BACKGROUND:Dietary fats may influence carcinogenesis through pathways involving lipid metabolism, oxidative stress, and inflammation. However, existing evidence from meta-analyses (MAs) remains inconsistent across cancer types. OBJECTIVES:We conducted an umbrella review and updated the MA to evaluate the associations between intakes of total fat, saturated fatty acid (SFA), monounsaturated fatty acid (MUFA), and polyunsaturated fatty acid (PUFA) and the risk of multiple cancers. METHODS:We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library from inception to September 2025 for systematic reviews and MAs of observational or interventional studies assessing dietary fat intake in relation to cancer incidence. Methodological quality was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2), and the certainty of evidence was graded with GRADE. RESULTS:Twenty-three systematic reviews and MAs were included. Higher total fat intake was associated with increased risks of bladder [relative risk (RR): 1.28; 95% confidence interval (CI): 1.04, 1.58)], breast (RR: 1.10; 95% CI: 1.05, 1.16), gastric (RR: 1.18; 95% CI: 1.00, 1.39), and esophageal cancer (RR: 1.31; 95% CI: 1.13, 1.49) and non-Hodgkin lymphoma (RR: 1.26; 95% CI: 1.12, 1.42). SFA intake was associated with higher risks of breast (RR: 1.10; 95% CI: 1.03, 1.17), gastric (RR: 1.31; 95% CI: 1.09, 1.58), liver (RR: 1.34; 95% CI: 1.06, 1.69), and esophageal cancer (RR: 1.88; 95% CI: 1.28, 2.77). MUFA intake was positively associated with esophageal (RR: 1.70; 95% CI: 1.01, 2.84) and breast cancer (RR: 1.08; 95% CI: 1.01, 1.16) but inversely associated with skin cancer (RR: 0.90; 95% CI: 0.85, 0.96). PUFA intake was inversely associated with gastric cancer (RR: 0.77; 95% CI: 0.65, 0.92). CONCLUSIONS:Higher intake of total and saturated fats was associated with increased risks of several site-specific cancers, whereas polyunsaturated fats may have protective effects. This trial was registered at PROSPERO CRD420251236506.

Anesthetics have been reported to promote Alzheimer’s disease neuropathogenesis by inducing amyloid beta (Aβ) protein accumulation and apoptosis. The aim of this study was to evaluate the effect of propofol on the apoptosis, Aβ accumulation, and inflammation induced by sevoflurane in human neuroglioma cells. Human neuroglioma cells were treated with or without sevoflurane and then co-incubated with or without propofol. Cell apoptosis was evaluated by fluorescence-activated cell sorting analysis (FACS) using AV-PI kits, and data showed that apoptosis induced by sevoflurane was significantly attenuated by propofol treatment. In addition, with the reactive oxygen species (ROS) production measured by FACS after staining with dichloro-dihydrofluorescein diacetate, propofol could significantly reduce the production of ROS as well as the accumulation of Aβ induced by sevoflurane assessed by enzyme-linked immuno sorbent assay (ELISA) analysis. On the other hand, the same treatment decreased the inflammation factor production of interleukin-6. Moreover, the level of nuclear factor-kappa B (NF-κB) was tested by Western blot and immunofluorescence assay. We found that the activation of NF-κB pathway was suppressed by propofol. The results suggest that propofol can effectively attenuate the apoptosis, Aβ accumulation, and inflammation induced by sevoflurane in human neuroglioma cells through NF-κB signal pathway.

Discovering new treatments for melanoma will benefit human health. The mechanism by which deoxyhypusine synthase (DHPS) promotes melanoma development remains elucidated. Multi-omics studies have revealed that DHPS regulates m6A modification and maintains mRNA stability in melanoma cells. Mechanistically, DHPS activates the hypusination of eukaryotic translation initiation factor 5A (eIF5A) to assist METTL3 localizing on its mRNA for m6A modification, then promoting METTL3 expression. Structure-based design, synthesis, and activity screening yielded the hit compound GL-1 as a DHPS inhibitor. Notably, GL-1 directly inhibits DHPS binding to eIF5A, whereas GC-7 cannot. Based on the clarification of the mode of action of GL-1 on DHPS, it is found that GL-1 can promote the accumulation of intracellular Cu2+ to induce apoptosis, and antibody microarray analysis shows that GL-1 inhibits the expression of several cytokines. GL-1 shows promising antitumor activity with good bioavailability in a xenograft tumor model. These findings clarify the molecular mechanisms by which DHPS regulates melanoma proliferation and demonstrate the potential of GL-1 for clinical melanoma therapy.

Biosimilars are a rapidly growing area of clinical research, yet they encounter significant challenges, especially in emerging markets where regulatory and clinical hurdles differ markedly from those in established regions like Europe and the US. This commentary addresses these unique challenges and offers new perspectives on the global adoption of biosimilars. It emphasizes the crucial role of real world evidence in supporting biosimilar approvals, an aspect often underrepresented in current literature. The commentary also provides a comparative analysis of the regulatory frameworks in China and Europe, highlighting how these differences shape biosimilar development and market approval processes. By focusing on the issues of indication extrapolation and immunogenicity, this commentary highlights the necessity of continuous real-world data collection to ensure the safety and efficacy of biosimilars across multiple indications. Our analysis enhances the understanding of biosimilar research and supports their broader adoption as safe, effective, and accessible healthcare solutions globally.

Background Hepatocellular carcinoma (HCC) is an aggressive malignancy and a growing global health problem. Reserpine (Res), a plant-derived hypertension drug, has been reported to possess anti-tumor efficacy. However, the role and function of Res in N6-methyladenosine (m6A) regulation and Lenvatinib (Len) resistance in HCC have not been clarified. Purpose To verify whether Res can be used as a natural small-molecule regulator of m6A to reverse Len resistance in HCC. Methods Dot blotting, Western blotting and m6A quantification were used to compare and analyze the differential expression of m6A and its methyltransferase METTL3. Western blotting, Real-Time PCR (RT-PCR), cellular thermal shift assay (CETSA) and molecular docking were used to explore the mechanism of interaction between Res and m6A. The effects of Res on the biological characteristics of Lenvatinib-resistant HCC cells were investigated through CCK-8, clone formation, and Transwell assays. Cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models were used to assess the ability of Res to reverse Len resistance in vivo. MeRIP m6A sequencing, PATHWAY analysis and Western blotting were used to analyze the downstream signaling pathways and genes involved in Res-mediated reversal of Len resistance. Results Len resistance in HCC is related to the increased m6A level and the high expression of METTL3. Res affects the activity of METTL3 protein by binding to it, thereby downregulating the level of m6A. In vitro study showed that Res can sensitize HCC cells to the anti-tumor effects of Len treatment, including blocking proliferation, inhibiting migration, and inducing apoptosis. Len-resistant CDX and PDX models revealed that Res can reverse the resistant phenotype, with the tumor inhibition rates of 77.46% and 62.1%, respectively, when combined with Len treatment. Analysis of xenograft tissues showed that the combination of Res and Len down-regulates the m6A level, reduces proliferation biomarkers, and induces apoptosis, which is consistent with the in vitro data. Mechanistically, our preliminary results indicate that Res can up-regulate the SMAD3 level by down-regulating m6A in Len-resistant cells. Conclusions Reserpine, a small-molecule regulator of m6A, reverses Lenvatinib-resistant phenotypes, including proliferation, migration and anti-apoptosis, in vitro and in vivo by targeting SMAD3 and down-regulating the m6A level in HCC.

BACKGROUND:Melanoma, a highly malignant skin tumor, can develop systemic metastases during the early stage. Several studies of melanoma animal models indicate that curcumin, a natural plant extract, inhibits melanoma growth through various mechanisms. To evaluate the relationships among different experimental conditions, curcumin itself, its derivatives, and special formulations, it is necessary to conduct a systematic review and meta-analysis. PURPOSE:This meta-analysis aims to evaluate the potential of Curcumin as a drug for inhibiting the growth of melanoma and to determine the optimal dosage range and treatment duration for Curcumin administration. METHODS:A systematic search of studies published from inception to December 2023 was conducted across six databases (PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Data, and VIP). Methodological quality was assessed using SYRCLE's RoB tool. Study heterogeneity was assessed using Cochran's Q test and I2 statistics. Publication bias risk was evaluated using a funnel plot. All analyses were performed using R (version 4.3.3). Additionally, three-dimensional effect analysis and machine learning techniques were utilized to determine the optimal dosage range and treatment duration for Curcumin administration. RESULTS:Forty studies involving 989 animals were included. The results demonstrated that, relative to the control group, administration of Curcumin resulted in a significant reduction in tumor volume. [SMD=-3.44; 95 % CI (-4.25, -2.63); P<0.01; I2 = 79 %] and tumor weight [SMD=-1.93; 95 % CI (-2.41, -1.45); P<0.01; I2 = 75 %]. Additionally, Curcumin demonstrated a significant capacity to decrease the number of lung tumor nodules and microangiogenesis, as well as to extend survival time, in animal models. The results from three-dimensional effect analysis and machine learning emphasize that the optimal dosage range for Curcumin is 25-50 mg/kg, with an intervention duration of 10-20 days. CONCLUSION:Curcumin can inhibit the growth of melanoma, and the dose-response relationship is not linear. However, further large-scale animal and clinical studies are required to confirm these conclusions.

β-内酰胺酶抑制剂后效应这一概念于1992年由Thorburn CE等学者首次提出,是指产酶细菌与β-内酰胺类抗菌药物/β-内酰胺酶抑制剂复方制剂接触一定的时间,只去除β-内酰胺酶抑制剂后,产酶细菌生长受到持续抑制的效应.这一效应为半衰期相差较大的β-内酰胺类抗菌药物与β-内酰胺酶抑制剂组成复方制剂的合理性提供了依据,为新药的开发提供了思路.该文综合了国内外相关研究文献,通过测定实验组和对照组细菌增长1个log10单位所需时间差值来确定β-内酰胺酶抑制剂后效应测定方法,对β-内酰胺酶抑制剂后效应可能的产生机制加以阐述,并讨论了细菌类型及产酶特点、β-内酰胺类抗菌药物及β-内酰胺酶抑制剂种类、抗菌药物浓度等影响因素以及已上市复方制剂的β-内酰胺酶抑制剂后效应研究结果,为后续研究提供参考.

ObjectiveAccurate biomarkers for evaluating mortality rates in patients with chronic obstructive pulmonary disease (COPD) remain scarce. This study aimed to explore the relationships between mortality rates in patients with COPD and blood eosinophil counts, neutrophil counts, and lymphocyte counts, along with the neutrophil–to–lymphocyte ratio (NLR). Additionally, we sought to identify the optimal response values for these biomarkers when utilizing inhaled corticosteroids (ICS).MethodsUtilizing a nationally representative, multistage cross–sectional design and mortality correlation study, we analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999–2018 involving US adults aged 40 years or older with COPD. The primary endpoint was all–cause mortality, with Kaplan–Meier survival curves and restricted cubic splines applied to illustrate the relationship between leukocyte–based inflammatory markers and mortality. The analysis was conducted in 2023.ResultsOur analysis included 1,715 COPD participants, representing 6,976,232 non–institutionalized US residents [weighted mean age (SE), 62.09 (0.28) years; range, 40–85 years]. Among the participants, men constituted 50.8% of the population, and the weighted mean follow–up duration was 84.9 months. In the ICS use group, the weighted proportion of participants over 70 years old was significantly higher compared with the non–ICS use group (31.39% vs 25.52%, p < 0.0001). The adjusted hazard ratios for all–cause mortality related to neutrophil counts, lymphocyte counts, and NLR were 1.10 [95% confidence interval (CI), 1.04–1.16, p < 0.001], 0.83 (95% CI, 0.71–0.98; p = 0.03), and 1.10 (95% CI, 1.05–1.15; p < 0.0001), respectively. Optimal ICS response was linked with higher levels of eosinophil count (≥240 cells/μL), neutrophil count (≥3,800 cells/μL), NLR (≥4.79), and lower levels of lymphocyte count (<2,400 cells/μL).ConclusionAdjusted baseline neutrophil, lymphocyte counts, and NLR serve as independent risk factors for all–cause mortality in patients with COPD. Further, ICS application appears to mitigate mortality risk, particularly when NLR levels reach 4.79 or higher, underlining the importance of ICS in COPD management.Graphical abstractInhaled Corticosteroid Use in COPD: A Comparative Analysis of Leukocyte-based Inflammatory Markers and Mortality Outcomes Based on NHANES Data (1999-2018).

Oxycodone is a highly prescribed opioid and its abuse has been rampant. Accumulating evidence shows that the cannabinoid CB1 receptor (CB1R) plays a key role in mediating rewarding effects to opioids. However, the downstream signalling of CB1R induced by oxycodone remains unclear. The neuropeptide oxytocin is well known as a potential remedy for drug addiction. Thus, our study aims to explore the mechanism of oxycodone-induced learning and memory deficits underlying the endocannabinoid system (ECS) and the effect of oxytocin. Rats were intraperitoneally injected with oxycodone once a day for eight consecutive day. Novel object recognition, resident-intruder and Morris Water Maze tests were employed to assess the cognitive, social and spatial memory of the rats after oxycodone withdrawal. The (co-)expression of CB1R, cyclin-dependent kinase 5 (Cdk5), regulatory protein p25, tau and phosphorylated tau was measured 1 day after the last behavioural test. The histopathological staining and synaptic density in the hippocampus were observed as well. We found that oxycodone upregulated the expression of p-GSK3β, co-expression of p-Cdk5 and p25 through CB1R. This finding was accompanied by elevation of pSer396, pSer404 in the tau, and reduction of the number of neurons, dendritic spines and synaptic density in the hippocampus. Furthermore, i.c.v. treatment with oxytocin ameliorates memory deficits in oxycodone-treated rats through inhibition of the ECS. We propose further studies on the clinical use of this neuropeptide, which may potentially cure drug addiction.

Anti-seizure medications (ASMs) are the main therapy for epilepsy.There are many kinds of ASMs with complex mechanism of action, so it is difficult for pharmacists to examine prescriptions.This paper put forward some suggestions on the indications, dosage forms/routes of administration, appropriateness of usage and dosage, combined medication and drug interaction, long-term prescription review, individual differences in pathophysiology of children, and drug selection when complicated with common epilepsy, for the reference of doctors and pharmacists.

目的 构建我国药品临床综合评价指标体系与量化分级,为科学开展药品临床综合评价提供参考依据.方法 应用层次分析模型建立药品临床综合评价指标体系,通过对专家咨询和模型运算确定评价指标的权重与各指标的量化分级.结果 应用层次分析模型对专家咨询结果进行整合,得到了包括有效性、安全性、经济性、适宜性、可及性和创新性6个一级指标及指南推荐地位、特殊人群用药、药品疗程费用等23个二级指标的药品临床综合评价指标体系,并通过判断矩阵法确定了各级指标的权重.结论 本研究应用层次分析模型构建了我国药品临床综合评价指标体系与量化分级,可为综合分析决策提供方法参考,从而使药品临床综合评价更完整、科学.

《医疗机构制剂管理标准》规范了医疗机构制剂管理工作中的基本条件、生产过程、质量管理与持续改进等要素.该标准内容借鉴《药品生产质量管理规范》(GMP)要求,兼顾各级各类医疗机构,覆盖医疗机构制剂管理的全流程.标准由中国医院协会药事专业委员会牵头编制,编制方法及流程包括问题梳理、框架建立、初稿撰写、意见征集、专家论证审议和标准形成等.该文阐述《医疗机构制剂管理标准》制订过程,并对该标准内容进行解析,以期为医疗机构制剂管理标准化、同质化提供指导.

Cerebral ischemia/reperfusion injury impairs learning and memory in patients. Studies have shown that synaptic function is involved in the formation and development of memory, and that DNA methylation plays a key role in the regulation of learning and memory. To investigate the role of DNA hypomethylation in cerebral ischemia/reperfusion injury, in this study, we established a rat model of cerebral ischemia/reperfusion injury by occlusion of the middle cerebral artery and then treated the rats with intraperitoneal 5-aza-2′-deoxycytidine, an inhibitor of DNA methylation. Our results showed that 5-aza-2′-deoxycytidine markedly improved the neurological function, and cognitive, social and spatial memory abilities, and dose-dependently increased the synaptic density and the expression of SYP and SHANK2 proteins in the hippocampus in a dose-dependent manner in rats with cerebral ischemia/reperfusion injury. The effects of 5-aza-2′-deoxycytidine were closely related to its reduction of genomic DNA methylation and DNA methylation at specific sites of the Syp and Shank2 genes in rats with cerebral ischemia/reperfusion injury. These findings suggest that inhibition of DNA methylation by 5-aza-2′-deoxycytidine promotes the recovery of learning and memory impairment in a rat model of cerebral ischemia/reperfusion injury. These results provide theoretical evidence for stroke treatment using epigenetic methods.

The discovery of new therapeutic strategies for diseases is essential for drug research. Deoxyhypusine synthase (DHPS) is a critical enzyme that modifies the conversion of the eukaryotic translation initiation factor 5A (eIF5A) precursor into physiologically active eIF5A (eIF5A-Hyp). Recent studies have revealed that the hypusine modifying of DHPS on eIF5A has an essential regulatory role in human diseases. The hypusination-induced DHPS/eIF5A pathway has been shown to play an essential role in various cancers, and it could regulate immune-related diseases, glucose metabolism-related diseases, neurological-related diseases, and aging. In addition, DHPS has a more defined substrate and a well-defined structure within the active pocket than eIF5A. More and more researchers are focusing on the prospect of advanced development of DHPS inhibitors. This review summarizes the regulatory mechanisms of the hypusination-induced DHPS/eIF5A pathway in a variety of diseases in addition to the inhibitors related to this pathway; it highlights and analyzes the structural features and mechanisms of action of DHPS inhibitors and expands the prospects of future drug development using DHPS as an anticancer target.

目的:调查终末期肾病患者万古霉素用药及治疗药物监测数据,为规范此类特殊人群万古霉素合理用药提供数据支持.方法:回顾性分析2014年4月至2021年2月中国医科大学附属盛京医院终末期肾病患者万古霉素治疗药物监测病例,调查患者基本情况、肾脏替代治疗、万古霉素用药及治疗药物监测,分析不同肾脏替代治疗万古霉素用药及治疗药物监测状况.结果:纳入患者51例,32例(62.7％)采用血液透析,腹膜透析13例(25.5％),连续肾脏替代治疗6例(11.8％).所有患者均采用固定剂量的给药模式,均未给予负荷剂量,给药频次和给药时机存在差异.监测时机合理率仅27.5％,49.1％患者住院期间仅监测1次.血液透析初次监测时机把控较为严格,腹膜透析及连续肾脏替代治疗监测时机随意性较大.所有51例患者共进行监测101例次,其中93例次为谷浓度,谷浓度＜10 mg·L-1为31例(33.3％),10～20 mg·L-1为40 例(43.0％),＞20 mg·L-1为22例(23.7％).依据监测结果,用药剂量或频次调整比例分别为23.9％,20.0％,45.5％.万古霉素谷浓度达标率由27.5％升至96.1％.结论:终末期肾病万古霉素用药应采取标准的负荷剂量和个体化维持剂量,配合治疗药物监测可提高治疗达标率.

我国药品临床综合评价工作目前还存在诸如评价内容设计不科学、评价方法和组织流程欠规范、评价结果无法满足决策需求等问题,亟须对药品临床综合评价项目的全过程进行质量控制.本文从技术角度出发,从评价内容与设计(给出主题遴选流程和方案设计的质量控制要点)、评价方法(探讨2种常用评价方法——文献证据法和真实世界研究的质量控制要素)、结果应用转化(从评价结果综合分析、评价结果转化与决策两方面给出质量控制的建议)3个环节探讨药品临床综合评价的质量控制方法,拟促进该项工作的质量提升.

In our previous study, compound L1-8m has an excellent ability to inhibit melanoma as DHPS inhibitor and deserves further optimization to obtain drugs for the treatment of melanoma. Hence, a new series of compounds was synthesized, and their potency was tested by DHPS enzyme activity assay and cell viability assay. Most compounds were superior than positive compound GC-7. Then, the hit compound 7k was conducted with further docking and MD simulations to verify its potential interactions with the residues of DHPS. Human tissue microarray and zebrafish melanin formation were used to experimentally clarify the specific expression of DHPS in melanoma. Besides, western blot analysis and cell invasion assay confirmed the ability of anti-melanoma of 7k, 7k effectively inhibited the expression of eIF5A2, GP-100, tyrosinase, and MC1R in melanoma cells. In vivo, the tumor xenograft model also verified the anti-melanoma ability of 7k, and the TGI of 7k was significantly enhanced to 72%, superior than that of L1-8m (the compound with the best activity in our previous work).

H 1-antihistamines are widely used in the treatment of various allergic diseases, but there are still many challenges in the safe and rational use of H 1-antihistamines in pediatrics, and there is a lack of guidance on the prescription review of H 1-antihistamines for children.In this paper, suggestions are put forward from the indications, dosage, route of administration, pathophysiological characteristics of children with individual difference and drug interactions, so as to provide reference for clinicians and pharmacists.

The intramuscular administration of long-acting injectable microparticles elicits a local macrophage uptake resulting in decreased bioavailability. Herein, we developed a ginkgolide B (GB) loaded Solid/Oil/Water (S/O/W) solid lipid microparticles (SLMs) which were modified by hydroxyethyl starch (HES) or poly(ethylene glycol) (PEG) with different surface densities to investigate the influence of surface properties on the cellular uptake and systemic drug exposure. The spherical SLMs with a mean particle size of 10 µm were prepared by melt emulsification and post-insertion method, showing controlled release profile with less than 10 % of GB released in first 2 h. HES-SLMs resulted in lowest degree of RAW264.7 macrophage uptake in vitro and a higher systemic drug exposure in rats than PEG coating SLMs, indicting the capability of thick HES layer of SLMs in evading cellular uptake and sustained GB release. Overall, HES modified SLMs possess a great potential as intramuscular injected drug delivery system to improved bioavailability.

铜绿假单胞菌是医院获得性感染的重要条件致病菌,具有易定植、易变异和多耐药的特点.下呼吸道因生理结构特殊而成为多重耐药铜绿假单胞菌感染的频发部位,往往难以治疗,导致医疗费用乃至院内死亡率增加.本文汇总了国内外细菌监测计划数据,分析近5年铜绿假单胞菌的检出率及耐药变化情况.在此基础上,分别归纳院内肺炎治疗指南和专家共识的用药建议、治疗研究进展和未来发展趋势,为临床制定抗感染决策以及今后抗菌治疗探索方向提供有价值的参考.