放疗联合免疫治疗对肺癌脑转移的疗效和安全性的meta分析

背景与目的免疫治疗(immunotherapy, IT)被推荐用于治疗晚期非小细胞肺癌(non-small cell lung cancer, NSCLC)，而脑放疗(radiation therapy, RT)是脑转移(brain metastasis, BM)患者的主流治疗方法。本研究旨在调查RT和IT联合使用的疗效及安全性。方法检索时限截至2022年5月1日，在中国知网、万方、PubMed、EMBASE、Cochranc数据库中进行了文献检索。异质性采用I²检验和P值进行判断。发表偏倚采用漏斗图评价。采用纽卡斯尔-渥太华量表(Newcastle Ottawa Scale, NOS)评估纳入研究的质量。采用Stata 16.0软件进行统计分析。结果纳入17篇文献共涉及2,636例患者。在RT+IT组和RT组的比较中，总生存期(overall survival, OS)(HR=0.85, 95%CI: 0.52-1.38, I²=73.9%, P_异质性=0.001)和颅内远距离控制(distant brain control, DBC)(HR=1.04, 95%CI: 0.55-1.05, I²=80.5%, P_异质性 < 0.001)未发现明显差异，但RT+IT组颅内控制(local control, LC)优于RT组(HR=0.46, 95%CI: 0.22-0.94, I²=22.2%, P_异质性=0.276)，发生放射性坏死/治疗相关影像学改变(radionecrosis/treatment related imaging changes, RN/TRIC)风险高于RT组(HR=1.72, 95%CI: 1.12-2.65, I²=40.2%, P_异质性=0.153)。在RT+IT同步治疗组和序贯组的比较中，未发现OS(HR=0.62, 95%CI: 0.27-1.43, I²=74.7%, P_异质性=0.003)和RN/TRIC(HR=1.72, 95%CI: 0.85-3.47, I²=0%, P_异质性=0.388)在两组中存在差异。但同步治疗组DBC优于序贯治疗组(HR=0.77, 95%CI: 0.62-0.96, I²=80.5%, P_异质性 < 0.001)。结论RT联合IT并未改善NSCLC BM患者的OS，而且还会增加RN/TRIC的风险。此外，相对于RT与IT序贯治疗，RT与IT同步治疗可改善DBC的疗效。     

Effect of Date Fruit Consumption on the Glycemic Control of Patients with Type 2 Diabetes: A Randomized Clinical Trial

Objective. Date fruit has been reported to have benefits in type 2 diabetes (T2D), though there is a concern, given the high sugar content, about its effects on glycemic control. Design and Setting. Prospective, interventional, randomized, parallel study. Participants. In total, 79 patients with T2D (39 male and 40 female). Intervention. Participants were randomly allocated to either 60 g date fruit or 60 g raisins daily of the equivalent glycemic index (amount split, given as midmorning and midafternoon snack) for 12 weeks. Main Outcome Measures. The primary outcome was to investigate the effect of date fruit on HbA1c and fasting blood glucose, and their variability, in patients with T2D in comparison to the same glycemic load of raisins. The secondary outcomes were to determine whether date fruit affected cardiovascular risk by measuring fasting lipids, C-reactive protein (CRP), blood pressure, and insulin resistance (IR) as measured by Homeostatic Model Assessment (HOMA-IR). Results. In total, 61 (27 female and 34 male) of 79 patients completed the study. There was no difference between or within groups for HbA1c or HbA1c variability, fasting glucose or glucose variability, insulin resistance (HOMA-IR), insulin sensitivity (HOMA-S), beta cell function (HOMA-B), the disposition index, lipids, systolic (SBP) or diastolic blood pressure (DBP), or C-reactive protein (CRP) (p > 0.05). Conclusion. No improvement in glycemic indices was seen following supplementation of 60 g daily date fruit or raisins, though neither had a deleterious effect on glycemic control over a 12-week period, indicating their safety when consumed in T2D. Additionally, no beneficial therapeutic effects of date fruit on other cardiovascular indices in T2D were seen.     

Recent Advances in the Neuroprotective Properties of Ferulic Acid in Alzheimer’s Disease: A Narrative Review

Alzheimer’s disease (AD) is a progressive degenerative disorder of the central nervous system, characterized by neuroinflammation, neurotransmitter deficits, and neurodegeneration, which finally leads to neuronal death. Emerging evidence highlighted that hyperglycemia and brain insulin resistance represent risk factors for AD development, thus suggesting the existence of an additional AD form, associated with glucose metabolism impairment, named type 3 diabetes. Owing to the limited pharmacological options, novel strategies, especially dietary approaches based on the consumption of polyphenols, have been addressed to prevent or, at least, slow down AD progression. Among polyphenols, ferulic acid is a hydroxycinnamic acid derivative, widely distributed in nature, especially in cereal bran and fruits, and known to be endowed with many bioactivities, especially antioxidant, anti-inflammatory and antidiabetic, thus suggesting it could be exploited as a possible novel neuroprotective strategy. Considering the importance of ferulic acid as a bioactive molecule and its widespread distribution in foods and medicinal plants, the aim of the present narrative review is to provide an overview on the existing preclinical and clinical evidence about the neuroprotective properties and mechanisms of action of ferulic acid, also focusing on its ability to modulate glucose homeostasis, in order to support a further therapeutic interest for AD and type 3 diabetes.     

Pterostilbene Fails to Rescue Insulin Secretion and Sensitivity in Multiple Murine Models of Diabetes

Diabetes incidence is rising globally at an accelerating rate causing issues at both the individual and societal levels. However, partly inspired by Ayurvedic medicine, a naturally occurring compound called pterostilbene has been demonstrated to protect against diabetes symptoms, though mainly in rats. The purpose of this study was to investigate the putative protective effect of pterostilbene on the two main aspects of diabetes, namely insulin resistance and decreased insulin secretion, in mice. To accomplish this, we employed diet-induced obese as well as streptozotocin-induced diabetic C57BL/6NTac mice for fasting glucose homeostasis assessment, tolerance tests and pancreas perfusions. In addition, we used the polygenic model of diabetes TALLYHO/JngJ to assess for prevention of β-cell burnout. We found that the diet-induced obese C57BL/6NTac mice were insulin resistant, but that pterostilbene had no impact on this or on overall glucose regulation. We further found that the reported protective effect of pterostilbene against streptozotocin-induced diabetes was absent in C57BL/6NTac mice, despite a promising pilot experiment. Lastly, we observed that pterostilbene does not prevent or delay onset of β-cell burnout in TALLYHO/JngJ mice. In conjunction with the literature, our findings suggest variations in the response to pterostilbene between species or between strains of species.     

CCN1/Integrin α5β1 Instigates Free Fatty Acid-Induced Hepatocyte Lipid Accumulation and Pyroptosis through NLRP3 Inflammasome Activation

Hyperlipidemia with high blood levels of free fatty acids (FFA) is the leading cause of non-alcoholic steatohepatitis. CCN1 is a secreted matricellular protein that drives various cellular functions, including proliferation, migration, and differentiation. However, its role in mediating FFA-induced pro-inflammatory cell death and its underlying molecular mechanisms have not been characterized. In this study, we demonstrated that CCN1 was upregulated in the livers of obese mice. The increase in FFA-induced CCN1 was evaluated in vitro by treating hepatocytes with a combination of oleic acid and palmitic acid (2:1). Gene silencing using specific small interfering RNAs (siRNA) revealed that CCN1 participated in FFA-induced intracellular lipid accumulation, caspase-1 activation, and hepatocyte pyroptosis. Next, we identified integrin α₅β₁ as a potential receptor of CCN1. Co-immunoprecipitation demonstrated that the binding between CCN1 and integrin α₅β₁ increased in hepatocytes upon FFA stimulation in the livers of obese mice. Similarly, the protein levels of integrin α₅ and β₁ were increased in vitro and in vivo. Experiments with specific siRNAs confirmed that integrin α₅β₁ played a part in FFA-induced intracellular lipid accumulation, NLRP3 inflammasome activation, and pyroptosis in hepatocytes. In conclusion, these results provide novel evidence that the CCN1/integrin α₅β₁ is a novel mediator that drives hepatic lipotoxicity via NLRP3-dependent pyroptosis.     

Critical Review for the Production of Antidiabetic Peptides by a Bibliometric Approach

The current bibliometric review evaluated recent papers that researched dietary protein sources to generate antidiabetic bioactive peptides/hydrolysates for the management of diabetes. Scopus and PubMed databases were searched to extract bibliometric data and, after a systematic four-step process was performed to select the articles, 75 papers were included in this review. The countries of origin of the authors who published the most were China (67%); Ireland (59%); and Spain (37%). The journals that published most articles on the subject were Food Chemistry (n = 12); Food & Function (n = 8); and Food Research International (n = 6). The most used keywords were ‘bioactive peptides’ (occurrence 28) and ‘antidiabetic’ (occurrence 10). The most used enzymes were Alcalase^® (17%), Trypsin (17%), Pepsin, and Flavourzyme^® (15% each). It was found that different sources of protein have been used to generate dipeptidyl peptidase IV (DPP-IV), α-amylase, and α-glucosidase inhibitory peptides. In addition to antidiabetic properties, some articles (n = 30) carried out studies on multifunctional bioactive peptides, and the most cited were reported to have antioxidant and antihypertensive activities (n = 19 and 17, respectively). The present review intended to offer bibliometric data on the most recent research on the production of antidiabetic peptides from dietary proteins to those interested in their obtention to act as hypoglycemic functional ingredients. The studies available in this period, compiled, are not yet enough to point out the best strategies for the production of antidiabetic peptides from food proteins and a more systematic effort in this direction is necessary to allow a future scale-up for the production of these possible functional ingredients.     

In Vitro and In Vivo Evaluation of Antidiabetic Properties and Mechanisms of Ficus tikoua Bur.

In folk medicine, Ficus tikoua (F. tikoua) has been used to treat diabetes for a long time, but there is a rare modern pharmacological investigation for its antidiabetic effect and mechanisms. Our study aimed to evaluate its hypoglycemic effect using in vitro and in vivo experimental models and then explore the possible mechanisms. In the ethanol extracts and fractions of F. tikoua, n-butanol fraction (NBF) exhibited the most potent effect on inhibiting α-glucosidase activity (IC₅₀ = 0.89 ± 0.04 μg/mL) and promoting glucose uptake in 3T3-L1 adipocytes. Further animal experiments showed that NBF could play an antidiabetic role by ameliorating random blood glucose, fasting blood glucose, oral glucose tolerance, HbA1c level, and islets damage in diabetic mice. Then, the activities of the five subfractions of NBF (NBF1-NBF5) were further evaluated; NBF2 showed stronger α-glucosidase inhibition activities (IC₅₀ = 0.32 ± 0.05 μg/mL) than NBF. Moreover, NBF2 also possessed the ability to promote glucose uptake, which was mediated via P13K/AKT and AMPK pathways. This study demonstrated that F. tikoua possesses antidiabetic efficacy in vitro and in vivo and provided a scientific basis for its folk medicinal use. NBF2 might be potential natural candidate drugs to treat diabetes mellitus. It is the first time the antidiabetic activity and the potential mechanisms of NBF2 were reported.     

Er:YAG激光-氟化钠联合法与亚甲基蓝-光动力疗法防龋效果及安全性的比较

目的比较Er:YAG激光-氟化钠联合法与亚甲基蓝-光动力疗法(MB-PDT)的防龋效果及安全性。方法建立28只大鼠龋齿模型,随机分成7组:不同功率密度的光动力疗法(PDT)组、激光+氟化钠联合组、激光组、氟化钠组和0.9%生理盐水组。分光光度法检测变异链球菌生长抑制情况;激光荧光诊断仪(LF)检测龋损脱矿程度;组织病理观察牙髓及颊黏膜损伤状况。结果 PDT组与激光+氟化钠联合组光密度值明显低于其他处理组(P<0.05);不同处理方法均可使LF值上升,出现不同程度的脱矿;组织病理学观察,70 mw·cm-2的联合组和Er:YAG激光组存在牙髓及颊黏膜损伤。结论相同参数下,联合组与PDT均有良好的杀菌效果,但PDT不良反应少、损伤小,是一种高效且安全的防龋手段。     

口腔癌合并全身系统性疾病患者的多学科协作诊疗模式专家共识

近年来,随着双向转诊、分级诊疗和医联体的建立,大型综合医院承担急危重症和疑难疾病诊疗的功能定位日益凸显,来诊的口腔癌患者常伴有全身情况复杂的系统性疾病,传统的单一诊疗模式难以达到医疗需求。为此,多学科协作诊疗(MDT)模式应运而生并在实践中应用,取得了良好的临床效果。为了进一步规范口腔癌患者的MDT,组织专家制订了本专家共识,对诊疗流程、常见系统性疾病的诊治等给出了规范化建议,供临床医师参考。     

Expanding the Chemical Space of Drug-like Passerini Compounds: Can α-Acyloxy Carboxamides Be Considered Hard Drugs?

With their three points of diversity, α-acyloxy carboxamides, which are accessible with the Passerini reaction, provide heterogeneity for the preparation of libraries of putative active agents or intermediates used for the formation of more complex structures. If on the one hand the presence of a hydrolyzable ester function has been exploited to design both prodrugs and soft drugs, on the other hand medicinal chemists are reluctant to use this skeleton to prepare hard drugs. Herein we investigated whether the stability of the ester could be controlled, leading to the formation of hydrolytically stable α-acyloxy carboxamides. When the group directly attached to the ester moiety (R³) is an ortho-substituted or ortho,ortho′-disubstituted aromatic ring, α-acyloxy carboxamides are stable. In human liver but not in rodents, due to the different expression of esterases, the ester function is also stable toward hydrolysis when the R¹ group is a bulky substituent regardless of the nature of the R³ substituent.