Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive decline and memory impairment in clinical. Currently, there are no effective treatments for AD. In recent years, a variety of therapeutic approaches from different perspectives have been explored to treat AD. Although the drug therapies targeted at the clearance of amyloid β-protein (Aβ) had made a breakthrough in clinical trials, there were associated with adverse events. Neuroinflammation plays a crucial role in the onset and progression of AD. Continuous neuroinflammatory was considered to be the third major pathological feature of AD, which could promote the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. At the same time, these toxic substances could accelerate the development of neuroinflammation, form a vicious cycle, and exacerbate disease progression. Reducing neuroinflammation could break the feedback loop pattern between neuroinflammation, Aβ plaque deposition and Tau tangles, which might be an effective therapeutic strategy for treating AD. Traditional Chinese herbs such as Polygonum multiflorum and Curcuma were utilized in the treatment of AD due to their ability to mitigate neuroinflammation. Non-steroidal anti-inflammatory drugs such as ibuprofen and indomethacin had been shown to reduce the level of inflammasomes in the body, and taking these drugs was associated with a low incidence of AD. Biosynthetic nanomaterials loaded with oxytocin were demonstrated to have the capability to anti-inflammatory and penetrate the blood-brain barrier effectively, and they played an anti-inflammatory role via sustained-releasing oxytocin in the brain. Transplantation of mesenchymal stem cells could reduce neuroinflammation and inhibit the activation of microglia. The secretion of mesenchymal stem cells could not only improve neuroinflammation, but also exert a multi-target comprehensive therapeutic effect, making it potentially more suitable for the treatment of AD. Enhancing the level of TREM2 in microglial cells using gene editing technologies, or application of TREM2 antibodies such as Ab-T1, hT2AB could improve microglial cell function and reduce the level of neuroinflammation, which might be a potential treatment for AD. Probiotic therapy, fecal flora transplantation, antibiotic therapy, and dietary intervention could reshape the composition of the gut microbiota and alleviate neuroinflammation through the gut-brain axis. However, the drugs of sodium oligomannose remain controversial. Both exercise intervention and electromagnetic intervention had the potential to attenuate neuroinflammation, thereby delaying AD process. This article focuses on the role of drug therapy, gene therapy, stem cell therapy, gut microbiota therapy, exercise intervention, and brain stimulation in improving neuroinflammation in recent years, aiming to provide a novel insight for the treatment of AD by intervening neuroinflammation in the future.

Objective To investigate the relationship between different interleukins (ILs) and gynecological tumors, including cervical cancer, endometrial cancer, and uterine leiomyoma using two-sample Mendelian randomization (MR) analysis. Methods IL and gynecological tumor data were obtained from European populations by using the IEU OpenGWAS open database. Two-sample MR analysis was applied, different interleukins were used as exposure factors, significant SNP in GWAS data were selected as instrumental variables, and the instrumental variables were independent of each other. The risk of three kinds of gynecological tumors was analyzed separately to explore the causal relationship between ILs predicted by genes and outcome indicators. The TwoSampleMR package in R language (4.3.1) software was used for statistical analysis. MR analysis was performed using inverse variance weighted, MR Egger regression, weighted median, simple mode, and weighted mode methods. Results IL-18 receptor 1 (P=0.039) and IL-24 (P=0.025) were negatively correlated with the risk of cervical cancer. IL-4 (P=0.040), IL-21 (P=0.026), and IL-37 (P=0.027) were positively correlated with the risk of endometrial cancer. IL-15 receptor subunit alpha (P=0.005) was negatively correlated with the risk of endometrial cancer. IL-17A (P=0.005) and IL-37 (P=0.018) were negatively correlated with the risk of uterine leiomyoma. IL-21 (P=0.035) was positively correlated with the risk of uterine leiomyoma. Conclusion Genetically predicted IL-4, IL-15Rα, IL-17A, IL-18R1, IL-21, IL-24, and IL-37 are causally associated with the risk of three gynecological tumors. Further exploration of the molecular mechanism of ILs in gynecological tumors may provide potential therapeutic targets for the treatment of gynecological tumors.

OBJECTIVE To establish the precise management model for the centralized preparation of cytotoxic drugs in pharmacy intravenous admixture services （PIVAS）， and evaluate the effects of its application. METHODS Pharmacists in PIVAS established the precise management model by soliciting clinical opinions and consulting literature on the centralized preparation of cytotoxic drugs and continuously refining every step of the preparation of cytotoxic drugs， based on data feedback from the information closed-loop management system and the limit of stability time of finished solutions. The indicators such as the preparation time， delivery time， the storage time of finished infusion solutions after preparation， and the completion rate of infusion within the stability time limit were analyzed before the implementation （January to December 2023） and after the implementation （January to December 2024） of this model， to evaluate its application effectiveness. RESULTS The overall framework for the precise management model included upgrading the functions of the prescription review system， improving the prescription review database， providing specialized training for PIVAS pharmacists， managing dynamic batch decision for drug preparation， managing special drugs， managing finished infusion distribution， and establishing a continuous improvement mechanism. Compared with before implementation， the average preparation time of the second and third batches of cytotoxic drugs with more concentrated morning preparation tasks in this model was significantly shorter than before implementation （P＜0.05）； the delivery time of finished infusion after implementation （[ 11.49±2.92） min] was significantly shorter than the delivery time before implementation （[ 22.11±5.03） min] （P＜0.001）； the storage time of some drugs with shorter stable time limit and carboplatin in combination regimens （paclitaxel or docetaxel+carboplatin） was significantly shortened compared to before implementation （P＜0.05）， and the completion rate of infusion within the stability time limit was significantly improved compared to before implementation （P＜0.05）. CONCLUSIONS Our hospital has successfully established a precise management model for the centralized preparation of cytotoxic drugs in PIVAS. This mode can significantly shorten the preparation time of each batch of PIVAS in the morning， make batch decisions more reasonable and improve the infusion completion rate within the stable time limit of the finished product.

Objective To identify the independent predictors of programmed death-1 (PD-1) inhibitor-related endocrine adverse events and construct a clinically usable risk prediction model. Methods A total of 302 patients with solid tumors treated with PD-1 inhibitors were retrospectively enrolled. According to the presence or absence of endocrine immune-related adverse events (irAEs), the patients were divided into case group and control group. The clinical and laboratory indexes were compared between the two groups. Multivariable logistic regression was used to confirm independent predictors of endocrine irAEs. The nomogram was constructed, while the receiver operating characteristic (ROC) curve was used to test the prediction performance of the model. Results The overall incidence of endocrine irAEs was 21.9% (66/302), and the incidence of hypothyroidism was 19.5% (59/302). The age, PD-1 inhibitors, free thyroxine, thyroid peroxidase antibody (TPOAb), thyroglobulin, amylase, lymphocyte subset CD3 expression were statistically different between the two groups (P＜0.05). Multivariable logistic regression showed that higher expression of lymphocyte subset CD3 was a protective factor to prevent endocrine irAEs occurrence (P＝0.004), while age＜60 years, higher TPOAb and use of pembrolizumab were independent risk factors of endocrine irAEs (P＜0.05). The nomogram model thus constructed, and when the threshold probability of the model exceeded 0.1, its net benefit was higher. ROC curve showed that the AUC of the model to predict endocrine irAEs was 0.760. The prediction result of the model was highly consistent with the actual result. Conclusions The age, type of PD-1 inhibitor, baseline TPOAb level, and baseline CD3 expression can independently predict endocrine irAEs occurrence or not. The nomogram model based on this model has good predictive efficiency, which can provide reference for early identification of high-risk patients and immunotherapy management.

Radiotherapy is the traditional means of treatment for non-small cell lung cancer (NSCLC), and immune checkpoint blockade (ICB) is a major breakthrough in the treatment of NSCLC in recent years. Following the PACIFIC study, several clinical studies of radiotherapy combined with ICB have been carried out successively and achieved better results, but the efficacy of NSCLC still needs to be further improved. Poly ADP-ribose polymerase 1 (PARP1) may be a target to increase the efficacy of radiotherapy combined with ICB. Studies have shown that PARP inhibitors can exert synergistic effects in combination with radiotherapy and ICB. In this paper, we describe the research progress of PARP inhibitors in radiotherapy combined with ICB in the treatment of NSCLC from the mechanism of PARP inhibitors in the treatment of NSCLC, the current status of radiotherapy combined with ICB, and the mechanism and application of PARP inhibitors in radiotherapy combined with ICB in the treatment of NSCLC, in order to assess the potential of the combination therapy in the treatment of NSCLC, and to provide some references for the development of clinical trials in NSCLC.

Objective To investigate the correlation between the characteristics of peritumoral edema and the aggressiveness of breast invasive ductal carcinoma in preoperative magnetic resonance imaging(MRI).Methods A total of 79 patients(79 lesions)who underwent radical mastectomy in the First Affiliated Hospital of Ningbo University from January 2020 to May 2021 and were pathologically diagnosed as invasive ductal carcinoma were included in invasive ductal carcinoma group,and 45 patients(49 lesions)with benign breast lesions were included in benign lesion group during the same period.The difference of peritumoral edema between two groups and the relationship between different pathological features of invasive ductal carcinoma and peritumoral edema were compared.Results The peritumoral edema in benign lesion group was significantly less severe than that in invasive ductal carcinoma group(χ2=25.330,P<0.05).The tumor size of invasive ductal carcinoma group was positively correlated with the degree of peritumoral edema(r=0.381,P<0.05).There were significant differences in molecular type,histological grade,T stage,lymph node metastasis and Ki-67 expression level among patients with different peritumoral edema grades(P<0.05).Ki-67 expression level and the number of lymph node metastasis were positively correlated with the degree of peritumoral edema(r=0.348,0.273,P<0.05).Conclusion The degree of peritumoral edema in MRI correlates with the aggressiveness of breast invasive ductal carcinoma and can be used as one of the tools to evaluate breast carcinoma.

Objective To analyze the effect of Xiaozhi Decoction in the treatment of hyperlipidemiain different classification of physical constitution in TCM.Methods We screened 206 patients with Hyperlipidemia in our hospital and had been treated with drugs during May 2020 to March 2023.Totally 103 patients in the TCM group were treated with Xiaozhi Decoction,103 patients in the western medicine group were treated with atorvastatin.Selected total cholesterol(TC),triglyceride(TG),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C)and liver transaminase before and after a period of treatment.The non-high-density lipoprotein cholesterol(non-HDL-C)will be calculated,too.Results In the Phlegm-Dampness constitution,TC,TG,LDL-C and non-HDL-C decreased significantly all in the TCM group(P<0.05);TC,TG and non-HDL-C decreased significantly all in the western medicine group(P<0.05).The TCM group is superior to the western medicine group in TC,LDL-C,non-HDL-C(P<0.05).In the Qi-Deficiency constitution,TC,TG,LDL-C and non-HDL-C decreased significantly all in the TCM group(P<0.05);TC,LDL-C and non-HDL-C decreased significantly all in the western medicine group(P<0.05).The TCM group is superior to the western medicine group in non-HDL-C(P<0.05).In the Blood-Stasis constitution,TC,TG,LDL-C and non-HDL-C decreased significantly all in the western medicine group only(P<0.05).The western medicine group is superior to the TCM group in TC,LDL-C,non-HDL-C(P<0.05).In the Yin-Yang Harmony constitution,TC and non-HDL-C decreased significantly both in the TCM group(P<0.05).TC,LDL-C and non-HDL-C decreased significantly all in the western medicine group(P<0.05).The western medicine group is superior to the TCM group in TC,LDL-C,non-HDL-C(P<0.05).Conclusion Xiaozhi Decoction is superior to the the atorvastatin in the treatment of hyperlipidemia for the Phlegm-Dampness constitution and Qi-deficiency constitution groups.But it is not superior to the atorvastatin in the treatment of hyperlipidemia for the Blood-Stasis constitution and Yin-Yang Harmony constitution groups.

ObjectiveThe purpose of this study was to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS) on cognitive function of vascular dementia (VD) rats and its mechanism. MethodsVD rat model was established by modified two-vessel occlusion (2-VO). After modeling, TEAS and electroacupuncture (EA) were used to stimulate Baihui and Zusanli points of rats respectively for 14 d. After treatment, novel object recognition test, Morris water maze test, and Y maze test were used to evaluate the spatial memory and learning ability of rats. Hematoxylin and eosin staining was used to observe the morphology of hippocampal neurons. Transmission electron microscopy was used to observe the ultrastructure of hippocampal mitochondria. Enzyme-linked immunosorbent assay kits were used to detected the levels of SOD, CAT, GSH-Px, MDA and ROS in serum of rats. Western blot was used to detect the expression of PGC-1α, TFAM, HO-1, NQO1 proteins in the hippocampus, Keap1 protein in the cytoplasm and Nrf2, NRF1 proteins in the nucleus. ResultsAfter treatment for 14 d, compared to the model group, the escape latency of VD rats decreased, while the discrimination index, the times of rats crossing the original platform area, the residence time in the original platform quadrant, and the percentage of alternation increased. TEAS can improve the structure of hippocampal neurons and mitochondria of VD rats, showing that neurons were arranged more regularly and distributed more evenly, nuclear membrane and nucleoli were clearer, and mitochondrial swelling were reduced, mitochondrial matrix density were increased, and mitochondrial cristae were more obvious. The levels of SOD, GSH-Px and CAT in serum increased significantly, while the concentration of MDA and ROS decreased. TEAS also up-regulated the expression levels of PGC-1α TFAM, NQO1 and HO-1 proteins in the hippocampus and Nrf2, NRF1 proteins in the nucleus, but down-regulated the Keap1 protein in the cytoplasm. ConclusionTEAS can improve cognition, hippocampal neurons and mitochondrial structure of VD rats, and the effect is better than EA. The mechanism may be the activation of PGC-1α mediated mitochondrial biogenesis and antioxidant stress, which also provides a potential therapeutic technology and experimental basis for the treatment of VD.

Alzheimer’s disease (AD) is a central neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment, and there is a lack of effective drugs to treat AD clinically. Existing medications for the treatment of AD, such as Tacrine, Donepezil, Rivastigmine, and Aducanumab, only serve to delay symptoms and but not cure disease. To add insult to injury, these medications are associated with very serious adverse effects. Therefore, it is urgent to explore effective therapeutic drugs for AD. Recently, studies have shown that a variety of enzyme inhibitors, such as cholinesterase inhibitors, monoamine oxidase (MAO)inhibitors, secretase inhibitors, can ameliorate cholinergic system dysfunction, Aβ production and deposition, Tau protein hyperphosphorylation, oxidative stress damage, and the decline of synaptic plasticity, thereby improving AD symptoms and cognitive function. Some plant extracts from natural sources, such as Umbelliferone, Aaptamine, Medha Plus, have the ability to inhibit cholinesterase activity and act to improve learning and cognition. Isochromanone derivatives incorporating the donepezil pharmacophore bind to the catalytic active site (CAS) and peripheral anionic site (PAS) sites of acetylcholinesterase (AChE), which can inhibit AChE activity and ameliorate cholinergic system disorders. A compound called Rosmarinic acid which is found in the Lamiaceae can inhibit monoamine oxidase, increase monoamine levels in the brain, and reduce Aβ deposition. Compounds obtained by hybridization of coumarin derivatives and hydroxypyridinones can inhibit MAO-B activity and attenuate oxidative stress damage. Quinoline derivatives which inhibit the activation of AChE and MAO-B can reduce Aβ burden and promote learning and memory of mice. The compound derived from the combination of propargyl and tacrine retains the inhibitory capacity of tacrine towards cholinesterase, and also inhibits the activity of MAO by binding to the FAD cofactor of monoamine oxidase. A series of hybrids, obtained by an amide linker of chromone in combine with the benzylpiperidine moieties of donepezil, have a favorable safety profile of both cholinesterase and monoamine oxidase inhibitory activity. Single domain antibodies (such as AAV-VHH) targeted the inhibition of BACE1 can reduce Aβ production and deposition as well as the levels of inflammatory cells, which ultimately improve synaptic plasticity. 3-O-trans-p-coumaroyl maslinic acid from the extract of Ligustrum lucidum can specifically inhibit the activity of γ-secretase, thereby rescuing the long-term potentiation and enhancing synaptic plasticity in APP/PS1 mice. Inhibiting γ-secretase activity which leads to the decline of inflammatory factors (such as IFN-γ, IL-8) not only directly improves the pathology of AD, but also reduces Aβ production. Melatonin reduces the transcriptional expression of GSK-3β mRNA, thereby decreasing the levels of GSK-3β and reducing the phosphorylation induced by GSK-3β. Hydrogen sulfide can inhibitGSK-3β activity via sulfhydration of the Cys218 site of GSK-3β, resulting in the suppression of Tau protein hyperphosphorylation, which ameliorate the motor deficits and cognitive impairment in mice with AD. This article reviews enzyme inhibitors and conformational optimization of enzyme inhibitors targeting the regulation of cholinesterase, monoamine oxidase, secretase, and GSK-3β. We are hoping to provide a comprehensive overview of drug development in the enzyme inhibitors, which may be useful in treating AD.

Background/Aims: Inflammatory bowel disease (IBD) may contribute to the development of hematologic malignancies. In this study, the potential relationship between IBD and hematologic malignancies was investigated. Methods: We searched the PubMed, Web of Science, Embase, and Cochrane Library databases for all cohort studies comparing the incidence of hematologic malignancies in non-IBD populations with that in IBD patients, and we extracted relevant data from January 2000 to June 2023 for meta-analysis. Results: Twenty cohort studies involving 756,377 participants were included in this study. The results showed that compared with the non-IBD cohort, the incidence of hematologic malignancies in the IBD cohort was higher (standardized incidence ratio [SIR]=3.05, p<0.001). According to the specific types of IBD, compared with the non-IBD patients, the incidences of hematologic malignancies in ulcerative colitis patients (SIR=2.29, p=0.05) and Crohn's disease patients (SIR=3.56, p=0.005) were all higher. In the subgroup analysis of hematologic malignancy types, compared with the control group, the incidences of non-Hodgkin's lymphoma (SIR=1.70, p=0.01), Hodgkin's lymphoma (SIR=3.47, p=0.002), and leukemia (SIR=3.69, p<0.001) were all higher in the IBD cohort. Conclusions The incidence of hematologic malignancies, including non-Hodgkin's lymphoma, Hodgkin's lymphoma, and leukemia is higher in patients with IBD (ulcerative colitis or Crohn's disease) than in non-IBD patients.