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：探讨扁蒴藤素（PT）通过蛋白激酶B（AKT）/糖原合成酶激酶-3β（GSK-3β）信号通路对人乳腺癌细胞MCF-7多柔比星（DOX）敏感性的影响。方法：体外培养MCF-7细胞并建立DOX耐药细胞MCF-7/DOX。MCF-7细胞设NC组、L-PT组（2 μmol/L PT）、M-PT组（4 μmol/L PT）、H-PT组（8 μmol/L PT）、H-PT + SC79组（8 μmol/L PT + 10 μmol/L的AKT/GSK-3β信号通路抑制剂SC79）、H-PT + LY294002组（8 μmol/L PT + 2.5 μmol/L的AKT/GSK-3β信号通路激活剂LY294002）。MCF-7/DOX细胞设MCF-7/DOX组（未处理）、DOX组（50 nmol/L DOX）、PT + DOX组（8 μmol/L PT和50 nmol/L DOX）、PT + DOX + SC79组（8 μmol/L PT + 50 nmol/L DOX + 10 μmol/L SC79）、PT + DOX + LY294002组（8 μmol/L PT + 50 nmol/L DOX + 2.5 μmol/L LY294002）。采用MTT法、平板克隆实验、划痕愈合实验、Transwell实验及WB法分别检测细胞增殖、集落形成数、迁移、侵袭和AKT/GSK-3β信号通路蛋白表达。建立MCF-7细胞裸鼠移植瘤模型，观察PT对移植瘤生长、移植瘤组织中AKT/GSK--3β 信号通路蛋白表达的影响。结果：与NC组相比，L-PT、M-PT、H-PT组MCF-7细胞增殖率、集落形成数、划痕愈合率、侵袭细胞数及p-AKT、p-GSK-3β蛋白表达均呈PT浓度依赖性降低（均P < 0.05）；与H-PT组对比，H-PT + SC79组MCF-7细胞上述指标变化趋势与上述相反，PT + DOX + LY294002组MCF-7细胞上述指标变化趋势与上述相同（均P < 0.05）。MCF-7/DOX组与DOX组细胞增殖率、集落形成数、划痕愈合率、侵袭细胞数及p-AKT、p-GSK-3β蛋白表达无明显差异（均P > 0.05）；分别与MCF-7/DOX组、DOX组对比，PT + DOX组MCF-7/DOX细胞上述指标均降低（均P < 0.05）；对比PT + DOX组，PT + DOX + SC79组上述指标均升高，PT + DOX + LY294002组上述指标均降低（均P < 0.05）。裸鼠移植瘤实验显示，与对照组和DOX相比，PT + DOX组移植瘤质量、体积、p-AKT、p-GSK-3β蛋白表达均降低（均P < 0.05）。结论：PT抑制乳腺癌细胞增殖、迁移和侵袭，并增强其对DOX的化疗敏感性，其机制与抑制AKT/GSK-3β信号通路有关。

Aim To explore the effect of curcumin on the growth of malignant glioma and the possible mecha-nism.Methods Human glioblastoma cell U87 was taken as the study object.They were randomly separa-ted into the blank control group(without any interven-tion)and low,medium and high curcumin group(10,20 and 40 μmol·L-1),temozolomide group(40μmol·L-1),curcumin 40 μmol·L-1+LY210976110 μmol·L-1,curcumin 40 μmol·L-1+SRI-011381 10 μmol·L-1,then they were intervened for 48 h.The activity,migration and invasion ability of U87 cells in each group were measured by CCK-8 method and Transwell method.The cell cycle changes of U87 cells were measured by flow cytometry.The ex-pression levels of TGF-β1/Smad signaling pathway in U87 cells were measured by Western blotting.Results After 48 h intervention,the percentage of U87 cell activity,cell migration and invasion number in curcu-min group and temozolomide group were lower than those in the blank control group(P＜0.05),and all decreased with the increase of curcumin dose(P＜0.05).Compared with the blank control group,the number of cells increased in Sub-G0 stage in the curcu-min group and temozolomide group(P＜0.05),and decreased in G2/M stage(P＜0.05).The protein rel-ative expression levels of TGF-β1,p-Smad 3,N-cad-herin,matrix metalloproteinase(MMP)-2 and MMP-9 in U87 cells in high curcumin group and temozolomide group were lower than those in the blank control group(P＜0.05),and the protein relative expression levels of Smad 7 and E-cadherin were higher than those in the blank control group(P＜0.05).There was no statisti-cally significant difference between the high curcumin group and temozolomide group(P＞0.05).Compared with the high curcumin group,inhibition of TGF-β1/Smad pathway could further inhibit the activity,migra-tion and invasion of U87 cells,reduce the relative ex-pression levels of TGF-β1,P-Smad 3,MMP-2 and MMP-9 proteins(P＜0.05),and increase the relative expression levels of Smad 7 and E-cadherin protein(P＜0.05),while the TGF-β1/Smad pathway activator was vice versa(P＜0.05).Conclusions Curcumin can inhibit the growth of malignant glioma U87 cells,and the mechanism may be related to the regulation of TGF-β1/Smad signaling pathway.

Objective To investigate the effects of galectin-3(Gal3)on skin abscess development and activation of mast cells(MC)in mice infected with methicillin-resistant Staphylococcus aureus(MRSA).Methods Wild type mice and Gal3-knockout(Gal3-/-)mice,at 6～8 weeks of age,were divided into four groups:Wild type mice+PBS group,Wild type mice+MRSA group,Gal3-/-mice+PBS group,Gal3-/-mice+MRSA group,were subcutaneously injected with MRSA or the same volume of phosphate buffer saline,with five mice per group.The development and pathological changes of skin abscess were monitored and recorded.The bacterial load in skin tissues was compared,and the expression of associated cytokines,degranulation of MC,and the distribution of MC activation marker 5-hydroxytryptamine(5-HT)were detected.Results The skin of Wild type mice showed progressive abscesses after subcutaneous infection with MRSA,but the Gal3-/-mice showed smaller abscess areas.Compared to the Wild type mice+MRSA group,the Gal3-/-mice+MRSA group showed lower bacterial loading in the skin tissues(P＜0.01)and fewer infiltrating inflammatory cells with histopathological observation.The expression of cytokines,including IL-1β,TNF-α,IL-33,TGF-β,and IL-10,were significantly lower in Gal3-/-mice than Wild type mice(P＜0.05).The toluidine blue staining showed a large number of degranulated MCs in the skin tissues of the wild type mice+MRSA group,whereas only a few degranulated MCs were observed in the Gal3-/-mice+MRSA group.It was further found that the expression of 5-HT in Gal3-/-mice+MRSA group was significantly lower than that in wild-type mice+MRSA group with immunohistochemical staining.Conclusion Gal3 deficiency reduced the activation and degranulation of mouse skin MC after MRSA infection,resulting in changes to inflammatory responses and alleviating the severity of skin tissue abscesses.

Objective:To investigate the influence of curative-intent resection with textbook outcomes of liver surgery (TOLS) on long-term prognosis of gallbladder carcinoma (GBC).Methods:The retrospective cohort study was conducted. The clinicopathological data of 824 patients with GBC in the national multicenter database of Biliary Surgery Group of Elite Group of Chinese Journal of Digestive Surgery, who were admitted to 15 medical centers from January 2014 to January 2021, were collected. There were 285 males and 539 females, aged (62±11)years. According to the evalua-tion criteria of TOLS, patients were divided into those who achieved TOLS and those who did not achieve TOLS. Measurement data with normal distribution were represented as Mean± SD, and com-parison between groups was conducted using the independent sample t test. Measurement data with skewed distribution were represented as M( Q1, Q3), and comparison between groups was conducted using the Mann-Whitney U test. Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data were conduc-ted using the Mann-Whitney U test. The Kaplan-Meier method was used to calculate survival rate and draw survival curve, and the Log-rank test was used for survival analysis. The COX stepwise regression model with backward Wald method was used for univariate and multivariate analyses. Results:(1) Achievement of TOLS. Of the 824 patients undergoing curative-intent resection for GBC, there were 510 cases achieving TOLS and 314 cases not achieving TOLS. (2) Follow-up. Of the 824 patients undergoing curative-intent resection for GBC, after excluding 112 deaths within 90 days after discharge, 712 cases were included for the survival analysis. The median follow-up time, median overall survival time and 5-year overall survival rate of the 510 patients achieving TOLS were 22.1(11.4,30.1)months, 47.6(30.6,64.6)months and 47.5%. The median follow-up time, median overall survival time and 5-year overall survival rate of the 202 patients not achieving TOLS were 14.0(6.8,25.5)months, 24.3(20.0,28.6)months and 21.0%. There was a significant difference in overall survival between patients achieving TOLS and patients not achieving TOLS ( χ2=58.491, P<0.05). (3) Analysis of factors influencing prognosis of patients. Results of multivariate analysis showed that TOLS, carcinoembryonic antigen (CEA), CA19-9, poorly differentiation of tumor, T2 stage of eighth edition of American Joint Committee on Cancer (AJCC) staging, T3 and T4 stage of eighth edition of AJCC staging, N1 stage of the eighth edition of AJCC staging, N2 stage of the eighth edition of AJCC staging, adjuvant therapy were independent factors influencing overall survival time of patients undergoing curative-intent resection for GBC ( hazard ratio=0.452, 1.479, 1.373, 1.612, 1.455, 1.481, 1.835, 1.978, 0.538, 95% c onfidence interval as 0.352-0.581, 1.141-1.964, 1.052-1.791, 1.259-2.063, 1.102-1.920, 1.022-2.147, 1.380-2.441, 1.342-2.915, 0.382-0.758, P<0.05). Conclusion:Patients under-going curative-intent resection for GBC with TOLS can achieve better long-term prognosis.

Objective To design a novel oxygenator to solve the existing problems of extracorporeal membrane oxygenation(ECMO)machine in high transmembrane pressure difference,low efficiency of blood oxygen exchange and susceptibility to thrombosis.Methods The main body of the oxygenator vascular access flow field was gifted with a flat cylindrical shape.The topology of the vascular access was modeled in three dimensions,and the whole flow field was cut into a blood inlet section,an inlet buffer,a heat exchange zone,a blood oxygen exchange zone,an outlet buffer and a blood outlet section.The oxygenator was compared with Quadrox oxygenator by means of ANSYS FLUENT-based simulation and prototype experiments.Results Simulation calculations showed the oxygenator designed was comparable to the clinically used ones in general,and gained advantages in transmembrane pressure difference,blood oxygen exchange and flow uniformity.Experimental results indicated that the oxygenator behaved better than Quadrox oxygenator in transmembrane pressure difference and blood oxygen exchange.Conclusion The oxygenator has advantages in transmem-brane pressure difference,temperature change,blood oxygen ex-change and low probability of thrombosis.[Chinese Medical Equipment Journal,2024,45(3):23-28]

AIM:This study utilized CRISPR/Cas9 technology to create Retnlb floxp knock-in mice,followed by the application of the Cre-LoxP recombination system to generate intestinal epithelial-specific Retnlb gene knockout mice(Retnlb-CKO).This model was developed to investigate the pathogenic mechanisms of Retnlb in inflammatory bowel disease.METHODS:Female and male C57BL/6N mice,aged 8 weeks with the Retnlbflox/+genotype,were housed togeth-er for breeding.Offsprings were screened to identify those with the Retnlbflox/flox genotype.These mice were then crossed with Vil1-Cre transgenic mice,which express Cre recombinase specifically in intestinal epithelial cells,resulting in Retnlb-flox/+,Cre+mice.Subsequent crosses between Retnlbflox/+,Cre+mice and Retnlbflox/flox mice produced Retnlbflox/flox,Cre+mice(Retnlb-CKO).Six 8-week-old Retnlbflox/flox,Cre+mice and their littermate Retnlbflox/flox mice were selected for experiments.RT-qPCR and immunohistochemistry were used to assess Retnlb mRNA and protein levels in colonic epithelium.Phenotypic observa-tions included body length,weight,diet,and reproductive capability.Tissue-to-body weight ratios were calculated to ana-lyze growth and development.Intestinal barrier integrity and colonic expression of inflammatory factors were evaluated.RESULTS:The conditional gene knockout mouse model with specific deletion of Retnlb in intestinal epithelial cells was successfully established and validated through genetic identification,mRNA and protein analysis.Compared to Retnlbflox/flox mice,Retnlb-CKO mice exhibited no significant differences in body length,weight,diet,or reproductive capability.There were no differences in the ratios of heart,liver,spleen,lung,kidney,and colon weight to body weight,nor were there morphological differences in various tissues.However,the mRNA expression of tight junction proteins ZO-1,Occlu-din,and Claudin3 in colon tissues of Retnlb-CKO mice was significantly reduced(P<0.01).PAS staining and immunohis-tochemistry revealed a significant decrease in the number of goblet cells and lysozyme-positive cells in the colon tissues of Retnlb-CKO mice(P<0.01).HE staining showed no obvious pathological change in colon tissues of Retnlb-CKO mice.RT-qPCR further demonstrated a significant downregulation of pro-inflammatory factors NLRP3,interleukin-6(IL-6),IL-1β,and tumor necrosis factor-α(TNF-α)in colon tissues(P<0.01),along with significant downregulation of inflamma-tion signaling pathway proteins TLR4,MyD88,and NF-κB(P<0.01).CONCLUSION:A conditional colon epithelial cell Retnlb gene knockout mouse model was successfully constructed and validated.The absence of Retnlb in colon cells led to impaired intestinal barrier function,decreased mRNA expression of pro-inflammatory factors in colon tissue,and downregulation of mRNA expression of inflammatory pathway proteins TLR4,MyD88,and NF-κB.

Osteoporotic proximal humeral fracture (OPHF) is one of the common osteoporotic fractures in the aged, with an incidence only lower than vertebral compression fracture, hip fracture, and distal radius fracture. OPHF, secondary to osteoporosis and characterized by poor bone quality, comminuted fracture pattern, slow healing, and severely impaired shoulder joint function, poses a big challenge to the current clinical diagnosis and treatment. In the field of diagnosis, treatment, and rehabilitation of OPHF, traditional Chinese and Western medicine have accumulated rich experience and evidence from evidence-based medicine and achieved favorable outcomes. However, there is still a lack of guidance from a relevant consensus as to how to integrate the advantages of the two medical systems and achieve the integrated diagnosis and treatment. To promote the diagnosis and treatment of OPHF with integrated traditional Chinese and Western medicine, relevant experts from Orthopedic Expert Committee of Geriatric Branch of Chinese Association of Gerontology and Geriatrics, Youth Osteoporosis Group of Orthopedic Branch of Chinese Medical Association, Osteoporosis Group of Orthopedic Surgeon Branch of Chinese Medical Doctor Association, and Osteoporosis Committee of Shanghai Association of Integrated Traditional Chinese and Western Medicine have been organized to formulate Expert consensus on the diagnosis and treatment of osteoporotic proximal humeral fracture with integrated traditional Chinese and Western medicine ( version 2024) by searching related literatures and based on the evidences from evidence-based medicine. This consensus consists of 13 recommendations about the diagnosis, treatment and rehabilitation of OPHF with integrated traditional Chinese medicine and Western medicine, aimed at standardizing, systematizing, and personalizing the diagnosis and treatment of OPHF with integrated traditional Chinse and Western medicine to improve the patients ′ function.

Objective:To investigate the clinical efficacy and safety of deep hyperthermia combined with sintilimab and nab-PC (albumin-bound paclitaxel + carboplatin) regimen in the treatment of advanced squamous non-small cell lung cancer (NSCLC) with driver gene negative and programmed death-1 receptor ligand 1 (PD-L1) expression positive.Methods:A prospective case-control study was performed. A total of 84 advanced squamous NSCLC patients with driver gene negative and PD-L1 expression positive in Hebei Seventh People's Hospital from January 2020 to December 2022 were collected, and all patients were divided into the observation group and the control group according to the random number table method, with 42 cases in each group. The control group was given the treatment of sintilimab combined with nab-PC regimen, and the observation group was given deep hyperthermia on the basis of the control group. After 4 consecutive cycles of treatment, the short-term efficacy of the two groups was compared. The levels of serum tumor markers [carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCCA), cytokeratin fragment 19 (CYFR21-1)], and the positive expression rates of immunohistochemistry markers [p40, p63, and cytokeratin 5/6 (CK5/6)] before and after treatment were compared between two groups. Functional Assessment of Cancer Therapy-Lung cancer module (FACT-L) scores, the adverse reactions and the long-term survival of the two groups were compared.Results:There were 26 males and 16 females in the observation group, and the age was (59±11) years; there were 22 males and 15 females in the control group, and the age was (58±11) years. The objective remission rate and the disease control rate were 71.43% (30/42), 90.48% (38/42), respectively in the observation group, and 50.00% (21/42), 80.95% (34/42), respectively in the control group; the objective remission rate in the observation group was higher than that in the control group, and the difference was statistically significant ( χ2 = 4.04, P = 0.044); and there was no statistically significant difference in the disease control rate of both groups ( χ2 = 1.56, P = 0.212). The levels of serum CEA, SCCA and CYFRA21-1, and the positive expression rates of p40, p63, and CK5/6 in the two groups after treatment were lower than those before treatment (all P < 0.05); and the scores of physiological status, functional status, additional concern in FACT-L scores and the total score of the scale after treatment were higher than those before treatment (all P < 0.05). There were no statistically significant differences in the incidence of adverse reactions including thrombocytopenia, neutropenia, leukopenia, anemia, fever of the two groups (all P > 0.05). The median progression-free survival (PFS) time was 6.5 months (95% CI: 3.82-12.75), 5.1 months (95% CI: 3.14-12.26),respectively in the observation group and the control group, and the difference in the median PFS time was statistically significantly of both groups ( χ2 = 4.21, P = 0.040). The median overall survival (OS) time was 12.9 months (95% CI: 6.25-15.46), 9.7 months (95% CI: 4.74-13.02), respectively in the observation group and the control group, and the difference in the median OS time was statistically significantly of both groups ( χ2 = 4.43, P = 0.035). Conclusions:Deep hyperthermia combined with sintilimab and nab-PC regimen in the treatment of advanced squamous NSCLC with driver gene negative and PD-L1 expression positive can effectively reduce the serum tumor markers levels and positive expression rate of immunohistochemical markers, improve the quality of life of patients, and increase the short-term and long-term efficacy.

Objective To observe the efficacy and safety of Morinda officinalis oligosaccharides in the continuation treatment of mild and moderate depression.Methods An open,single-arm,multi-center design was adopted in our study.Adult patients with mild and moderate depression who had received acute treatment of Morinda officinalis oligosaccharides were enrolled and continue to receive Morinda officinalis oligosaccharides capsules for 24 weeks,the dose remained unchanged during continuation treatment.The remission rate,recurrence rate,recurrence time,and the change from baseline to endpoint of Hamilton Depression Scale(HAMD),Hamilton Anxiety Scale(HAMA),Clinical Global Impression-Severity(CGI-S)and Arizona Sexual Experience Scale(ASEX)were evaluated.The incidence of treatment-related adverse events was reported.Results The scores of HAMD-17 at baseline and after treatment were 6.60±1.87 and 5.85±4.18,scores of HAMA were 6.36±3.02 and 4.93±3.09,scores of CGI-S were 1.49±0.56 and 1.29±0.81,scores of ASEX were 15.92±4.72 and 15.57±5.26,with significant difference(P＜0.05).After continuation treatment,the remission rate was 54.59％(202 cases/370 cases),and the recurrence rate was 6.49％(24 cases/370 cases),the recurrence time was(64.67±42.47)days.The incidence of treatment-related adverse events was 15.35％(64 cases/417 cases).Conclusion Morinda officinalis oligosaccharides capsules can be effectively used for the continuation treatment of mild and moderate depression,and are well tolerated and safe.