Mice ; Amyloid beta-Peptides/metabolism* ; Cholinesterase Inhibitors/therapeutic use* ; Humans ; Autophagy/drug effects* ; Cognitive Dysfunction/pathology* ; Neuroprotective Agents/pharmacology*

Acute kidney injury (AKI) has high morbidity and mortality, but effective clinical drugs and management are lacking. Previous studies have suggested that macrophages play a crucial role in the inflammatory response to AKI and may serve as potential therapeutic targets. Emerging evidence has highlighted the importance of forkhead box protein O1 (FoxO1) in mediating macrophage activation and polarization in various diseases, but the specific mechanisms by which FoxO1 regulates macrophages during AKI remain unclear. The present study aimed to investigate the role of FoxO1 in macrophages in the pathogenesis of AKI. We observed a significant upregulation of FoxO1 in kidney macrophages following ischemia-reperfusion (I/R) injury. Additionally, our findings demonstrated that the administration of FoxO1 inhibitor AS1842856-encapsulated liposome (AS-Lipo), mainly acting on macrophages, effectively mitigated renal injury induced by I/R injury in mice. By generating myeloid-specific FoxO1-knockout mice, we further observed that the deficiency of FoxO1 in myeloid cells protected against I/R injury-induced AKI. Furthermore, our study provided evidence of FoxO1's pivotal role in macrophage chemotaxis, inflammation, and migration. Moreover, the impact of FoxO1 on the regulation of macrophage migration was mediated through RhoA guanine nucleotide exchange factor 1 (ARHGEF1), indicating that ARHGEF1 may serve as a potential intermediary between FoxO1 and the activity of the RhoA pathway. Consequently, our findings propose that FoxO1 plays a crucial role as a mediator and biomarker in the context of AKI. Targeting macrophage FoxO1 pharmacologically could potentially offer a promising therapeutic approach for AKI.

Objective To analyze the value of peripheral blood helper T cell 17(Th17)/regulatory T cell(Treg),programmed death receptor-1(PD-1)+CD3+,miR-146a,miR-122 and serum C-reactive protein(CRP)in the diagnosis of postoperative infection of endometrial cancer,and to explore the influencing factors of postoperative infection for endometrial cancer.Methods A total of 289 patients with endometrial cancer who underwent surgery from January 2021 to August 2024 were selected and divided into the infection group(n=53)and the non-infection group(n=236)according to the postoperative infection of the patients.Clinical data of two groups were collected and compared.The levels of Th17,Treg and PD-1+CD3+in peripheral blood of the two groups were detected by flow cytometry,and the ratio of Th17/Treg was calculated.The levels of miR-146a and miR-122 in peripheral blood of the two groups were detected by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR).The serum CRP levels of the two groups were detected by enzyme-linked immunosorbent assay(ELISA),and the influencing factors of postoperative infection in endometrial cancer were analyzed by multivariate Logistic regression.The receiver operating characteristic(ROC)curve was drawn to analyze the diagnostic value of peripheral blood Th17/Treg,PD-1+CD3+,miR-146a,miR-122 and serum CRP for postoperative infection of endometrial cancer.Results Compared with the non-infection group,the infection group had higher proportions of diabetes,anemia,adjuvant chemoradiotherapy,open abdominal surgery,drainage and catheterization time≥7 d,as well as higher levels of Th17,Th17/Treg,PD-1+CD3+,miR-122,and serum CRP(P<0.01),while the levels of Treg and miR-146a in peripheral blood were lower(P<0.01).Multivariate Logistic regression analysis showed that combined diabetes,anemia,adjuvant chemoradiotherapy,open abdominal surgery,drainage and catheterization time≥7 d,peripheral blood Th17/Treg,PD-1+CD3+,miR-122 and serum CRP levels were all risk factors for postoperative infection of endometrial cancer(P<0.05,P<0.01),while miR-146a in peripheral blood was its protective factor(P<0.05).ROC curve analysis showed that the area under the curve of the combined detection of Th17/Treg,PD-1+CD3+,miR-146a,miR-122 in peripheral blood and serum CRP was higher than that of the individual detection of Th17/Treg,PD-1+CD3+,miR-146a,miR-122 and serum CRP in peripheral blood(P<0.01).Conclusion Postoperative infection of endometrial cancer is closely related to the patients'combined diabetes,anemia,adjuvant chemoradiotherapy,open surgery,and drainage and catheterization time≥7 d.Moreover,Th17/Treg,PD-1+CD3+,miR-122 in peripheral blood and serum CRP are highly expressed in patients with postoperative infection of endometrial cancer,while miR-146a in peripheral blood is expressed at a low level.The combined detection of the five has more advantages in evaluating postoperative infection of endometrial cancer.

Objective To analyze the value of peripheral blood helper T cell 17(Th17)/regulatory T cell(Treg),programmed death receptor-1(PD-1)+CD3+,miR-146a,miR-122 and serum C-reactive protein(CRP)in the diagnosis of postoperative infection of endometrial cancer,and to explore the influencing factors of postoperative infection for endometrial cancer.Methods A total of 289 patients with endometrial cancer who underwent surgery from January 2021 to August 2024 were selected and divided into the infection group(n=53)and the non-infection group(n=236)according to the postoperative infection of the patients.Clinical data of two groups were collected and compared.The levels of Th17,Treg and PD-1+CD3+in peripheral blood of the two groups were detected by flow cytometry,and the ratio of Th17/Treg was calculated.The levels of miR-146a and miR-122 in peripheral blood of the two groups were detected by real-time fluorescence quantitative polymerase chain reaction(RT-qPCR).The serum CRP levels of the two groups were detected by enzyme-linked immunosorbent assay(ELISA),and the influencing factors of postoperative infection in endometrial cancer were analyzed by multivariate Logistic regression.The receiver operating characteristic(ROC)curve was drawn to analyze the diagnostic value of peripheral blood Th17/Treg,PD-1+CD3+,miR-146a,miR-122 and serum CRP for postoperative infection of endometrial cancer.Results Compared with the non-infection group,the infection group had higher proportions of diabetes,anemia,adjuvant chemoradiotherapy,open abdominal surgery,drainage and catheterization time≥7 d,as well as higher levels of Th17,Th17/Treg,PD-1+CD3+,miR-122,and serum CRP(P<0.01),while the levels of Treg and miR-146a in peripheral blood were lower(P<0.01).Multivariate Logistic regression analysis showed that combined diabetes,anemia,adjuvant chemoradiotherapy,open abdominal surgery,drainage and catheterization time≥7 d,peripheral blood Th17/Treg,PD-1+CD3+,miR-122 and serum CRP levels were all risk factors for postoperative infection of endometrial cancer(P<0.05,P<0.01),while miR-146a in peripheral blood was its protective factor(P<0.05).ROC curve analysis showed that the area under the curve of the combined detection of Th17/Treg,PD-1+CD3+,miR-146a,miR-122 in peripheral blood and serum CRP was higher than that of the individual detection of Th17/Treg,PD-1+CD3+,miR-146a,miR-122 and serum CRP in peripheral blood(P<0.01).Conclusion Postoperative infection of endometrial cancer is closely related to the patients'combined diabetes,anemia,adjuvant chemoradiotherapy,open surgery,and drainage and catheterization time≥7 d.Moreover,Th17/Treg,PD-1+CD3+,miR-122 in peripheral blood and serum CRP are highly expressed in patients with postoperative infection of endometrial cancer,while miR-146a in peripheral blood is expressed at a low level.The combined detection of the five has more advantages in evaluating postoperative infection of endometrial cancer.

Objective To explore the patterns of functional gait asymmetry during the support phase and the differentiation of bilateral foot functions,to gain insights into the human movement compensa-tion mechanisms and stability control characteristics,so as to provide theoretical references for the pre-vention and rehabilitation treatment of unilateral foot and ankle injuries.Methods Twelve young females with normal feet were recruited,and the time percentage of each phase of the support period,the change of longitudinal arch angle,the vertical ground reaction force and the center of plantar pressure trajectory of the dominant and non-dominant feet were collected by using a three-dimensional motion capture and a high-frequency plantar pressure testing system when the subjects walked at the optimum speed with the incremental loading of weights[0%body weight(BW),10%BW and 20%BW].The ef-fects of laterality(dominant foot,non-dominant foot)and load(0%BW,10%BW,20%BW)on arch changes and gait parameters,and the interactions between them,were analyzed using a two-way re-peated-measures ANOVA.Results The factors of laterality and load interacted significantly on arch changes,but not on gait parameters.(2)Compared with 0%BW,the time percentage of the buffering phase of the nondominant feet with the load of 20%BW increased(P<0.05),while that of the domi-nant ones decreased(P<0.05),with an increase in the buffering load of both feet with the load of 20%BW(P<0.05)and the buffering force excursion of both feet with the load of 10%BW(P<0.05).More-over,changes in longitudinal arch angle increased(P<0.05)with the load of 10%and 20%BW,the pedal extension load rate increased(P<0.05)with the above BW load in the non-dominant feet,and the horizontal slope of pedal extension decreased(P<0.05)with 20%BW load in the dominant feet.Compared with 10%BW,when the feed was loaded 20%BW,the time percentage in the buffering phase and the buffering force offset of the dominant feet decreased(P<0.05),while the buffering load of both feet increased(P<0.05).(3)Compared with the non-dominant feet,for the dominant feet,the buffering load rate at the load of 10%and 20%BW and changes in the longitudinal arch angle at the load of 20%BW decreased(P<0.05),while the horizontal slope of the pedal extension without load in-creased(P<0.05).Conclusion Walking with load induces function differentiation in bilateral feet.The dominant foot has more efficient horizontal extension without load and better buffering function in the vertical direction with loads,while the non-dominant feet perform a more adequate weight-bearing and extension function vertically with larger load.It is suggested that unilateral injury feet should not be given too much load,and it is inappropriate to select a single foot to represent and evaluate the func-tion and injury risk of the double feet in loaded walking.

Objective:To investigate the association between tumor necrosis factor-β (TNF-β) gene polymorphisms and genetic predisposition to gastric cancer, and to analyze the relationship between specific genotype of TNF-β and serum levels of TNF-β.Methods:Using case control study, we selected 153 patients with gastric cancer in Fudan University Shanghai Cancer Center between September 2021 and December 2022 as the gastric cancer group, and 150 healthy individuals were chosen as the healthy control group. In the previous study, 30 peripheral blood DNA samples of gastric cancer patients and healthy controls respectively were amplified by conventional PCR, which were sequenced to identify the genotype frequencies of TNF-β polymorphic loci (rs1041981, rs2229092, rs2229094 and rs78613290); consequently, Allele-Specific Quantitative PCR was used to further detect and analyze the genotype and genotype frequencies of TNF-β polymorphic loci; serum TNF-β levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA), and the relationship with specific genotypes of TNF-β was analyzed. Chi-square test and Fisher test were used to analyze the genotype distribution frequency of TNF-β polymorphic loci, and non-parametric statistics was used to analyze the differences in serum TNF-β expression levels.Results:The sequencing results showed that the genotype distribution of rs1041981 in gastric cancer group was CC 16.67% (5/30), CA 40.00% (12/30) and AA 43.33% (13/30). The genotype distribution in control group was CC 40.0% (12/30), CA 43.33% (13/30), AA 16.7% (5/30). The difference of genotype frequency between the two groups was statistically significant (χ 2=6.478, P=0.039). The genotypes of the polymorphic loci rs2229092 in both groups were AA, AG, and GG, with no statistically significant difference between the two groups (χ 2=1.888, P=0.612). The distribution frequencies of the genotypes of the polymorphic loci rs2229094 (TT and TC) and rs78613290 (GG and AG) showed no statistically significant differences between the two groups (both P>0.05). Further validation with an expanded clinical samples (153 cases in the gastric cancer group and 150 cases in the control group) found that the difference of rs1041981 genotype distribution between the gastric cancer group [CC 15.69%(24/153), CA 54.9%(84/153), AA 29.4%(45/153)] and the control group [CC 27.3%(41/150), CA 58.0%(87/150), AA 14.7%(22/150)] was significantly different (χ 2=12.366, P=0.002). Analysis of the influence of different allele frequencies on the risk of gastric cancer revealed that the odds ratio ( OR) of the A allele of rs1041981 for the risk of gastric cancer compared to the C allele was 1.701 (95% CI 1.235?2.355). Gene phenotype analysis combining the clinicopathological characteristics of gastric cancer patients found that the distribution frequency of the rs1041981 genotype was significantly different among groups of different genders, tumor invasion depths, and the lymph node metastasis, with statistically significant differences (All P>0.05). Additionally, gastric cancer patients with rs1041981 AA genotypes had higher serum TNF-β expression levels than those with CA and CC genotypes, (both P<0.05). Conclusions:The gene type frequency of the TNF-β gene polymorphic loci (rs1041981, C>A) exhibited significant differences between the gastric cancer group and the healthy control group. The presence of the A allele in rs1041981 site increased the susceptibility to gastric cancer, and patients with different gene types displayed vaning levels of serum TNF-β, among which AA genotype ranks the highest level.

Objective:To explore the clinical risk factors of post-transplantation diabetes mellitus (PTDM) and establish a risk prediction model in kidney recipients.Methods:The clinical data and postoperative bedside measurements of blood glucose (BG) were retrospectively reviewed for 305 renal transplant recipients at First Affiliated Hospital of Zhejiang University School of Medicine from October 2018 to August 2019.According to whether or not PTDM occurred, they were assigned into two groups of PTDM (n=34) and non-PTDM (n=271). Risk factors were screened through single/multi-factor Logistic regression and PTDM prediction model was established.Results:The incidence rate of PTDM was 11.15%(34/305). Logistic regression analysis indicated that deceased donor, age ≥40 years, female, pre-hemoglobin A1c (Pre-HbA1c) and postoperative bedside BG value ≥11.1 mmol/L were the correlated factors for the occurrence of PTDM.Among them, female ( OR=3.13, 95% CI: 1.28-7.61), Pre-HbA1c ( OR=2.05, 95% CI: 1.12-3.74) and BG ≥11.1 mmol/L at 4pm Day 2/3 post-operation ( OR=19.08, 95% CI: 4.34-83.87) were risk factors for the occurrence of PTDM, The area under the model curve was 0.86 (95% CI: 0.79-0.93) with a Jordan index of 0.65, a sensitivity of 82.8% and a specificity of 82.3%. Conclusions:Female, Pre-HbA1c and fasting BG at 4 pm Day 2/3 post-operation ≥ 11.1 mmol/L are risk factors for the occurrence of PTDM.The prediction model has a decent predictive value.It is conducive to early clinical interventions and lowering the incidence rate of PTDM.

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (MPN) featured by clonal proliferation of platelets, thrombosis and hemorrhage. Portal hypertension is a serious complication of ET associated with poor prognosis. We report a patient with ET complicated with acute upper gastrointestinal hemorrhage and intestinal perforation due to portal hypertension. She had an uneventful recovery after surgical and endoscopic treatment.

Fetal adenocarcinoma of the lung (FLAC) is an extremely rare subtype of lung cancer, accounting for only 0.1% to 0.5% of primary pulmonary malignancy. In 2011, international multidisciplinary classification of lung adenocarcinoma developed by the International Association for the Study of Lung Cancer (IALSC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) classified FLAC as a variant of invasive adenocarcinoma. FLAC has been further divided into low-grade fetal adenocarcinoma (L-FLAC) and high-grade fetal adenocarcinoma (H-FLAC) as these two categories exhibit different clinicopathological features and biological behaviors. Here we report a case of high-grade fetal adenocarcinoma and summarize clinicopathologic features of fetal lung adenocarcinoma.
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Adenocarcinoma of Lung ; diagnostic imaging ; pathology ; surgery ; Fetus ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Prognosis ; Tomography, X-Ray Computed

Objective To analysis the occurrence status of breast disease in married women in Tangshan area,and to provide basis for early prevention of breast cancer in this region.Methods 773 married women in Tangshan area were given mammography examination.The tissue biopsy or surgical treatment was recommended for patients with above grade 3 of breast imaging reporting and data system (BI-RADS) classification to obtain pathological diagnosis.Results In 773 women,482 cases (62.35 ％) were diagnosed as BI-RADS grade 2 or below,256 cases (33.12 ％) were BI-RADS grade 3,33 cases (4.27 ％) were BI-RADS grade 4,2 cases (0.26 ％) were BI-RADS grade 5.The distribution of each BI-RADS grade among different age group was statistically significant (x2 =17.90,P ＜ 0.001),35 cases got pathological diagnosis by biopsy or surgical treatment,including 30 cases of mammary gland hyperplasia,3 cases of breast fibroadenoma,and 2 cases of breast cancer.Conclusion Women's mammography screening is important for the prevention and early detection of mammary gland diseases.