Biomedicine & Pharmacotherapy最新文献_第4页

RNA splicing dysregulation in hepatocellular carcinoma: Molecular mechanisms, therapeutic targets, and intervention strategies—A comprehensive review 肝细胞癌中RNA剪接失调：分子机制、治疗靶点和干预策略综述

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-21 DOI: 10.1016/j.biopha.2026.119025

Shuai Xiong , Lei Hu , Yun-Yang Sun , Wei Huang , Xiao-Yu Hu

Alternative splicing (AS) is a fundamental biological process that expands genomic diversity and finely regulates cellular functions through the generation of multiple mRNA isoforms from a single gene. Its dysregulation has been strongly implicated in the pathogenesis of hepatocellular carcinoma (HCC). This review expounds on the pivotal role of aberrant AS events in driving HCC initiation and progression, highlighting how etiological factors, including metabolic dysfunction-associated steatotic liver disease (MASLD) and viral hepatitis, disrupt normal splicing mechanisms, thereby promoting carcinogenesis. Although AS contributes significantly to key malignant features of HCC, such as metabolic reprogramming, enhanced invasion, metastasis, and drug resistance, a systematic understanding of these mechanisms remains incomplete. In this review, we comprehensively explore the regulatory networks mediated by AS in HCC, identify promising therapeutic targets, and elucidate their functional crosstalk during multistep hepatocarcinogenesis. Furthermore, recent advances in pharmacological strategies are summarized, including small-molecule inhibitors and antisense oligonucleotides (ASOs) that target AS, followed by a discussion of persistent challenges along with future research directions. By synthesizing current evidence, this review establishes a robust theoretical foundation and provides innovative perspectives for the development of AS-based precision therapeutics against HCC.

选择性剪接（AS）是一个基本的生物学过程，它通过从一个基因产生多个mRNA亚型来扩大基因组多样性和精细调节细胞功能。它的失调与肝细胞癌（HCC）的发病机制密切相关。本文阐述了异常AS事件在驱动HCC发生和发展中的关键作用，强调了包括代谢功能障碍相关脂肪变性肝病（MASLD）和病毒性肝炎在内的病因因素如何破坏正常剪接机制，从而促进癌变。尽管AS对HCC的关键恶性特征有重要作用，如代谢重编程、侵袭、转移增强和耐药性，但对这些机制的系统理解仍不完整。在这篇综述中，我们全面探讨了AS在HCC中的调节网络，确定了有希望的治疗靶点，并阐明了它们在多步骤肝癌发生过程中的功能串扰。此外，本文还总结了近年来针对AS的药物策略的进展，包括小分子抑制剂和反义寡核苷酸（ASOs），随后讨论了持续的挑战以及未来的研究方向。通过综合目前的证据，本综述建立了坚实的理论基础，并为基于as的HCC精确治疗的发展提供了创新的视角。

{"title":"RNA splicing dysregulation in hepatocellular carcinoma: Molecular mechanisms, therapeutic targets, and intervention strategies—A comprehensive review","authors":"Shuai Xiong , Lei Hu , Yun-Yang Sun , Wei Huang , Xiao-Yu Hu","doi":"10.1016/j.biopha.2026.119025","DOIUrl":"10.1016/j.biopha.2026.119025","url":null,"abstract":"<div><div>Alternative splicing (AS) is a fundamental biological process that expands genomic diversity and finely regulates cellular functions through the generation of multiple mRNA isoforms from a single gene. Its dysregulation has been strongly implicated in the pathogenesis of hepatocellular carcinoma (HCC). This review expounds on the pivotal role of aberrant AS events in driving HCC initiation and progression, highlighting how etiological factors, including metabolic dysfunction-associated steatotic liver disease (MASLD) and viral hepatitis, disrupt normal splicing mechanisms, thereby promoting carcinogenesis. Although AS contributes significantly to key malignant features of HCC, such as metabolic reprogramming, enhanced invasion, metastasis, and drug resistance, a systematic understanding of these mechanisms remains incomplete. In this review, we comprehensively explore the regulatory networks mediated by AS in HCC, identify promising therapeutic targets, and elucidate their functional crosstalk during multistep hepatocarcinogenesis. Furthermore, recent advances in pharmacological strategies are summarized, including small-molecule inhibitors and antisense oligonucleotides (ASOs) that target AS, followed by a discussion of persistent challenges along with future research directions. By synthesizing current evidence, this review establishes a robust theoretical foundation and provides innovative perspectives for the development of AS-based precision therapeutics against HCC.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119025"},"PeriodicalIF":7.5,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacological inhibition of myosin reduces the cytotoxic effect of a Lys49 PLA2-like myotoxin on human and rat cardiac muscle 肌球蛋白的药理抑制降低了Lys49 pla2样肌毒素对人和大鼠心肌的细胞毒性作用。

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-20 DOI: 10.1016/j.biopha.2026.119017

Wilson Agyapong , Natalie Weber , Florian J.G. Waleczek , Konstantin Neumann , Susanne Neumüller , Marlen Möllmann , Lara Thieße , Theresia Kraft , Arjang Ruhparwar , Julián Fernández , José María Gutiérrez , Bruno Lomonte , Thomas Thum , Alfredo Jesús López-Dávila

Viperid snake venoms contain a group of cytotoxic proteins called Lys49 phospholipase A₂ (PLA₂)-like myotoxins. These proteins lack enzymatic activity, but can still disrupt the sarcolemma and induce cell death. On skeletal and cardiac muscle, PLA₂-like myotoxins induce substantial alterations to the sequence of events in the excitation-contraction coupling, including increased Ca²⁺ influx and consequent hypercontraction. This study aimed to quantify the increase in force development induced by a Lys49 PLA₂-like myotoxin and to assess whether this effect contributes to the overall cytotoxicity induced by the toxin. Force transients generated by mechanically loaded living myocardial slices (LMS) obtained from rat and human hearts were characterized in response to Mt-II, a well-described Lys49 PLA₂-like myotoxin found in the venom of the viperid snake Bothrops asper. Over a 24-hour period, Mt-II initially increased the amplitude of the force transients, which was then replaced by a permanent increase in baseline force. This dual effect may be attributed to progressive sarcolemmal disruption, which initially induces an increase in force development as a consequence of an influx of Ca²⁺. However, at advanced stages of cell damage, this renders the calcium extrusion mechanisms ineffective. The amplitude of the force transients and the baseline force observed during Mt-II exposure were several times greater than the amplitude of the force transients observed before Mt-II exposure. Inhibiting force development by a myosin inhibitor in the presence of Mt-II significantly reduced the release of cytosolic enzymes LDH and CK-MB from the LMS preparations. Therefore, mechanical stress resulting from Ca²⁺ influx and hypercontraction exacerbates Mt-II-induced striated muscle damage.

毒蛇毒液含有一组细胞毒性蛋白，称为Lys49磷脂酶A2 （PLA2）样肌毒素。这些蛋白缺乏酶活性，但仍能破坏肌膜并诱导细胞死亡。在骨骼肌和心肌上，pla2样肌毒素诱导兴奋-收缩耦合事件序列发生实质性改变，包括ca2 +内流增加和随之而来的过度收缩。本研究旨在量化Lys49 pla2样肌毒素诱导的力量发育的增加，并评估这种效应是否有助于毒素诱导的整体细胞毒性。从大鼠和人类心脏中获得的机械负载活心肌切片（LMS）产生的力瞬变对Mt-II的响应进行了表征，Mt-II是一种在蝮蛇Bothrops asper毒液中发现的一种描述良好的Lys49 pla2样肌毒素。在24小时内，Mt-II最初增加了力瞬态的振幅，然后被基线力的永久增加所取代。这种双重效应可能归因于渐进式肌层破坏，由于Ca 2 +的流入，肌层破坏最初导致了力发展的增加。然而，在细胞损伤的晚期，这使得钙挤出机制失效。Mt-II暴露期间观察到的力瞬态振幅和基线力比Mt-II暴露前观察到的力瞬态振幅大几倍。在Mt-II存在的情况下，肌球蛋白抑制剂抑制力的发展显著减少了LMS制剂中胞质酶LDH和CK-MB的释放。因此，Ca 2 +内流和过度收缩引起的机械应力加剧了mt - ii诱导的横纹肌损伤。

{"title":"Pharmacological inhibition of myosin reduces the cytotoxic effect of a Lys49 PLA2-like myotoxin on human and rat cardiac muscle","authors":"Wilson Agyapong , Natalie Weber , Florian J.G. Waleczek , Konstantin Neumann , Susanne Neumüller , Marlen Möllmann , Lara Thieße , Theresia Kraft , Arjang Ruhparwar , Julián Fernández , José María Gutiérrez , Bruno Lomonte , Thomas Thum , Alfredo Jesús López-Dávila","doi":"10.1016/j.biopha.2026.119017","DOIUrl":"10.1016/j.biopha.2026.119017","url":null,"abstract":"<div><div>Viperid snake venoms contain a group of cytotoxic proteins called Lys49 phospholipase A<sub>2</sub> (PLA<sub>2</sub>)-like myotoxins. These proteins lack enzymatic activity, but can still disrupt the sarcolemma and induce cell death. On skeletal and cardiac muscle, PLA<sub>2</sub>-like myotoxins induce substantial alterations to the sequence of events in the excitation-contraction coupling, including increased Ca²⁺ influx and consequent hypercontraction. This study aimed to quantify the increase in force development induced by a Lys49 PLA<sub>2</sub>-like myotoxin and to assess whether this effect contributes to the overall cytotoxicity induced by the toxin. Force transients generated by mechanically loaded living myocardial slices (LMS) obtained from rat and human hearts were characterized in response to Mt-II, a well-described Lys49 PLA<sub>2</sub>-like myotoxin found in the venom of the viperid snake <em>Bothrops asper</em>. Over a 24-hour period, Mt-II initially increased the amplitude of the force transients, which was then replaced by a permanent increase in baseline force. This dual effect may be attributed to progressive sarcolemmal disruption, which initially induces an increase in force development as a consequence of an influx of Ca²⁺. However, at advanced stages of cell damage, this renders the calcium extrusion mechanisms ineffective. The amplitude of the force transients and the baseline force observed during Mt-II exposure were several times greater than the amplitude of the force transients observed before Mt-II exposure. Inhibiting force development by a myosin inhibitor in the presence of Mt-II significantly reduced the release of cytosolic enzymes LDH and CK-MB from the LMS preparations. Therefore, mechanical stress resulting from Ca²⁺ influx and hypercontraction exacerbates Mt-II-induced striated muscle damage.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119017"},"PeriodicalIF":7.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Plasma metabolomic profiling of patients with acute coronary syndrome treated with potent platelet inhibitors 强效血小板抑制剂治疗急性冠状动脉综合征患者的血浆代谢组学分析

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-20 DOI: 10.1016/j.biopha.2026.119013

Jovan Rogozarski , Gloria M. Steiner-Gager , Karin Preindl , Zofia Wicik , Ceren Eyileten , Christof Skos , Christopher Gerner , Almedina Dizdarevic , Marek Postula , Samuel M. Meier-Menches , Jolanta M. Siller-Matula

Ticagrelor and prasugrel are key antiplatelet agents used in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Beyond their antiplatelet effects, both drugs exhibit pleiotropic actions that may contribute to side effects. Notably, ticagrelor has been associated with dyspnea in clinical trials. This study aimed to identify metabolomic markers linked to the effects of ticagrelor and prasugrel using targeted metabolomics. Plasma samples from 207 ACS patients treated with either prasugrel (n = 106) or ticagrelor (n = 101) were analyzed for up to 631 metabolites. Several metabolites differed significantly between the groups (p < 0.05). The most notable changes were found in DHEAS (p = 0.0004, FC = −1.66) and 3-Met-His (p = 0.0024, FC = 1.75). After adjusting for risk factors, lysoPC a C17:0, 3-Met-His, and DHEAS remained significantly altered. Subgroup analysis revealed that diabetic patients had distinct metabolic profiles, including elevated TMAO and choline and reduced GUDCA levels, compared to non-diabetics. Additional changes were observed in hexoses, Met-SO, and TCDCA. The findings support a novel hypothesis that ticagrelor-induced dyspnea may be linked to low DHEAS levels. Reduced methionine and Met-SO levels could suggest lower oxidative stress. Moreover, diabetic patients showed a gut microbiome-related metabolic shift associated with a more ischemic profile.

替格瑞洛和普拉格雷是急性冠脉综合征（ACS）患者经皮冠状动脉介入治疗（PCI）的关键抗血小板药物。除了抗血小板作用外，这两种药物都表现出可能导致副作用的多效性作用。值得注意的是，替格瑞洛在临床试验中与呼吸困难有关。本研究旨在利用靶向代谢组学技术鉴定与替格瑞洛和普拉格雷作用相关的代谢组学标志物。207名接受普拉格雷（n = 106）或替格瑞洛（n = 101）治疗的ACS患者的血浆样本进行了多达631种代谢物的分析。几种代谢物在两组间差异显著(p

{"title":"Plasma metabolomic profiling of patients with acute coronary syndrome treated with potent platelet inhibitors","authors":"Jovan Rogozarski , Gloria M. Steiner-Gager , Karin Preindl , Zofia Wicik , Ceren Eyileten , Christof Skos , Christopher Gerner , Almedina Dizdarevic , Marek Postula , Samuel M. Meier-Menches , Jolanta M. Siller-Matula","doi":"10.1016/j.biopha.2026.119013","DOIUrl":"10.1016/j.biopha.2026.119013","url":null,"abstract":"<div><div>Ticagrelor and prasugrel are key antiplatelet agents used in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Beyond their antiplatelet effects, both drugs exhibit pleiotropic actions that may contribute to side effects. Notably, ticagrelor has been associated with dyspnea in clinical trials. This study aimed to identify metabolomic markers linked to the effects of ticagrelor and prasugrel using targeted metabolomics. Plasma samples from 207 ACS patients treated with either prasugrel (n = 106) or ticagrelor (n = 101) were analyzed for up to 631 metabolites. Several metabolites differed significantly between the groups (p < 0.05). The most notable changes were found in DHEAS (p = 0.0004, FC = −1.66) and 3-Met-His (p = 0.0024, FC = 1.75). After adjusting for risk factors, lysoPC a C17:0, 3-Met-His, and DHEAS remained significantly altered. Subgroup analysis revealed that diabetic patients had distinct metabolic profiles, including elevated TMAO and choline and reduced GUDCA levels, compared to non-diabetics. Additional changes were observed in hexoses, Met-SO, and TCDCA. The findings support a novel hypothesis that ticagrelor-induced dyspnea may be linked to low DHEAS levels. Reduced methionine and Met-SO levels could suggest lower oxidative stress. Moreover, diabetic patients showed a gut microbiome-related metabolic shift associated with a more ischemic profile.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119013"},"PeriodicalIF":7.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CXCR2 antagonism as a promising therapeutic approach for pulmonary fibrosis therapy CXCR2拮抗剂作为肺纤维化治疗的一种有前景的治疗方法

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-20 DOI: 10.1016/j.biopha.2026.118998

Eliza Mathias Melo , Filipe Resende , Fernando Roque Ascenção , Celso Martins Queiroz-Junior , Mario Amatruda , Mara Tomassetti , Laura Brandolini , Gianluca Bianchini , Andrea Aramini , Frederico Marianetti Soriani , Rafael Cypriano Dutra , Mauro Martins Teixeira

Pulmonary inflammation is a central feature of several chronic lung diseases. The chemokine receptor CXCR2 plays a key role in regulating recruitment and activation of leukocytes and other cell types involved in acute and chronic inflammation of the lungs. In this study, we evaluated and compared the anti-inflammatory effects of four CXCR2 antagonists - DF2755A, AZD-5069, SX-682, and SCH527123 - in a murine model of bleomycin-induced lung injury. C57BL/6 mice received intranasal bleomycin and were treated once a day with known active doses of the antagonists by oral gavage. Following disease induction through bleomycin inoculation on day 0, animals were either treated at days 0–2 and then evaluated at day 2 (focus on the early inflammatory response) or treated from days 0–16 (preventive schedule) or from days 8–16 (therapeutic schedule) and then evaluated at day 16 (focus on fibrosis). We assessed inflammatory responses in bronchoalveolar lavage fluid (BALF) and lung tissue by analyzing total and differential leukocyte counts, cytokine levels, myeloperoxidase (MPO) activity, BALF protein content, and lung histopathology. All compounds displayed anti-inflammatory effects (day 2), with DF2755A and AZD-5069 standing out for their greater efficacy in reducing early neutrophils influx. Importantly, DF2755A and SX-682 were particularly effective in mitigating fibrosis and chronic inflammatory changes when administered in both preventive and therapeutic schedules, even at later stages of disease progression. These findings underscore the potential of CXCR2 antagonism, especially with DF2755A, as a promising strategy to limit inflammation and fibrosis in experimental lung injury.

肺部炎症是几种慢性肺部疾病的中心特征。趋化因子受体CXCR2在调节急性和慢性肺部炎症中涉及的白细胞和其他细胞类型的募集和激活中起关键作用。在这项研究中，我们评估并比较了四种CXCR2拮抗剂——DF2755A、AZD-5069、SX-682和SCH527123——在博莱霉素诱导的小鼠肺损伤模型中的抗炎作用。C57BL/6小鼠接受鼻内博莱霉素治疗，并以已知活性剂量的拮抗剂灌胃，每天1次。在第0天通过接种博来霉素诱导疾病后，在第0-2天对动物进行治疗，然后在第2天进行评估（重点关注早期炎症反应），或在第0-16天进行治疗（预防方案）或在第8-16天进行治疗（治疗方案），然后在第16天进行评估（重点关注纤维化）。我们通过分析总白细胞计数和差异白细胞计数、细胞因子水平、髓过氧化物酶（MPO）活性、BALF蛋白含量和肺组织病理学来评估支气管肺泡灌洗液（BALF）和肺组织中的炎症反应。所有化合物均表现出抗炎作用（第2天），其中DF2755A和AZD-5069在减少早期中性粒细胞内流方面表现出更大的功效。重要的是，当以预防和治疗方案给药时，DF2755A和SX-682在减轻纤维化和慢性炎症变化方面特别有效，即使在疾病进展的后期也是如此。这些发现强调了CXCR2拮抗剂的潜力，特别是DF2755A，作为一种有希望的策略来限制实验性肺损伤中的炎症和纤维化。

{"title":"CXCR2 antagonism as a promising therapeutic approach for pulmonary fibrosis therapy","authors":"Eliza Mathias Melo , Filipe Resende , Fernando Roque Ascenção , Celso Martins Queiroz-Junior , Mario Amatruda , Mara Tomassetti , Laura Brandolini , Gianluca Bianchini , Andrea Aramini , Frederico Marianetti Soriani , Rafael Cypriano Dutra , Mauro Martins Teixeira","doi":"10.1016/j.biopha.2026.118998","DOIUrl":"10.1016/j.biopha.2026.118998","url":null,"abstract":"<div><div>Pulmonary inflammation is a central feature of several chronic lung diseases. The chemokine receptor CXCR2 plays a key role in regulating recruitment and activation of leukocytes and other cell types involved in acute and chronic inflammation of the lungs. In this study, we evaluated and compared the anti-inflammatory effects of four CXCR2 antagonists - DF2755A, AZD-5069, SX-682, and SCH527123 - in a murine model of bleomycin-induced lung injury. C57BL/6 mice received intranasal bleomycin and were treated once a day with known active doses of the antagonists by oral gavage. Following disease induction through bleomycin inoculation on day 0, animals were either treated at days 0–2 and then evaluated at day 2 (focus on the early inflammatory response) or treated from days 0–16 (preventive schedule) or from days 8–16 (therapeutic schedule) and then evaluated at day 16 (focus on fibrosis). We assessed inflammatory responses in bronchoalveolar lavage fluid (BALF) and lung tissue by analyzing total and differential leukocyte counts, cytokine levels, myeloperoxidase (MPO) activity, BALF protein content, and lung histopathology. All compounds displayed anti-inflammatory effects (day 2), with DF2755A and AZD-5069 standing out for their greater efficacy in reducing early neutrophils influx. Importantly, DF2755A and SX-682 were particularly effective in mitigating fibrosis and chronic inflammatory changes when administered in both preventive and therapeutic schedules, even at later stages of disease progression. These findings underscore the potential of CXCR2 antagonism, especially with DF2755A, as a promising strategy to limit inflammation and fibrosis in experimental lung injury.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 118998"},"PeriodicalIF":7.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146020848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hydrogen sulphide as a potential contributer to cardiovascular protection with sodium-glucose cotransporter 2 inhibition 硫化氢作为钠-葡萄糖共转运蛋白2抑制心血管保护的潜在贡献者。

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-19 DOI: 10.1016/j.biopha.2026.119012

Andrea Berenyiova , Fedor Simko

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), developed for the treatment of diabetes mellitus, exert remarkable cardiovascular benefits beyond glycaemic control. The underlying mechanism of this pluripotent protection is heterogeneous and involves interactions with a number of haemodynamic, metabolic and cellular signalling pathways. Emerging findings demonstrate that a natural gaseous product of arterial wall, H₂S, participates in a number of physiological reactions, and its deficiency is associated with cardiovascular pathologies, such as arterial hypertension, heart failure and chronic kidney disease. Recent experimental observations have suggested the possibility of a functional link between SGLT2i and H₂S signalling in the context of cardiovascular protection. Emerging data suggest that SGLT2i- and H₂S-dependent pathways may overlap or complement each other in protective mechanisms. Several plausible areas of interaction between SGLT2i and H₂S have recently emerged. Both agents stimulate PI3K/Akt/eNOS signalling, thereby increasing the bioavailability of NO with beneficial vasodilatory and antiproliferative effects. SGLT2i and H₂S also favourably regulate the redox state through inhibition of NADPH oxidase, thus protecting subcellular structures. Moreover, both SGLT2i and H₂S appear to affect autophagy and improve mitochondrial function through AMPK and sirtuin signalling, thus contributing to the restoration of physiological substrate processing pathways and cellular energy balance. In addition, both SGLT2i and H₂S supposedly downregulate the Na⁺/H⁺ exchanger, normalize the Fe²⁺ cytosolic level in cardiomyocytes and promote erythropoietin release, actions that could improve the metabolism and function of cardiovascular organs. Elucidating the nature of possible crosstalk between H₂S, delivered by endogenous stimulation or exogenous supplementation, and SGLT2i may desirably modify the approach to the treatment of cardiovascular diseases and represents a challenging research topic.

钠-葡萄糖共转运蛋白2抑制剂（SGLT2i）是为治疗糖尿病而开发的，除了血糖控制外，还具有显著的心血管益处。这种多能性保护的潜在机制是异质的，涉及与许多血流动力学、代谢和细胞信号通路的相互作用。新的研究结果表明，动脉壁的天然气态产物H2S参与了许多生理反应，其缺乏与心血管疾病有关，如动脉高血压、心力衰竭和慢性肾脏疾病。最近的实验观察表明，在心血管保护的背景下，SGLT2i和H2S信号之间可能存在功能联系。新出现的数据表明，SGLT2i和h2s依赖性通路可能在保护机制中重叠或互补。最近出现了几个SGLT2i和H2S之间可能相互作用的区域。这两种药物均刺激PI3K/Akt/eNOS信号传导，从而提高NO的生物利用度，具有有益的血管扩张和抗增殖作用。SGLT2i和H2S也通过抑制NADPH氧化酶来有利地调节氧化还原状态，从而保护亚细胞结构。此外，SGLT2i和H2S似乎都通过AMPK和sirtuin信号传导影响自噬并改善线粒体功能，从而有助于恢复生理底物加工途径和细胞能量平衡。此外，SGLT2i和H2S可能下调Na+/H+交换，使心肌细胞内Fe2+水平正常化，促进促红细胞生成素的释放，从而改善心血管器官的代谢和功能。阐明通过内源性刺激或外源性补充传递的H2S与SGLT2i之间可能的串扰的性质可能会改变心血管疾病的治疗方法，这是一个具有挑战性的研究课题。

{"title":"Hydrogen sulphide as a potential contributer to cardiovascular protection with sodium-glucose cotransporter 2 inhibition","authors":"Andrea Berenyiova , Fedor Simko","doi":"10.1016/j.biopha.2026.119012","DOIUrl":"10.1016/j.biopha.2026.119012","url":null,"abstract":"<div><div>Sodium-glucose cotransporter 2 inhibitors (SGLT2i), developed for the treatment of diabetes mellitus, exert remarkable cardiovascular benefits beyond glycaemic control. The underlying mechanism of this pluripotent protection is heterogeneous and involves interactions with a number of haemodynamic, metabolic and cellular signalling pathways. Emerging findings demonstrate that a natural gaseous product of arterial wall, H<sub>2</sub>S, participates in a number of physiological reactions, and its deficiency is associated with cardiovascular pathologies, such as arterial hypertension, heart failure and chronic kidney disease. Recent experimental observations have suggested the possibility of a functional link between SGLT2i and H<sub>2</sub>S signalling in the context of cardiovascular protection. Emerging data suggest that SGLT2i- and H<sub>2</sub>S-dependent pathways may overlap or complement each other in protective mechanisms. Several plausible areas of interaction between SGLT2i and H<sub>2</sub>S have recently emerged. Both agents stimulate PI3K/Akt/eNOS signalling, thereby increasing the bioavailability of NO with beneficial vasodilatory and antiproliferative effects. SGLT2i and H<sub>2</sub>S also favourably regulate the redox state through inhibition of NADPH oxidase, thus protecting subcellular structures. Moreover, both SGLT2i and H<sub>2</sub>S appear to affect autophagy and improve mitochondrial function through AMPK and sirtuin signalling, thus contributing to the restoration of physiological substrate processing pathways and cellular energy balance. In addition, both SGLT2i and H<sub>2</sub>S supposedly downregulate the Na<sup>+</sup>/H<sup>+</sup> exchanger, normalize the Fe<sup>2+</sup> cytosolic level in cardiomyocytes and promote erythropoietin release, actions that could improve the metabolism and function of cardiovascular organs. Elucidating the nature of possible crosstalk between H<sub>2</sub>S, delivered by endogenous stimulation or exogenous supplementation, and SGLT2i may desirably modify the approach to the treatment of cardiovascular diseases and represents a challenging research topic.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119012"},"PeriodicalIF":7.5,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146013898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrated transcriptomic and proteomic profiling identifies an interferon-dependent inflammatory endotype in sepsis 综合转录组学和蛋白质组学分析鉴定干扰素依赖性炎症内型败血症。

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-19 DOI: 10.1016/j.biopha.2026.119014

Andrian Fratea , Anca-Lelia Riza , Florentina Dumitrescu , Stefania Dorobantu , Andrei Pirvu , Adina Dragos , Andra Grigorescu , Ioana Streata , Mihai G. Netea , Vinod Kumar , Collins K. Boahen

Background

Sepsis is a major cause of mortality worldwide, with modest improvements in the last decades. A significant challenge for the outcome improvement lies in the marked disease heterogeneity among patients. Stratifying patients into distinct endotypes is needed for more precise interventions. This study investigates the transcriptomic landscape of sepsis patients stratified by their inflammatory endotype.

Methods

We obtained peripheral blood mononuclear cells from 125 sepsis patients (as per Sepsis-2 criteria) and 299 volunteers as part of the Functional Genomics in Severe Infections project (FUSE). RNA sequencing was conducted to identify differentially expressed genes and enriched pathways. We compared the transcriptomic profiles of previously defined “high-” and “low-inflammatory” endotypes, obtained through targeted inflammatory proteomics.

Results

Sepsis was linked to widespread transcriptional changes in innate immunity genes, notably those linked to phagocytosis and antimicrobial peptides, alongside paradoxical reduced NK cell-mediated immunity. Adaptive immunity genes, particularly those involved in T cell differentiation, were downregulated. Importantly, infection etiology and infection site had no discernible impact on gene expression profiles. In the “high-inflammatory” endotype, interferon-associated chemokines CXCL9 and CXCL10 were markedly upregulated at the transcription level in peripheral blood mononuclear cells, with concordant elevations in their circulating serum concentrations, as assessed by targeted proteomics and ELISA.

Conclusion

Immune dysregulation in sepsis is more driven by disease severity than infection site. The robust activation of the interferon-gamma-CXCL9-CXCL10 axis observed in the “high-inflammatory” endotype may present a promising target for personalized immunotherapies.

背景：脓毒症是世界范围内死亡的主要原因，在过去的几十年里有适度的改善。结果改善的一个重大挑战在于患者之间明显的疾病异质性。为了更精确的干预，需要将患者分层为不同的内源性类型。这项研究调查了脓毒症患者的转录组学景观分层他们的炎症内型。方法：我们从125名脓毒症患者（根据脓毒症-2标准）和299名志愿者中获得外周血单个核细胞，作为严重感染项目功能基因组学（FUSE）的一部分。RNA测序鉴定差异表达基因和富集途径。我们比较了先前定义的“高”和“低”炎症内型的转录组学特征，这些内型是通过靶向炎症蛋白质组学获得的。结果：脓毒症与先天免疫基因的广泛转录变化有关，特别是与吞噬和抗菌肽相关的基因，以及NK细胞介导的免疫力的矛盾降低。适应性免疫基因，特别是那些参与T细胞分化的基因，被下调。重要的是，感染病因和感染部位对基因表达谱没有明显的影响。在“高炎症”内型中，干扰素相关趋化因子CXCL9和CXCL10在外周血单个核细胞的转录水平上显著上调，其循环血清浓度也随之升高，通过靶向蛋白质组学和ELISA进行了评估。结论：脓毒症的免疫失调更多是由疾病严重程度而不是感染部位引起的。在“高炎症”内型中观察到的干扰素- γ - cxcl9 - cxcl10轴的强大激活可能为个性化免疫治疗提供了一个有希望的靶点。

{"title":"Integrated transcriptomic and proteomic profiling identifies an interferon-dependent inflammatory endotype in sepsis","authors":"Andrian Fratea , Anca-Lelia Riza , Florentina Dumitrescu , Stefania Dorobantu , Andrei Pirvu , Adina Dragos , Andra Grigorescu , Ioana Streata , Mihai G. Netea , Vinod Kumar , Collins K. Boahen","doi":"10.1016/j.biopha.2026.119014","DOIUrl":"10.1016/j.biopha.2026.119014","url":null,"abstract":"<div><h3>Background</h3><div>Sepsis is a major cause of mortality worldwide, with modest improvements in the last decades. A significant challenge for the outcome improvement lies in the marked disease heterogeneity among patients. Stratifying patients into distinct endotypes is needed for more precise interventions. This study investigates the transcriptomic landscape of sepsis patients stratified by their inflammatory endotype.</div></div><div><h3>Methods</h3><div>We obtained peripheral blood mononuclear cells from 125 sepsis patients (as per Sepsis-2 criteria) and 299 volunteers as part of the Functional Genomics in Severe Infections project (FUSE). RNA sequencing was conducted to identify differentially expressed genes and enriched pathways. We compared the transcriptomic profiles of previously defined “high-” and “low-inflammatory” endotypes, obtained through targeted inflammatory proteomics.</div></div><div><h3>Results</h3><div>Sepsis was linked to widespread transcriptional changes in innate immunity genes, notably those linked to phagocytosis and antimicrobial peptides, alongside paradoxical reduced NK cell-mediated immunity. Adaptive immunity genes, particularly those involved in T cell differentiation, were downregulated. Importantly, infection etiology and infection site had no discernible impact on gene expression profiles. In the “high-inflammatory” endotype, interferon-associated chemokines CXCL9 and CXCL10 were markedly upregulated at the transcription level in peripheral blood mononuclear cells, with concordant elevations in their circulating serum concentrations, as assessed by targeted proteomics and ELISA.</div></div><div><h3>Conclusion</h3><div>Immune dysregulation in sepsis is more driven by disease severity than infection site. The robust activation of the interferon-gamma-CXCL9-CXCL10 axis observed in the “high-inflammatory” endotype may present a promising target for personalized immunotherapies.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119014"},"PeriodicalIF":7.5,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146013861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene expression profiles associated with carboplatin chemoresistance in high-grade serous ovarian cancer: insights from 2D and 3D models 高级别浆液性卵巢癌中与卡铂化疗耐药相关的基因表达谱：来自2D和3D模型的见解

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-17 DOI: 10.1016/j.biopha.2026.119010

Vesna Kokondoska Grgič , Nika Marolt , Ajla Kubat , Tamara Dokmanović , Katja Kološa , Ivana Jovčevska , Tea Lanišnik Rižner

Carboplatin resistance remains a major challenge in the treatment of high-grade serous ovarian cancer (HGSOC), the most lethal subtype of epithelial ovarian cancer. To uncover mechanisms driving chemoresistance, we combined patient-derived transcriptomic data with advanced 3D in vitro models. Analysis of TCGA datasets revealed significant upregulation of matrix remodelling gene MMP9. To mimic clinical response, 3D models of four HGSOC cell lines were compared with conventional 2D models. The IC₅₀ values for carboplatin were substantially higher in 3D models, indicating increased chemoresistance, consistent with the results of other studies. This difference is mainly due to reduced drug penetration within the dense 3D spheroid structure, which limits the exposure of cells inside the spheroids to the chemotherapeutic agent. Functional assays showed that carboplatin induced G0/G1 cell cycle arrest and decreased Ki67 levels at IC₅₀ concentrations, suggesting a cytostatic effect. qPCR confirmed geometry- and treatment-dependent significant upregulation of the genes MMP9, TWIST2, ZEB2, and WNT11 in 3D models, that recapitulate the adaptive resistance patterns observed in patient tumours. These results identify MMP9, TWIST2, ZEB2, and WNT11 as promising biomarkers for overcoming chemoresistance in HGSOC. Further functional validation of these genes is needed to confirm the biological significance of the observed correlations.

卡铂耐药仍然是治疗高级别浆液性卵巢癌（HGSOC）的主要挑战，HGSOC是上皮性卵巢癌中最致命的亚型。为了揭示驱动化疗耐药的机制，我们将患者衍生的转录组学数据与先进的3D体外模型相结合。TCGA数据集分析显示基质重塑基因MMP9显著上调。为了模拟临床反应，将4种HGSOC细胞系的3D模型与常规2D模型进行比较。卡铂的IC50值在3D模型中显著升高，表明化疗耐药增加，与其他研究结果一致。这种差异主要是由于致密的三维球体结构内药物渗透减少，这限制了球体内细胞暴露于化疗药物。功能分析显示，卡铂诱导G0/G1细胞周期阻滞，并在IC50浓度下降低Ki67水平，表明卡铂具有细胞抑制作用。qPCR证实了三维模型中MMP9、TWIST2、ZEB2和WNT11基因的几何依赖性和治疗依赖性显著上调，这概括了在患者肿瘤中观察到的适应性耐药模式。这些结果确定了MMP9、TWIST2、ZEB2和WNT11是克服HGSOC化学耐药的有希望的生物标志物。需要对这些基因进行进一步的功能验证，以确认观察到的相关性的生物学意义。

{"title":"Gene expression profiles associated with carboplatin chemoresistance in high-grade serous ovarian cancer: insights from 2D and 3D models","authors":"Vesna Kokondoska Grgič , Nika Marolt , Ajla Kubat , Tamara Dokmanović , Katja Kološa , Ivana Jovčevska , Tea Lanišnik Rižner","doi":"10.1016/j.biopha.2026.119010","DOIUrl":"10.1016/j.biopha.2026.119010","url":null,"abstract":"<div><div>Carboplatin resistance remains a major challenge in the treatment of high-grade serous ovarian cancer (HGSOC), the most lethal subtype of epithelial ovarian cancer. To uncover mechanisms driving chemoresistance, we combined patient-derived transcriptomic data with advanced 3D <em>in vitro</em> models. Analysis of TCGA datasets revealed significant upregulation of matrix remodelling gene <em>MMP9.</em> To mimic clinical response, 3D models of four HGSOC cell lines were compared with conventional 2D models. The IC<sub>50</sub> values for carboplatin were substantially higher in 3D models, indicating increased chemoresistance, consistent with the results of other studies. This difference is mainly due to reduced drug penetration within the dense 3D spheroid structure, which limits the exposure of cells inside the spheroids to the chemotherapeutic agent. Functional assays showed that carboplatin induced G0/G1 cell cycle arrest and decreased Ki67 levels at IC<sub>50</sub> concentrations, suggesting a cytostatic effect. qPCR confirmed geometry- and treatment-dependent significant upregulation of the genes <em>MMP9, TWIST2, ZEB2</em>, and <em>WNT11</em> in 3D models, that recapitulate the adaptive resistance patterns observed in patient tumours. These results identify <em>MMP9, TWIST2, ZEB2</em>, and <em>WNT11</em> as promising biomarkers for overcoming chemoresistance in HGSOC. Further functional validation of these genes is needed to confirm the biological significance of the observed correlations.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119010"},"PeriodicalIF":7.5,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Engineering a fifth-generation CAR T cells to overcome PD-L1-mediated immunosuppression in lung cancer 设计第五代CAR - T细胞以克服肺癌中pd - l1介导的免疫抑制

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-17 DOI: 10.1016/j.biopha.2025.118967

Yupanun Wutti-in , Piriya Luangwattananun , Nunghathai Sawasdee , Preeyanat Vongchan , Pa-thai Yenchitsomanus , Aussara Panya

The tumor microenvironment (TME) significantly hinders chimeric antigen receptor (CAR) T cell therapy in solid tumors, despite its success in hematological malignancies. This disparity is attributable to immunosuppressive factors, such as program death ligand 1 (PD-L1) upregulation in non-small-cell-lung cancer (NSCLC). This study aims to create and assess anti-FRα-CAR5, a novel anti-folate receptor alpha (FRα) CAR T cell designed to secrete a PD-L1 blocking single chain variable fragment (scFv). Human T lymphocytes were engineered with a lentiviral vector to express anti-FRα-CAR5, which incorporates a fourth-generation CAR backbone (CD28, 4–1BB, CD27, and CD3 zeta) augmented by a secreted anti-PD-L1 scFv derived from atezolizumab. Transfected HEK293T cells were used to evaluate surface expression of anti-FRα-CAR. The secreted anti-PD-L1 scFv was tested for binding ability on lung adenocarcinoma cell lines. Furthermore, the secreted anti-PD-L1 scFv demonstrated over 80 % inhibitory activity against PD-L1 monoclonal antibody. Importantly, anti-FRα-CAR5 T cells enhanced expansion and cytotoxicity against FRα and PD-L1 expressing lung cancer cell lines in vitro compared to an anti-FRα-CAR4 lacking the secreted anti-PD-L1 scFv. This fifth-generation CAR offers a promising strategy to enhance CAR T cell therapy efficacy in PD-L1-mediated immunosuppressive TMEs. These findings suggest that anti-FRα-CAR5 T cells therapy warrants further preclinical validation as a potential treatment strategy for NSCLC patients.

肿瘤微环境（TME）显著阻碍了嵌合抗原受体（CAR） T细胞治疗实体瘤，尽管它在血液系统恶性肿瘤中取得了成功。这种差异可归因于免疫抑制因素，如程序死亡配体1 （PD-L1）在非小细胞肺癌（NSCLC）中的上调。本研究旨在创建和评估抗FRα- car5，一种新的抗叶酸受体α (FRα) CAR - T细胞，旨在分泌PD-L1阻断单链可变片段（scFv）。用慢病毒载体对人T淋巴细胞进行工程改造，以表达抗fr α- car5，其中包含第四代CAR骨架（CD28, 4-1BB， CD27和CD3 zeta），由源自atezolizumab的分泌抗pd - l1 scFv增强。用转染的HEK293T细胞评价抗fr α- car的表面表达。检测分泌的抗pd - l1 scFv在肺腺癌细胞系上的结合能力。此外，分泌的抗PD-L1 scFv对PD-L1单克隆抗体的抑制活性超过80% %。重要的是，与缺乏分泌的抗PD-L1 scFv的抗FRα- car4相比，抗FRα- car5 T细胞增强了体外表达FRα和PD-L1的肺癌细胞系的扩增和细胞毒性。这种第五代CAR提供了一种有希望的策略来增强CAR - T细胞治疗pd - l1介导的免疫抑制性TMEs的疗效。这些发现表明，抗fr α- car5 T细胞疗法作为NSCLC患者的潜在治疗策略值得进一步的临床前验证。

{"title":"Engineering a fifth-generation CAR T cells to overcome PD-L1-mediated immunosuppression in lung cancer","authors":"Yupanun Wutti-in , Piriya Luangwattananun , Nunghathai Sawasdee , Preeyanat Vongchan , Pa-thai Yenchitsomanus , Aussara Panya","doi":"10.1016/j.biopha.2025.118967","DOIUrl":"10.1016/j.biopha.2025.118967","url":null,"abstract":"<div><div>The tumor microenvironment (TME) significantly hinders chimeric antigen receptor (CAR) T cell therapy in solid tumors, despite its success in hematological malignancies. This disparity is attributable to immunosuppressive factors, such as program death ligand 1 (PD-L1) upregulation in non-small-cell-lung cancer (NSCLC). This study aims to create and assess anti-FRα-CAR5, a novel anti-folate receptor alpha (FRα) CAR T cell designed to secrete a PD-L1 blocking single chain variable fragment (scFv). Human T lymphocytes were engineered with a lentiviral vector to express anti-FRα-CAR5, which incorporates a fourth-generation CAR backbone (CD28, 4–1BB, CD27, and CD3 zeta) augmented by a secreted anti-PD-L1 scFv derived from atezolizumab. Transfected HEK293T cells were used to evaluate surface expression of anti-FRα-CAR. The secreted anti-PD-L1 scFv was tested for binding ability on lung adenocarcinoma cell lines. Furthermore, the secreted anti-PD-L1 scFv demonstrated over 80 % inhibitory activity against PD-L1 monoclonal antibody. Importantly, anti-FRα-CAR5 T cells enhanced expansion and cytotoxicity against FRα and PD-L1 expressing lung cancer cell lines <em>in vitro</em> compared to an anti-FRα-CAR4 lacking the secreted anti-PD-L1 scFv. This fifth-generation CAR offers a promising strategy to enhance CAR T cell therapy efficacy in PD-L1-mediated immunosuppressive TMEs. These findings suggest that anti-FRα-CAR5 T cells therapy warrants further preclinical validation as a potential treatment strategy for NSCLC patients.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 118967"},"PeriodicalIF":7.5,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Emerging role of Saikosaponin A in tumor therapy and tumor microenvironment immunomodulation 柴草皂苷A在肿瘤治疗和肿瘤微环境免疫调节中的新作用

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-17 DOI: 10.1016/j.biopha.2026.119000

Lijie Zhang , Chunjian Wang , Xizhong Zhang , Zhijuan Lin , Feng Chen

Saikosaponin A(SSA), a type of saponin compound, is extracted from Bupleurum and is the main active component of this plant. Recent studies have shown that SSA plays important roles in tumor therapy and tumor microenvironment (TME) immunomodulation. Although many new experimental studies on SSA in tumor treatment and immune regulation have been reported, the reviews about its role in tumor treatment and TME are relatively limited. Therefore, this review elaborates the anti-tumor effects of SSA in tumors and their potential mechanisms, including anti-proliferation, induction of apoptosis and ferroptosis, inhibition of metastasis, anti-angiogenesis, inhibition of glycolysis and drug resistance, etc. Moreover, this review reveals the roles of SSA in the TME, points out its regulation on tumor immune cells and cytokines, and clarifies the advantages, limitations and challenges of SSA in tumor treatment. In conclusion, this review summarizes the roles of SSA in tumor treatment and TME regulation, and analyzes the application prospects and challenges of SSA in cancer therapy, which will provide new directions and theoretical basis for clinical cancer treatment.

柴胡皂苷A（Saikosaponin A， SSA）是从柴胡中提取的一种皂苷类化合物，是该植物的主要活性成分。近年来的研究表明，SSA在肿瘤治疗和肿瘤微环境（TME）免疫调节中发挥着重要作用。虽然有许多关于SSA在肿瘤治疗和免疫调节中的新实验研究报道，但关于其在肿瘤治疗和TME中的作用的综述相对有限。因此，本文就SSA在肿瘤中的抗肿瘤作用及其可能的机制进行综述，包括抗增殖、诱导细胞凋亡和铁凋亡、抑制转移、抑制血管生成、抑制糖酵解和耐药等。此外，本文还揭示了SSA在TME中的作用，指出了SSA对肿瘤免疫细胞和细胞因子的调节作用，并阐明了SSA在肿瘤治疗中的优势、局限性和挑战。综上所述，本文综述了SSA在肿瘤治疗和TME调控中的作用，分析了SSA在肿瘤治疗中的应用前景和面临的挑战，为临床肿瘤治疗提供新的方向和理论依据。

{"title":"Emerging role of Saikosaponin A in tumor therapy and tumor microenvironment immunomodulation","authors":"Lijie Zhang , Chunjian Wang , Xizhong Zhang , Zhijuan Lin , Feng Chen","doi":"10.1016/j.biopha.2026.119000","DOIUrl":"10.1016/j.biopha.2026.119000","url":null,"abstract":"<div><div>Saikosaponin A(SSA), a type of saponin compound, is extracted from Bupleurum and is the main active component of this plant. Recent studies have shown that SSA plays important roles in tumor therapy and tumor microenvironment (TME) immunomodulation. Although many new experimental studies on SSA in tumor treatment and immune regulation have been reported, the reviews about its role in tumor treatment and TME are relatively limited. Therefore, this review elaborates the anti-tumor effects of SSA in tumors and their potential mechanisms, including anti-proliferation, induction of apoptosis and ferroptosis, inhibition of metastasis, anti-angiogenesis, inhibition of glycolysis and drug resistance, etc. Moreover, this review reveals the roles of SSA in the TME, points out its regulation on tumor immune cells and cytokines, and clarifies the advantages, limitations and challenges of SSA in tumor treatment. In conclusion, this review summarizes the roles of SSA in tumor treatment and TME regulation, and analyzes the application prospects and challenges of SSA in cancer therapy, which will provide new directions and theoretical basis for clinical cancer treatment.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119000"},"PeriodicalIF":7.5,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974903","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuroprotective effects of calcitriol in a rat model of type 2 diabetes: Targeting neuroinflammation, glycation, oxidative stress and metabolic dysfunction 骨化三醇在2型糖尿病大鼠模型中的神经保护作用：针对神经炎症、糖基化、氧化应激和代谢功能障碍

IF 7.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Biomedicine & Pharmacotherapy

Pub Date : 2026-01-17 DOI: 10.1016/j.biopha.2026.119008

Cezary Pawlukianiec , Kamila Karpienko , Małgorzata Żendzian-Piotrowska , Anna Zalewska , Mateusz Maciejczyk

Diabetes mellitus is increasingly recognised as a contributor to neurodegeneration through oxidative stress, chronic inflammation, and protein glycation within the brain. Calcitriol - the active form of vitamin D - is postulated to target these molecular disturbances, but its neuroprotective potential remains poorly understood. This study investigated the effects of calcitriol on neuroinflammatory responses, glycooxidative damage, and intracellular signaling within two anatomically distinct brain regions - the hypothalamus and cerebral cortex - in a rat model of type 2 diabetes. Male Wistar rats were assigned to three groups: control, diabetes, and diabetes treated with calcitriol. Type 2 diabetes was induced using a high-fat diet followed by streptozotocin administration at week 4, while calcitriol was given orally at 0.1 μg/kg for eight weeks. Multiplex immunoassays and biochemical analyses were used to evaluate cytokines, chemokines, lipid and protein oxidation products, and signaling proteins associated with metabolic and neurodegenerative pathways. Diabetic rats exhibited metabolic dysfunction, pronounced neuroinflammation, increased lipid and protein glycooxidation, mitochondrial impairment, and dysregulation of apoptosis- and insulin-related signaling. Calcitriol significantly improved systemic metabolic indices and attenuated pro-inflammatory cytokine and chemokine profiles, reduced advanced glycation end products, malondialdehyde, and protein carbonyls, and partially restored mitochondrial and intracellular signaling homeostasis. Notably, the hypothalamus exhibited a stronger response to calcitriol than the cerebral cortex, suggesting region-specific neuroprotective effects. These findings indicate that calcitriol may represent a promising therapeutic strategy for mitigating type 2 diabetes-related neurodegeneration by targeting oxidative stress, glycation, and inflammatory signaling within the brain.

糖尿病越来越被认为是通过氧化应激、慢性炎症和脑内蛋白糖基化导致神经变性的一个因素。骨化三醇——维生素D的活性形式——被认为是针对这些分子紊乱的，但它的神经保护潜力仍然知之甚少。本研究研究了骨化三醇对2型糖尿病大鼠模型中两个解剖结构不同的大脑区域（下丘脑和大脑皮层）的神经炎症反应、糖氧化损伤和细胞内信号传导的影响。雄性Wistar大鼠分为三组：对照组、糖尿病组和骨化三醇治疗组。采用高脂饮食诱导2型糖尿病，第4周给予链脲佐菌素，同时以0.1 μg/kg剂量口服骨化三醇，连续8周。多重免疫分析和生化分析用于评估细胞因子、趋化因子、脂质和蛋白质氧化产物以及与代谢和神经退行性途径相关的信号蛋白。糖尿病大鼠表现出代谢功能障碍、明显的神经炎症、脂质和蛋白糖协同氧化增加、线粒体损伤、细胞凋亡和胰岛素相关信号失调。骨化三醇显著改善了全身代谢指标，减弱了促炎细胞因子和趋化因子谱，减少了晚期糖基化终产物、丙二醛和蛋白质羰基，并部分恢复了线粒体和细胞内信号稳态。值得注意的是，下丘脑对骨化三醇的反应比大脑皮层更强烈，这表明它具有特定区域的神经保护作用。这些发现表明，骨化三醇可能是一种很有前途的治疗策略，可以通过靶向氧化应激、糖基化和脑内炎症信号来缓解2型糖尿病相关的神经变性。

{"title":"Neuroprotective effects of calcitriol in a rat model of type 2 diabetes: Targeting neuroinflammation, glycation, oxidative stress and metabolic dysfunction","authors":"Cezary Pawlukianiec , Kamila Karpienko , Małgorzata Żendzian-Piotrowska , Anna Zalewska , Mateusz Maciejczyk","doi":"10.1016/j.biopha.2026.119008","DOIUrl":"10.1016/j.biopha.2026.119008","url":null,"abstract":"<div><div>Diabetes mellitus is increasingly recognised as a contributor to neurodegeneration through oxidative stress, chronic inflammation, and protein glycation within the brain. Calcitriol - the active form of vitamin D - is postulated to target these molecular disturbances, but its neuroprotective potential remains poorly understood. This study investigated the effects of calcitriol on neuroinflammatory responses, glycooxidative damage, and intracellular signaling within two anatomically distinct brain regions - the hypothalamus and cerebral cortex - in a rat model of type 2 diabetes. Male Wistar rats were assigned to three groups: control, diabetes, and diabetes treated with calcitriol. Type 2 diabetes was induced using a high-fat diet followed by streptozotocin administration at week 4, while calcitriol was given orally at 0.1 μg/kg for eight weeks. Multiplex immunoassays and biochemical analyses were used to evaluate cytokines, chemokines, lipid and protein oxidation products, and signaling proteins associated with metabolic and neurodegenerative pathways. Diabetic rats exhibited metabolic dysfunction, pronounced neuroinflammation, increased lipid and protein glycooxidation, mitochondrial impairment, and dysregulation of apoptosis- and insulin-related signaling. Calcitriol significantly improved systemic metabolic indices and attenuated pro-inflammatory cytokine and chemokine profiles, reduced advanced glycation end products, malondialdehyde, and protein carbonyls, and partially restored mitochondrial and intracellular signaling homeostasis. Notably, the hypothalamus exhibited a stronger response to calcitriol than the cerebral cortex, suggesting region-specific neuroprotective effects. These findings indicate that calcitriol may represent a promising therapeutic strategy for mitigating type 2 diabetes-related neurodegeneration by targeting oxidative stress, glycation, and inflammatory signaling within the brain.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"195 ","pages":"Article 119008"},"PeriodicalIF":7.5,"publicationDate":"2026-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145974687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0