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.

[摘 要] 目的：探讨RNA结合蛋白15（RBM15）通过三磷酸腺苷酶家族蛋白3A（ATAD3A）调控Wnt/β-catenin通路对宫颈癌细胞恶性生物学行为的影响。方法：利用TCGA数据库分析宫颈癌组织中RBM15 mRNA表达水平及其与患者预后的关系。收集2024年1月至10月期间在赣州市人民医院手术切除的32例宫颈癌组织及癌旁组织标本，以及宫颈癌细胞HeLa、MS-751、C-33A和SiHa，通过免疫组化、WB法检测宫颈癌组织和细胞中RBM15的表达水平。利用SRAMP在线数据库筛选ATAD3A mRNA的m6A修饰位点。通过RNA免疫沉淀实验、RNA衰变实验及挽救实验鉴定RBM15与ATAD3A mRNA的相互作用。采用RNA干扰技术和病毒感染技术，在宫颈癌HeLa和SiHa细胞敲低或过表达RBM15和ATAD3A，qPCR和WB法检测mRNA和蛋白表达，CCK-8法、划痕实验和Transwell实验检测各组细胞的增殖、迁移和侵袭能力。结果：宫颈癌组织中RBM15 mRNA和蛋白阳性率均显著高于癌旁组织（均P < 0.001）。宫颈癌HeLa、MS-751、C-33A和SiHa细胞RBM15蛋白表达水平显著高于正常宫颈细胞Ect1/E6E7（均P < 0.01）。RBM15 mRNA高表达组患者5年无进展生存率低于低表达组患者（P < 0.01）。宫颈癌组织中ATAD3A的表达水平显著高于癌旁组织（P < 0.001），RBM15 mRNA与ATAD3A mRNA呈正相关（r = 0.601，P < 0.05）。ATAD3A mRNA的501、5 312、12 137位点存在高可信度的m6A修饰位点。HeLa、SiHa细胞中过表达RBM15后，ATAD3A mRNA和蛋白表达升高，而敲低RBM15后，ATAD3A mRNA和蛋白表达降低（均P < 0.001）。RNA免疫沉淀实验显示，与IgG组相比，RBM15抗体的免疫沉淀中ATAD3A mRNA显著富集（均P < 0.001）。MeRIP-qPCR实验显示，ATAD3A mRNA 501、5 312、12 137位点均存在明显的m6A甲基化富集（均P < 0.001）。RNA衰变实验显示，敲低RBM15能降低HeLa、SiHa细胞ATAD3A mRNA的半衰期和稳定性（均P < 0.001）。敲低HeLa、SiHa细胞RBM15的表达，显著抑制癌细胞的增殖、迁移及侵袭，Wnt/β-catenin通路相关蛋白Wnt3、β-catenin、vimentin表达均显著降低（均P < 0.001）；而过表达ATAD3A可完全逆转上述抑制作用（均P < 0.001）。结论：RBM15通过m6A修饰ATAD3A mRNA调控Wnt/β-catenin信号通路，从而促进宫颈癌细胞增殖、迁移及侵袭。

Objective To evaluation the bioequivalence of telmisartan tablets(80 mg)between test formulation and reference formulation in Chinese healthy subjects.Methods A single-center,randomized,open-label,two-preparations,single administration,partial repeat crossover of three sequences in three postprandial cycles and complete repeat crossover of two sequences in four fasting cycles,bioequivalence test was designed.Chinese healthy subjects were included in the bioequivalence trial,with 33 randomly assigned to the postprandial group and 32 randomly assigned to the fasting group.In each period,blood samples was collected before and after administration.The plasma concentration of the drug was determined by LC-MS/MS,using WinNonlin version 8.3 calculate the pharmacokinetic parameters and perform a statistical analysis using SAS version 9.4.Results The main pharmacokinetic parameters of telmisartan tablets after oral administration of test or reference were as follows.Fasting group Cmax were(556.10±456.06)and(580.99±533.50)ng·mL-1;AUC0-t were(3 475.15±3 785.16)and(3 450.54±3 681.02)ng·mL-1·h;AUC0-∞ were(3 214.06±2 272.06)and(3 194.84±2 187.45)ng·mL-1·h.The 90％confidence intervals of the geometric mean ratio of Cmax,AUC0-t,AUC0-∞ were within the requirements of the equivalent range of bioequivalence(80.00％-125.00％).Postprandial group Cmax were(299.26±124.72)and(291.29±126.34)ng·mL-1;AUC0-t were(3 682.24±2 799.72)and(3 636.71±2 158.42)ng·mL-1·h;AUC0-were(3 544.53±1 553.06)and(3 969.38±2 528.22)ng·mL-1·h.The 90％confidence intervals of the geometric mean ratio of Cmax,AUC0-t,AUC0-∞ were within the requirements of the equivalent range of bioequivalence(80.00％-125.00％).Conclusion Under fasting and fed conditions,two kinds of telmisartan tablets are bioequivalent in Chinese healthy subjects.

Pafolacianine is a fluorescent agent that specifically targets folate receptors,employed in the treatment of adult ovarian cancer patients to support the detection of malignant growths during surgical interventions.Pafolacianine binds to cancer cells expressing folate receptors,accumulating within folate-receptor-positive tumor tissue through receptor-mediated endocytosis.It can be excited by near-infrared fluorescence imaging,facilitating the surgical removal of tumors during procedures.This article gives an introduction to the mechanism of action,pharmacokinetics,clinical studies,and safety aspects of Pafolacianine.

On May 27,2021,the U.S.Food and Drug Administration(FDA)officially approved Lantheus'PYLARIFY?(Piflufolastat F 18,18 F-labeled imaging agent),which can be used for positron emission computed tomography(PET)of prostate-specific membrane antigen(PSMA)-positive lesions in prostate cancer patients to accurately identify prostate cancer with suspected metastasis or recurrence.Piflufolastat F 18 is approved by FDA for two indications.The first is the initial staging for suspected metastatic lesions in men with newly diagnosed prostate cancer.The second is restaging,with the goal of identifying lesions in the setting of biochem ical recurrence.

Objective To study the effect of Hedysarum polysaccharides(HPS)on the expression of transforming growth factor-β,(TGF-β1),smad homologue 3 recombinant protein(smad3)and smad7 in renal tissue of db/db mice with diabetic nephropathy(DN).Methods According to their body weight,6-week-old male db/db mice were randomly divided into 5 groups:model group(0.9％NaCl 0.2 mL·d-1),positive control group(22.75 mg·kg-1·d-1 irbesartan)and experimental-H,-M,-L groups(200,100,50 mg kg-1·d-1 HPS),with 10 mice in each group;another 10 SPF grade male C57BL/6 mice of the same week were selected as normal group(0.9％NaCl 0.2mL·d-1).The mice in the 6 groups were given intragastric administration once a day for 12 weeks.The blood glucose concentration of mice was measured before treatment and at the 4th,8th and 12th week after treatment.The expression levels of TGF-β1,smad3 and smad7 were detected by Western blotting.Results After treatment,the blood glucose levels of the model group was significantly higher than those of the normal group(all P＜0.01);compared with the model group,the levels of blood glucose in the experimental-H,-M groups decreased significantly,and the differences were statistically significant(P＜0.05,P＜0.01).The relative expression levels of TGF-β,protein in normal group,model group,positive control group and experimental-H,-M groups were 0.71±0.16,1.66±0.18,1.00±0.17,0.88±0.15 and 1.23±0.15;the relative expression levels of smad3 protein were 0.89±0.32,2.26±0.35,1.24±0.31,1.05±0.30 and 1.67±0.35;the relative expression levels of smad7 protein were 1.66±0.03,0.60±0.03,1.10±0.07,1.48±0.08 and 0.97±0.09;there were statistically significant differences between the experimental-H,-M groups and the model group(P＜0.05,P＜0.01).Conclusion Hedysarum polysaccharides can improve renal fibrosis and delay the development of diabetic nephropathy by regulating the level of blood glucose,inhibiting TGF-β1,smad3 and increasing the expression of smad7.

Objective To evaluate tolerability,safety and pharmacokinetics of JS026 and JS026-JS016 single dose intravenous infusion in healthy adults.Methods This phase 1,randomized,double-blind,placebo-controlled,dose-escalation study totally included 48 participants:32 healthy subjects were enrolled in JS026 single intravenous infusion groups and 16 healthy subjects were enrolled in JS026-JS016 groups.JS026 was sequentially administered from low dose to high dose(30-1 000 mg),with intravenous infusion of JS026 or placebo in JS026 single-dose groups,and intravenous infusion of JS026-JS016 or placebo in the combination drug groups.Blood was collected according to the time point designed for trial.Serum concentrations of JS026 and JS016 were determined by enzyme linked immunosorbnent assay(ELISA),and pharmacokinetics parameters were calculated by WinNonlin 8.2.The power model method was used to evaluate the linear analysis of dose and drug exposure.Results 47 subjects completed trial and 1 subject lost to follow-up.After a single intravenous injection of JS026 of 30 mg,100 mg,300 mg,600 mg,and 1 000 mg,mean Cmax were(9.47±1.53),(33.20±4.95),(96.10±13.70),(177.00±22.20)and(353.00±56.70)μg·mL-1,respectively;mean AUC0-∞ were(4 225.00±607.00),(1.78 × 104±3 268.00),(5.83 × 104±1 038.00),(1.07 × 105±152.00),(1.66 × 105±327.00)μg·h·mL-1,respectively;mean t1/2 of JS026 were 563-709 h.The Cmax and AUC0-∞ of JS026 were basically similar alone or in combination with JS016.The results of Power model showed that Cmax and AUC0-∞ increased approximately linearly with the increasing dose of JS026.Treatment emergent adverse event was not increasing when dose increased and most of adverse event associated with drugs were abnormal on laboratory tests and haematuria,thus JS026 and JS016 was well tolerated in all groups.Conclusion The single intravenous infusion of JS026 can almost be thought to be a linear relationship between the doses and drug serum exposure.JS016 had no significant effect on serum concentration of JS026 and JS026 was well tolerated and safe in healthy subjects within 30-1 000 mg.

Schimke immuno-osseous dysplasia (SIOD)caused by SMARCAL1 gene mutations is a rare genetic disorder characterized by multi-system involvement, including T-cell dysfunction, skeletal dysplasia, disproportionate short stature, nephrotic syndrome, and kidney failure. This multidisciplinary consultation involved a 9-year-old boy with intrauterine growth retardation, presenting with short stature, T-cell lymphopenia, proteinuria, and degenerative bone and joint disease. Treatment primarily focused on symptomatic and supportive care. Through the multidisciplinary rare disease consultation, holistic support was provided to the patient, offering comprehensive care from various specialtiesx.We also aim to use this case report to enhance clinicians′ under-standing of SIOD and improve the management and treatment of rare diseases.

OBJECTIVE To explore the impact of placental polypeptide on the Runt-related transcription factor 3 （RUNX3）/ Notch signaling pathway in rats with cyclophosphamide-induced premature ovarian failure （POF）， and its effects on ovarian function and oxidative stress. METHODS A POF rat model was induced by intraperitoneal injection of cyclophosphamide. Sixty POF rats of the model were randomly assigned to model group， low-dose （1 mg/kg） and high-dose （2 mg/kg） placental polypeptide groups， placental polypeptide plus empty vector group [placental polypeptide （2 mg/kg）， empty vector （1 μg）]， and placental polypeptide plus RUNX3 silencing group [placental polypeptide （2 mg/kg）， RUNX3 small interfering RNA （1 μg）]， with 12 rats in each group. Additionally， 12 healthy rats were selected as a control group. The intervention lasted for 4 weeks for all groups. After the final administration， the levels of sex hormones [estradiol （E2）， anti-Müllerian hormone （AMH）， follicle- stimulating hormone （FSH）] in rat serum and oxidative stress indicators [malondialdehyde （MDA）， superoxide dismutase （SOD）， catalase （CAT）， reactive oxygen species （ROS）] in ovarian tissue were measured. The pathology of rat ovarian tissue and apoptosis of ovarian granulosa cells were examined； the expression of apoptosis-related proteins [caspase-3， cleaved-caspase-3， B-cell lymphoma-2 （Bcl-2）， Bcl-2 associated X protein （Bax）and RUNX3/Notch signaling pathway-related proteins in rat ovarian tissue were detected. RESULTS Compared with the model group， the low and high doses of placental polypeptide groups showed an increase in the number of normal follicles and a marked decrease in the number of atretic follicles， with significant increases in the serum levels of E2 and AMH， the ovarian tissue levels of SOD and CAT， as well as the expression levels of Bcl-2， RUNX3 and Notch1 proteins， and significant decreases in the serum FSH levels， the ovarian granulosa cell apoptosis rate， and the ovarian tissue levels of MDA and ROS， as well as the expression levels of cleaved-caspase-3， caspase-3 and Bax proteins （P＜0.05）； the changes in the high-dose group were significantly more pronounced （P＜0.05）. Compared with the high-dose placental polypeptide group and the placental polypeptide plus empty vector group， the placental polypeptide plus RUNX3 silencing group showed a decrease in the number of normal follicles and a significant reversal of the above indicators （P＜0.05）. CONCLUSIONS Placental polypeptide may alleviate the symptoms of rats with POF by upregulating the RUNX3/Notch signaling pathway， improving sex hormone secretion， oxidative stress， ovarian granulosa cell apoptosis and ovarian function.

Acute liver injury (ALI) is one of the common severe diseases in clinic, which is characterized by redox imbalance and inflammatory storm. Untimely treatment can easily lead to liver failure and even death. Rosmarinic acid (RA) has been proved to have anti-inflammatory and antioxidant activity, but it is not clear how to protect ALI through antioxidation and inhibition of inflammation. Therefore, this study explored the therapeutic effect and molecular mechanism of RA on ALI through in vitro and in vivo experiments. In the mouse ALI model, the effects of RA on liver function and inflammatory indexes were studied, the pathological changes of liver were observed by HE, the effect of RA on reactive oxygen species in liver was detected by fluorescence method, and the level of F4/80 in liver tissue was detected by immunohistochemical method. The levels of thioredoxin interacting protein (TXNIP), NOD-like receptor protein 3 (NLRP3) and cysteinyl aspartate specific proteinase-1 (CASPASE-1) in liver tissue were measured by Western blot. All animal welfare and experimental procedures follow the rules of the Animal Ethics Committee of Southwest Minzu University. In vitro, human hepatoma cell line HepG2 was used to establish the model of oxidative damage induced by H₂O₂. The cell viability was detected by CCK-8 method. The level of interleukin-1β (IL-1β) in the supernatant was detected by enzyme linked immunosorbent assay (ELISA), the activity of lactatede hydrogenase (LDH) was detected by LDH kit, and the level of ROS was detected by fluorescence probe DCFH-DA labeling. The mRNA expression of Txnip, Nlrp3, Caspase 1, Il1β was detected by real-time fluorescence quantitative PCR (qPCR), and the protein levels of nuclear factor erythroid-2 related factor 2 (NRF2), TXNIP, NLRP3 and CASPASE-1 were measured by Western blot. The results showed that compared with the model group, the degree of liver swelling, tissue injury, liver function index in RA group were significantly lower than those in model group. And RA significantly attenuated the increases of ROS in liver tissue. The expression levels of TXNIP, NLRP3 and CASPASE-1 in liver tissue were significantly lower than those in model group. Additionally, RA inhibited the expressions of F4/80 and IL-1β. In vitro experiment, compared with model group, RA effectively inhibited the secretion of IL-1β and LDH. The level of ROS also decreased significantly. RA inhibited the mRNA expressions of Txnip, Caspase 1, Il1β. Furthermore, RA significantly increased the expression level of NRF2 protein in nucleus, and decreased the expression level of TXNIP and NLRP3 protein. Specifically, with the addition of ML385, the effect of RA on NRF2, TXNIP, NLRP3, CASPASE-1 protein expression was reversed. Collectively, these findings suggested that RA may inhibit the production of ROS by promoting NRF2 nuclear transfer, and then reduce the activation of NLRP3 inflammatory bodies by TXNIP, reduce cell death and inflammatory response to prevent the liver injury.