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.

Surgery is the preferred treatment for resectable esophageal cancer, but in locally advanced esophageal cancer, the effect of surgery alone is not ideal, so surgery-based comprehensive treatment is the best option. Neoadjuvant therapy has become a standard treatment in the treatment of locally advanced resectable esophageal cancer. Neoadjuvant therapy includes neoadjuvant chemotherapy, radiochemotherapy, immunotherapy, targeted therapy, etc. With the significant efficacy and acceptable toxicity of immunotherapy in the first-line and second-line treatment of advanced esophageal cancer, neoadjuvant immunotherapy has become a research hotspot of locally advanced resectable esophageal cancer. This article reviews the latest research progress and some limitations of neoadjuvant immunotherapy in locally advanced resectable esophageal cancer.

Objective To evaluate the perioperative safety of lung surgery for patients with corona virus disease 2019 (COVID-19). Methods We retrospectively analyzed the clinical data of the patients recovered from COVID-19 infection and received lung surgery from December 2022 to February 2023 in the Department of Thoracic Surgery at Beijing Hospital. Patients who received lung surgery and without COVID-19 at the same time were selected as a control group. Perioperative data between the two groups were compared. Results A total of 103 patients were included with 44 males and 49 females at an average age of (62.2±12.1) years. All surgeries were performed by uniportal video-assisted thoracoscopic surgery (VATS). Among patients who recovered from COVID-19, 53 (51.5%) received lobectomy, 30 (29.1%) received segmentectomy, and 20 (19.4%) received wedge resection. The interval between diagnosis of infection and lung surgery was ≤1 month in 32 (31.1%) patients, and >1 month in 71 (68.9%) patients. The results of virus nucleic acid test for all patients before surgery were negative. A total of 13 (12.6%) patients had positive IgM, and 100 (97.1%) patients had positive IgG. A total of 20 patients experienced perioperative complications (13 patients with pulmonary air leakage, 3 patients with chylothorax, 2 patients with atrial fibrillation, and 2 patients with severe pulmonary complications). There was one perioperative death. Comparing the patients who recovered from COVID-19 with those without COVID-19, we found no statistical difference in perioperative outcomes including surgical duration, postoperative drainage, duration of thoracic tube, and duration of postoperative stay (P>0.05). There was no significant difference in perioperative complications between the two groups (P>0.05). Multivariable logistical regression analysis demonstrated that positive IgM before surgery (OR=7.319, 95%CI 1.669 to 32.103, P=0.008), and longer duration of surgery (OR=1.016, 95%CI 1.003 to 1.028, P=0.013) were independent risk factors of perioperative complications for patients who recovered from COVID-19. Conclusion It is safe for patients recover from COVID-19 to receive lung surgery when symptoms disappear and the nucleic acid test turn negative. However, positive COVID-19 IgM is an independent risk factor for perioperative complications. We suggest that lung surgery could be performed when the nucleic acid test and COVID-19 IgM are both negative for patients recover from COVID-19 infection.

In recent years,the infection of nontuberculous mycobacterium(NTM)has been increasing rapidly,which captivates widespread attention.The infection rate of NTM in kidney transplant recipients is more significantly elevated due to the impact of immunosuppressive drugs and other factors.However,due to the lack of sufficient research evidence,relevant guidelines for the diagnosis and treatment of NTM after kidney transplantation are still lacking.To further standardize the diagnosis and treatment of NTM disease in kidney transplant recipients,and deepen medical practitioners'understanding and diagnosis and treatment of NTM disease in organ transplantation in China,Branch of Organ Transplantation of Chinese Medical Association organized relevant experts to formulate this guideline by referring to the latest edition of"An official ATS/IDSA statement:diagnosis,treatment,and prevention of nontuberculous mycobacterial diseases","Expert Consensus on the Diagnosis and Treatment of Nontuberculous Mycobacterial Disease",and"Technical Specification for Clinical Diagnosis and Treatment of Nontuberculous Mycobacteria in Organ Transplant Recipients(2019 Edition)",and considering the characteristics of kidney transplant recipients.

Background:Following the short-term outbreak of coronavirus disease 2019(COVID-19)in December 2022 in China,clinical data on kidney transplant recipients(KTRs)with COVID-19 are lacking.Methods:We conducted a single-center retrospective study to describe the clinical features,complications,and mortality rates of hospitalized KTRs infected with COVID-19 between Dec.16,2022 and Jan.31,2023.The patients were followed up until Mar.31,2023.Results:A total of 324 KTRs with COVID-19 were included.The median age was 49 years.The median time between the onset of symptoms and admission was 13 d.Molnupiravir,azvudine,and nirmatrelvir/ritonavir were administered to 67(20.7%),11(3.4%),and 148(45.7%)patients,respectively.Twenty-nine(9.0%)patients were treated with more than one antiviral agent.Forty-eight(14.8%)patients were treated with tocilizumab and 53(16.4%)patients received baricitinib therapy.The acute kidney injury(AKI)occurred in 81(25.0%)patients and 39(12.0%)patients were admitted to intensive care units.Fungal infections were observed in 55(17.0%)patients.Fifty(15.4%)patients lost their graft.The 28-d mortality rate of patients was 9.0%and 42(13.0%)patients died by the end of follow-up.Multivariate Cox regression analysis identified that cerebrovascular disease,AKI incidence,interleukin(IL)-6 level of>6.8 pg/mL,daily dose of corticosteroids of>50 mg,and fungal infection were all associated with an increased risk of death for hospitalized patients.Conclusions:Our findings demonstrate that hospitalized KTRs with COVID-19 are at high risk of mortality.The administration of immunomodulators or the late application of antiviral drugs does not improve patient survival,while higher doses of corticosteroids may increase the death risk.

Objective To explore the optimal ratio of Baitong decoction based on efficacy,clarify its spectrum-effect relationship,and identify its potential quality markers.Methods An ulcerative colitis(UC)model in mice was established using dextran sulfate sodium.The efficacy of Baitong decoction with varying drug ratios was assessed by evaluating the apparent score,pathological score and inflammatory factor changes of UC in each group of experimental animals.The fingerprints of Baitong decoction with different ratios were established by high performance liquid chromatography(HPLC),and the relationship between the content of each substance and its efficacy was analyzed by partial least squares regression to determine the potential quality markers of Baitong decoction.Results Baitong decoction was most effective in relieving ulcerative colitis when the mass ratio of Fuzi,Ganjiang and Congbai was 1∶2∶2.The fingerprinting identified 14 common peaks across 7 ratios,with 9 peaks were found to be associated with the remission of ulcerative colitis by partial least squares regression analysis.Conclusion The optimal ratio of Fuzi,Ganjiang and Congbai for treating UC is 1∶2∶2.The spectrum-effect relationship analysis suggested that the quality markers of Baitong decoction may be the substances represented by peak 2(benzoylaconine),3,5,6,8(mesaconine),9(aconitine),10(hypaconitine),13(10-gingerol)and 14.

Objective:To explore mechanism of Chaihu Longgu Muli Decoction and Ganmai Dazao Decoction in treatment of post-stroke depression(PSD)based on network pharmacology,molecular docking and animal experiment.Methods:TCMSP and other databases were used to predict active components and targets of Chaihu Longgu Muli Decoction and Ganmai Dazao Decoction.Targets of PSD were retrieved from PharmGKB and other databases,and"component-intersection target-disease"network was constructed by Cytoscape(v3.9.1)software.PPI network was constructed by String(v11.5)database,and GO enrichment and KEGG pathway analy-sis of intersection targets were performed by DAVID6.8 database.AutoDock vina(v1.1.2)software was used for molecular docking.Pymol(v 2.5)and other softwares were used to visualize optimal docking results.Animal experiments were setup in control group,model group,fluoxetine group,TCM group and TCM+fluoxetine group,neurobehavioral scores and expressions of neurotransmitters and inflammatory factors in brain tissues were detected.mRNA and protein expressions of key genes PPARG,MAPK3,AKT1,PIK3CA were detected by RT-qPCR and Western blot.Results:A total of 225 kinds of active ingredients of Chaihu Longgu Muli Decoction and Ganmai Dazao Decoction were obtained,which acted on 119 targets of PSD,among which key targets included MAPK3,AKT1,PIK3CA and PPARG,key pathways including MAPK signaling pathway,PI3K-Akt signaling pathway and etc.Compared with model group,MAPK3 mRNA and protein expressions were decreased,AKT1,PIK3CA,PPARG mRNA and protein expressions were increased in TCM group and TCM+fluoxetine group(P<0.05).Conclusion:Mechanism of Chaihu Longgu Muli Decoction and Ganmai Dazao Decoction in treatment of PSD may be related to inhibition of MAPK3 expression,promotion of AKT1,PIK3CA,PPARG expressions,alleviation of inflammatory response and oxidative stress in brain tissues.

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.

There is currently a huge worldwide demand for donor kidneys for organ transplantation. Consequently, numerous marginal donor kidneys, such as kidneys with microthrombi, are used to save patients' lives. While some studies have shown an association between the presence of microthrombi in donor kidneys and an increased risk for delayed graft function (DGF) (McCall et al., 2003; Gao et al., 2019), other studies have demonstrated that microthrombi negatively impact the rate of DGF (Batra et al., 2016; Hansen et al., 2018), but not graft survival rate (McCall et al., 2003; Batra et al., 2016; Gao et al., 2019). In contrast, Hansen et al. (2018) concluded that fibrin thrombi were not only associated with reduced graft function six months post-transplantation but also with increased graft loss within the first year of transplantation. On the other hand, Batra et al. (2016) found no significant differences in the DGF rate or one-year graft function between recipients in diffuse and focal microthrombi groups. To date, however, the overall influence of donor kidney microthrombi and the degree of influence on prognosis remain controversial, necessitating further research.
Humans ; Thrombotic Microangiopathies ; Transplantation, Homologous ; Tissue Donors ; Kidney ; Allografts

Phosphatidylinositol-3-kinase (PI3K) inhibitors can increase the sensitivity of tumor cells to Poly ADP-ribose polymerase-1 (PARP-1) inhibitors. Therefore, the simultaneous inhibition of the PARP-1 and PI3K activities are expected to overcome the drug resistance of PARP-1 inhibitors.In our previous work, two compounds XW-1 and WZ-1 with excellent activities against PARP-1 and PI3K were obtained with the limitation to further study due to their poor water solubility.Therefore, XW-1 and WZ-1 were chosen as lead compounds to optimize their solubility by introducing a salt-forming site via a urea group, and 11 novel compounds were designed and synthesized. The structure of all target compounds was confirmed by 1H NMR, 13C NMR, and HRMS.The enzyme activities of the compounds against PARP-1 and PI3K were measured, and the results showed that most of the compounds demonstrated good inhibitory activities against PARP-1 and PI3K.Based on the above result, the inhibitory activities of compounds 8b, 8e, and 8f against MDA-MB-231, MDA-MB-468, HCC1937, HCT116, and olaparib-resistant HCT116R were determined by MTT, respectively.Additionally, the structure-activity relationship was discussed. The results showed that these compounds displayed excellent antiproliferation activity.Among them, compound 8f demonstrated antiproliferation remarkably against all five tumor cells, which was more potent than that of olaparib, and was comparable to that of BKM120.Furthermore, the solubility of hydrochloride salts of compound 8b and 8f was significantly improved compared to the lead compounds.The results of this study will provide a theoretical basis for the further development of PARP-1 and PI3K dual-target inhibitors with good pharmaceutical properties and strong inhibitory activities.