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Unveiling hidden risks: pharmacogenetic insights from a cross-sectional study of statin therapy in the Indian population. 揭示隐藏的风险:药物遗传学的见解从横断面研究他汀类药物治疗在印度人口。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-06-09 DOI: 10.1007/s43440-025-00746-1
Shaik Mohammad Naushad, Palani Kumar Palanichamy, Jagadeesh Babu Sreemanthula, Yadam Reddy Kanaka Durga Devi, Palakonda Gopi, Tajamul Hussain, Vijay Kumar Kutala

Background: Statin usage has increased significantly in India due to the very high incidence of dyslipidemia, however, approximately 18% of the population is at risk for statin-induced myopathy. Hence, we conducted a population-level screening for pharmacogenetic determinants of statin therapy, particularly Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) and ATP-binding cassette sub-family G member 2 (ABCG2).

Materials and methods: Whole exome sequencing was performed in 2180 subjects, and the variant data were segregated further into diplotypes and phenotypes.

Results: SLCO1B1 normal function was observed in 81% of subjects (diplotypes: 1/*1, *1/*14, *1/*20, *1/*37, and *37/*37). Increased SLCO1B1 function was observed in 8% of the population (diplotypes: *14/*14 and *20/*20). Decreased function of SLCO1B1 (*1/*15) was observed in 5% of the population. Poor function of SLCO1B1 was observed in 6% of the population (diplotypes: *5/*5 and *15/*15). About 81.46% of subjects displayed normal ABCG2 function, while 17.34% had decreased and 1.19% had poor function. Combined SLCO1B1/ABCG2 functional defects were observed in 7.4% of subjects. Two rare SLCO1B1 variants in SLCO1B1 i.e., rs201722521 and rs71581988, were reported to affect the binding affinity of certain statins. The SLCO1B1 C-C-C-A-A-A haplotype was associated with a 2.22-fold risk for hyperbilirubinemia (95% CI: 1.13-4.36, p = 0.02). Rosuvastatin's daily dose of up to 10 mg is well tolerated across the different SLCO1B1 functionality groups.

Conclusions: This study demonstrates that 11% of our population exhibit decreased or poor function of SLCO1B1 and 7.4% exhibit decreased or poor function of both SLCO1B1 and ABCG2, necessitating adjustments in daily statin doses to minimize the risk for statin-induced myopathy.

背景:由于血脂异常的高发生率,他汀类药物的使用在印度显著增加,然而,大约18%的人口处于他汀类药物诱发的肌病的风险中。因此,我们对他汀类药物治疗的药理学决定因素进行了人群水平的筛选,特别是溶质载体有机阴离子转运蛋白家族成员1B1 (SLCO1B1)和atp结合盒亚家族G成员2 (ABCG2)。材料和方法:对2180名受试者进行全外显子组测序,并将变异数据进一步分离为二倍型和表型。结果:81%的受试者SLCO1B1功能正常(双倍型:1/*1、*1/*14、*1/*20、*1/*37、*37/*37)。在8%的人群中观察到SLCO1B1功能增加(双倍型:*14/*14和*20/*20)。在5%的人群中观察到SLCO1B1功能下降(*1/*15)。SLCO1B1功能低下的人群占6%(双倍型:*5/*5和*15/*15)。81.46%的受试者ABCG2功能正常,17.34%的受试者ABCG2功能下降,1.19%的受试者ABCG2功能差。7.4%的受试者存在SLCO1B1/ABCG2复合功能缺陷。据报道,SLCO1B1中两个罕见的SLCO1B1变异rs201722521和rs71581988会影响某些他汀类药物的结合亲和力。SLCO1B1 c - c - c - a - a单倍型与高胆红素血症的2.22倍风险相关(95% CI: 1.13-4.36, p = 0.02)。瑞舒伐他汀每日剂量高达10mg在不同的SLCO1B1功能组中具有良好的耐受性。结论:该研究表明,11%的人群表现出SLCO1B1功能下降或较差,7.4%的人群表现出SLCO1B1和ABCG2功能下降或较差,需要调整每日他汀类药物剂量,以尽量减少他汀类药物引起的肌病的风险。
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引用次数: 0
Residence time in drug discovery: current insights and future perspectives. 药物发现中的停留时间:当前的见解和未来的展望。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-06-09 DOI: 10.1007/s43440-025-00748-z
Szymon K Kordylewski, Ryszard Bugno, Sabina Podlewska

The temporal stability of ligand-receptor complexes is increasingly acknowledged as a critical factor in drug discovery, influencing both efficacy and pharmacodynamics. Although the relationship between the duration of compound action and complex stability can be traced back to Paul Ehrlich's 19th-century doctrine Corpora non agunt nisi fixata, its significance has gained renewed attention in recent years. This review comprehensively examines the concept of residence time (RT). We first summarize key ligand binding models (lock-and-key, induced-fit, and conformational selection) and delve into various perspectives on how RT impacts functional outcomes. Furthermore, we discuss experimental methods for measuring RT, highlighting both radioligand and non-radioligand approaches. The growing interest in RT has spurred advancements in computational techniques, particularly molecular dynamics simulations, which utilize diverse strategies to observe dissociation events. We outline these molecular dynamics-based methods, their theoretical foundations, and provide examples of their application in assessing RT. Finally, we highlight molecular determinants of prolonged RT, focusing primarily on G protein-coupled receptors (GPCRs) while also incorporating relevant data from other receptor classes.

配体-受体复合物的时间稳定性越来越被认为是药物发现的一个关键因素,影响药效和药效学。虽然复合作用持续时间和复合稳定性之间的关系可以追溯到保罗·埃利希(Paul Ehrlich) 19世纪的学说“非固定体”(Corpora nonagunt nisfixata),但其重要性近年来得到了重新关注。本文综述了停留时间(RT)的概念。我们首先总结了关键配体结合模型(锁-键、诱导拟合和构象选择),并深入探讨了RT如何影响功能结果的各种观点。此外,我们讨论了测量RT的实验方法,重点介绍了辐射配体和非辐射配体方法。对RT的日益增长的兴趣刺激了计算技术的进步,特别是分子动力学模拟,它利用不同的策略来观察解离事件。我们概述了这些基于分子动力学的方法及其理论基础,并提供了它们在评估RT中的应用实例。最后,我们强调了延长RT的分子决定因素,主要关注G蛋白偶联受体(gpcr),同时也结合了其他受体类别的相关数据。
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引用次数: 0
Adolescent cannabidiol treatment produces antidepressant-like effects without compromising long-term cognition in rats. 青少年大麻二酚治疗产生类似抗抑郁的效果,而不损害大鼠的长期认知能力。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-06-16 DOI: 10.1007/s43440-025-00750-5
Laura Gálvez-Melero, Itziar Beruete-Fresnillo, Sandra Ledesma-Corvi, M Julia García-Fuster

Background: Recent preclinical studies have shown sex-dependent antidepressant-like responses of cannabidiol in adolescence, which were dependent on biological sex, early-life stress, and dose. In particular, cannabidiol (10 mg/kg) induced acute and sustained antidepressant-like responses in adolescent male rats, while it lacked efficacy in females. This follow-up study aimed at further characterizing cannabidiol's effects in adolescence, in an attempt to overcome female unresponsiveness, while also evaluating its long-term safety profile in adulthood.

Methods: Groups of adolescent rats of both sexes were treated (ip) with cannabidiol (10, 30, 60 mg/kg) or vehicle (1 ml/kg) for 7 days. Acute (30 min post-injection) and repeated (24 h post-treatment) antidepressant-like responses were measured in the forced-swim test. Brains were collected to evaluate several neurochemical correlates in the hippocampus (CBR1, CBR2, BDNF, and cell proliferation) after adolescent cannabidiol exposure (acute and repeated). Some rats were left undisturbed until adulthood, when long-term effects on cognition were measured in the Barnes maze (short- and long-term memory) or affective-like responses in the forced-swim test. Data was analyzed with two-way ANOVAs (independent variables: sex and treatment).

Results: While the dose of 10 mg/kg of cannabidiol induced antidepressant-like effects in adolescent rats, higher doses had no effect in adolescent rats of both sexes. No changes were observed in any of the hippocampal neuroplasticity markers evaluated. Adolescent cannabidiol exposure did not induce long-term changes in cognitive performance or affective-like behavior.

Conclusions: Overall, our data suggest that adolescent cannabidiol treatment produces dose-dependent antidepressant-like effects of moderate magnitude without compromising long-term cognition in rats.

背景:最近的临床前研究表明,大麻二酚在青春期的抗抑郁样反应依赖于生理性别、早期生活压力和剂量。特别是,大麻二酚(10 mg/kg)在青春期雄性大鼠中诱导急性和持续的抗抑郁样反应,而在雌性大鼠中缺乏疗效。这项后续研究旨在进一步表征大麻二酚在青春期的作用,试图克服女性的无反应性,同时评估其在成年期的长期安全性。方法:将青春期大鼠分为两组,分别给予大麻二酚(10、30、60 mg/kg)或对照(1 ml/kg)治疗7 d。在强迫游泳试验中测量急性(注射后30分钟)和重复(治疗后24小时)抗抑郁样反应。在青少年大麻二酚暴露(急性和重复)后,收集大脑以评估海马中的几种神经化学相关物质(CBR1, CBR2, BDNF和细胞增殖)。一些大鼠不受干扰,直到成年,在巴恩斯迷宫(短期和长期记忆)中测量对认知的长期影响,或在强迫游泳测试中测量情感反应。数据采用双因素方差分析(自变量:性别和治疗)。结果:10 mg/kg剂量的大麻二酚对青春期大鼠有类似抗抑郁的作用,而更高剂量的大麻二酚对雌雄大鼠均无作用。未观察到海马神经可塑性指标的任何变化。青少年接触大麻二酚不会引起认知表现或情感行为的长期变化。结论:总的来说,我们的数据表明,青少年大麻二酚治疗在不影响大鼠长期认知的情况下产生中等程度的剂量依赖性抗抑郁样作用。
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引用次数: 0
Naltrexone dose-selectively modulates goal-directed behavior and the hypothalamic proteome in rats. 纳曲酮剂量选择性调节大鼠目标定向行为和下丘脑蛋白质组。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-05-28 DOI: 10.1007/s43440-025-00735-4
Natalia Malikowska-Racia, Przemysław Mielczarek, Piotr Popik

Background: Naltrexone is an opioid receptor antagonist that can modulate reward processing in opposite directions depending on the dose. Whether naltrexone similarly affects motivation remains unexplored. This study investigates the effects of naltrexone on behavioral measures of motivation and search for potential mechanisms, including the endogenous opioid pathway dependent on proopiomelanocortin (POMC).

Methods: Male Sprague Dawley rats received naltrexone (0.01, 0.1, or 1 mg/kg, ip) for two weeks. During this period, rats were tested daily using a progressive ratio schedule of reinforcement (PR) test and effort-based choice (EBC) that address motivational vigor, directedness, and effort-based decision-making. After tests, the hypothalami were collected for proteomic analysis using data-independent acquisition (DIA).

Results: Low-dose naltrexone (0.01 mg/kg; LDN) transiently increased PR response vigor without altering decision-making in EBC. At 0.1 mg/kg, but not at the high dose of 1 mg/kg, it impaired effort-based decision-making and goal-directedness. Proteomic analysis correlated LDN with the downregulation of a growth hormone (GH) pathway and altered G protein-coupled receptors (GPCR) signaling. Naltrexone's intermediate dose predominantly impacted proteins involved in neural growth, while the 1 mg/kg dose affected proteins related to gene regulation.

Conclusions: Different doses of naltrexone had varying effects on motivational measures and the rat's hypothalamic proteome. Naltrexone 0.1 mg/kg impaired motivational directedness and effort-based decision-making that corresponds to reduced reward signaling due to opioid blockade. In contrast, LDN enhanced vigor, but only early in the treatment. Naltrexone had no effects on the POMC-dependent endogenous opioid pathway, suggesting that a different mechanism underlies its motivational effects.

背景:纳曲酮是一种阿片受体拮抗剂,可以根据剂量调节相反方向的奖励加工。纳曲酮是否也会对动机产生类似的影响尚不清楚。本研究探讨了纳曲酮对动机行为测量的影响,并寻找潜在的机制,包括依赖于propropiomanocortin (POMC)的内源性阿片途径。方法:雄性sd大鼠给予纳曲酮(0.01、0.1、1 mg/kg, ig)治疗2周。在此期间,每天对大鼠进行递进比例强化(PR)测试和基于努力的选择(EBC)测试,以解决动机活力、方向性和基于努力的决策。测试后,收集下丘脑进行蛋白质组学分析,使用数据独立采集(DIA)。结果:低剂量纳曲酮(0.01 mg/kg;LDN在不改变EBC决策的情况下短暂地增加了PR反应活力。当剂量为0.1 mg/kg时,而不是高剂量为1 mg/kg时,它会损害基于努力的决策和目标导向。蛋白质组学分析将LDN与生长激素(GH)通路下调和G蛋白偶联受体(GPCR)信号通路改变相关。纳曲酮的中剂量主要影响与神经生长有关的蛋白质,而1mg /kg剂量影响与基因调控有关的蛋白质。结论:不同剂量纳曲酮对大鼠的动机测量和下丘脑蛋白质组有不同的影响。纳曲酮0.1 mg/kg会损害动机方向性和基于努力的决策,这与阿片类药物阻断导致的奖励信号减少相对应。相比之下,LDN增强活力,但仅在治疗早期。纳曲酮对pomc依赖性内源性阿片通路没有影响,表明其动机作用背后有不同的机制。
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引用次数: 0
Combined effects of HCRTR1/2 gene variants and non-genetic factors on sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia. HCRTR1/2基因变异和非遗传因素对异丙酚、右美托咪定和瑞芬太尼麻醉时睡眠-觉醒转换和血流动力学稳定性的联合影响
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-05-29 DOI: 10.1007/s43440-025-00740-7
Zhuoling Zheng, Faling Xue, Haini Wang, Qingling Gu, Rong Hu, Xiaoyan Li, Min Huang, Wenqi Huang, Zhongxing Wang, Jiali Li

Background: Propofol-remifentanil-dexmedetomidine-based total intravenous anesthesia is widely utilized in clinical practice. However, maintaining safety during the sleep-wake transition and ensuring hemodynamic stability continues to pose significant challenges. This study aimed to investigate the impact of genes that are expressed specifically in orexinergic neurons on interindividual variability in the time to loss of consciousness (LOC), time to wake, and cardiovascular fluctuations.

Methods: A total of 250 patients were included in the study. Gene polymorphisms were detected using the Agena Bioscience MassARRAY system. Anesthesia induction began with propofol and was maintained with propofol and remifentanil. Dexmedetomidine was administered before anesthesia induction. The time to LOC, time to wake, heart rate (HR), and mean arterial pressure (MAP) were documented.

Results: HCRTR2 (Hypocretin receptor 2) rs2292040 and rs76380807 were significantly associated with the time to LOC, and HCRTR2 rs7774031 was correlated with the time to wake. HCRTR2 rs3122162, rs3122169, and rs74296544 were correlated with HR fluctuations, and HCRTR1 (Hypocretin receptor 1) rs2176807, rs2271933, rs871634, and HCRTR2 rs74296544 were associated with MAP fluctuations. Multiple linear regression analysis revealed that the Target-controlled infusion (TCI) plasma concentration (Cp) of propofol > 4 µg ml- 1 at the time of LOC and dexmedetomidine were influencing factors for the time to LOC, whereas HCRTR2 rs7774031 influenced the time to wake. Baseline HR, baseline MAP, dexmedetomidine, HCRTR2 rs3122162, and HCRTR1 rs2176807 were predictive factors for cardiovascular susceptibility. The predictive models for the time to LOC, time to wake, mean HR, and mean MAP fluctuations accounted for 41.89%, 3.36%, 35.56%, and 47.41% of variations, respectively.

Conclusions: Genetic variants of HCRTR1 and HCRTR2 may affect sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia.

背景:异丙酚-瑞芬太尼-右美托咪定为基础的全静脉麻醉在临床中应用广泛。然而,维持睡眠-觉醒转换期间的安全性和确保血流动力学稳定性仍然构成重大挑战。本研究旨在探讨在食欲能神经元中特异性表达的基因对意识丧失时间(LOC)、苏醒时间和心血管波动等个体间变异的影响。方法:共纳入250例患者。基因多态性检测采用Agena Bioscience MassARRAY系统。麻醉诱导以异丙酚开始,并以异丙酚和瑞芬太尼维持。麻醉诱导前给予右美托咪定。记录LOC时间、苏醒时间、心率(HR)和平均动脉压(MAP)。结果:HCRTR2(下丘脑分泌素受体2)rs2292040和rs76380807与LOC时间显著相关,HCRTR2 rs7774031与醒来时间显著相关。HCRTR2 rs3122162、rs3122169和rs74296544与HR波动相关,HCRTR1(下丘脑分泌素受体1)rs2176807、rs2271933、rs871634和HCRTR2 rs74296544与MAP波动相关。多元线性回归分析显示,LOC时异丙酚> 4µg ml- 1的靶控输注(TCI)血浆浓度(Cp)和右美托咪定是LOC时间的影响因素,而HCRTR2 rs7774031影响苏醒时间。基线HR、基线MAP、右美托咪定、HCRTR2 rs3122162和HCRTR1 rs2176807是心血管易感性的预测因素。LOC时间、wake - up时间、平均HR和平均MAP波动的预测模型分别占变化的41.89%、3.36%、35.56%和47.41%。结论:HCRTR1和HCRTR2基因变异可能影响异丙酚、右美托咪定和瑞芬太尼麻醉时的睡眠-觉醒转换和血流动力学稳定性。
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引用次数: 0
Inflammatory lung diseases: a clinical and scientific review of the latest advances and challenges. 炎症性肺病:最新进展和挑战的临床和科学回顾。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-06-13 DOI: 10.1007/s43440-025-00749-y
Ahmed A Katamesh, Khaled Almansour, Shimaa M Hassoun, Ossama M Sayed, Mohammed Khaled Bin Break, Randa Mohammed Zaki, Obaid Afzal, Amr Radwan

Inflammatory lung diseases, including chronic obstructive pulmonary disease (COPD), asthma, pulmonary sarcoidosis, and interstitial lung diseases (ILDs), represent a significant cause of morbidity and mortality globally. These conditions are characterized by chronic inflammation and tissue damage, leading to substantial respiratory compromise and impairing quality of life. This review aims to provide a comprehensive overview of pathogenesis, clinical features, and diagnostic approaches for inflammatory lung diseases, emphasizing their shared and distinct characteristics. The review synthesizes current literature on the genetic predisposition, environmental exposures, and immune responses involved in the development and progression of inflammatory lung diseases. It also examines the classification and staging of these conditions to highlight the importance of accurate diagnosis and effective management. Key findings include the complex interplay of numerous factors that contribute to disease development and progression, as well as an analysis of classification and staging systems that support clinical practice. By elucidating the underlying mechanisms and clinical features of inflammatory lung diseases, this review aims to inform the development of novel therapeutic strategies and enhance patient outcomes.

炎性肺病,包括慢性阻塞性肺病(COPD)、哮喘、肺结节病和间质性肺病(ILDs),是全球发病率和死亡率的一个重要原因。这些疾病的特点是慢性炎症和组织损伤,导致严重的呼吸系统损害和生活质量下降。本文综述了肺部炎症性疾病的发病机制、临床特点和诊断方法,强调了它们的共同特点和各自的特点。这篇综述综合了目前关于炎症性肺部疾病发生和发展的遗传易感性、环境暴露和免疫反应的文献。它还检查了这些条件的分类和分期,以强调准确诊断和有效管理的重要性。主要发现包括导致疾病发展和进展的众多因素的复杂相互作用,以及支持临床实践的分类和分期系统的分析。通过阐明炎症性肺部疾病的潜在机制和临床特征,本综述旨在为开发新的治疗策略和提高患者预后提供信息。
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引用次数: 0
Emerging role of neural stem/progenitor cell secretome in brain inflammatory response modulation. 神经干/祖细胞分泌组在脑炎症反应调节中的新作用。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-05-19 DOI: 10.1007/s43440-025-00733-6
Krzysztof Łukowicz, Beata Grygier, Agnieszka Basta-Kaim

Adult stem cells residing in the body's tissues are responsible for the regeneration and replacement of old cells by new ones, thanks to their ability to differentiate. Scientific research increasingly focuses on the regeneration processes associated with these cells and the ability to modulate the microenvironment in which they are located. The modulatory effect can occur through direct interactions of stem cells with other cells or through their paracrine activity by releasing biologically active substances. For the nervous system, neural stem/progenitor cells are located in the subgranular zone in the hippocampal dentate gyrus and the subventricular zone around the lateral ventricles. This type of cell, in addition to giving rise to new neurons depending on the physiological state of the body, is also involved in the modulation of the niche in which they are found. This process plays a particular role in inflammation associated with many neurodegenerative diseases, which is connected with increased activity of the immune system cells. In this review article, we wanted to present the biologically active factors found in the neural stem/progenitor cells' secretome, which are key factors that can contribute physiologically to the silencing of inflammatory processes.

由于具有分化能力,存在于人体组织中的成体干细胞负责再生和新细胞替换旧细胞。科学研究越来越关注与这些细胞相关的再生过程以及调节它们所处微环境的能力。这种调节作用可以通过干细胞与其他细胞的直接相互作用或通过释放生物活性物质的旁分泌活性发生。对于神经系统,神经干/祖细胞位于海马齿状回的颗粒下区和侧脑室周围的室下区。这种类型的细胞,除了根据身体的生理状态产生新的神经元外,还参与调节它们所在的生态位。这个过程在与许多神经退行性疾病相关的炎症中起着特殊的作用,这与免疫系统细胞活性的增加有关。在这篇综述文章中,我们希望介绍在神经干/祖细胞分泌组中发现的生物活性因子,这些因子是生理上有助于炎症过程沉默的关键因素。
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引用次数: 0
Novel receptor tyrosine kinase-targeted strategies to overcome resistance in oral squamous cell carcinoma. 新的受体酪氨酸激酶靶向策略克服口腔鳞状细胞癌的耐药。
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-06-05 DOI: 10.1007/s43440-025-00745-2
Shahryar Irannejadrankouhi, Hassan Mivehchi, Aisan Eskandari-Yaghbastlo, Seyedeh Tabasom Nejati, Sahand Emrahoglu, Fatemeh Azarang, Abbas Nikroo, Mohsen Nabi-Afjadi

Treatment for oral squamous cell carcinoma (OSCC) has seen the rise of receptor tyrosine kinase inhibitors (RTKIs). However, their therapeutic effectiveness is severely limited by the emergence of resistance. Epidermal growth factor receptor (EGFR)-independent survival pathways, extracellular vesicle (EV)-mediated drug sequestration, lysosomal exocytosis, and metabolic reprogramming mediated by METTL1 (methyltransferase-like protein 1) are some of the molecular and cellular mechanisms that underlie RTKI resistance in OSCC. In this line, specific resistance methods are carefully studied, including the signaling processes involving SHP2, the different ways ErbB2 and AKT, and features related to tumor stemness. Additionally, the interaction between resistance and the tumor microenvironment (TME), namely via EVs and modified angiogenic signaling, is emphasized. Novel therapy approaches are put forth to address these issues. The effectiveness of treatment may be improved by combination treatments that include RTKIs with other medications, such as mTOR inhibitors, chemotherapy, radiation, and immunotherapies. Innovative nanotechnology-based strategies, such as exosome-based drug carriers and liposomal drug delivery systems, provide encouraging answers for overcoming resistance and enhancing precise targeting. Furthermore, phytochemicals and herbal remedies are investigated as supplementary approaches to enhance RTKI responses. Despite the potential of these approaches, obstacles, including resolving tumor heterogeneity, limiting off-target effects, and improving delivery methods, continue to be major obstacles to clinical use. To inform personalized medicine strategies, future studies should concentrate on finding predictive biomarkers and conducting thorough preclinical validation. By integrating emerging therapies and addressing these limitations, this work provides a comprehensive foundation for advancing the management of OSCC and improving patient outcomes.

口腔鳞状细胞癌(OSCC)的治疗已经看到受体酪氨酸激酶抑制剂(RTKIs)的上升。然而,由于耐药性的出现,它们的治疗效果受到严重限制。表皮生长因子受体(EGFR)独立的生存途径、细胞外囊泡(EV)介导的药物隔离、溶酶体胞吐和METTL1(甲基转移酶样蛋白1)介导的代谢重编程是OSCC中RTKI耐药的一些分子和细胞机制。在这条线中,我们仔细研究了具体的耐药方法,包括涉及SHP2的信号过程,ErbB2和AKT的不同途径,以及与肿瘤干性相关的特征。此外,还强调了耐药性与肿瘤微环境(TME)之间的相互作用,即通过ev和修饰的血管生成信号。新的治疗方法被提出来解决这些问题。通过将RTKIs与其他药物(如mTOR抑制剂、化疗、放疗和免疫疗法)联合治疗,可以提高治疗的有效性。基于创新纳米技术的策略,如基于外泌体的药物载体和脂质体药物递送系统,为克服耐药性和提高精确靶向性提供了令人鼓舞的答案。此外,还研究了植物化学物质和草药作为增强RTKI反应的补充方法。尽管这些方法具有潜力,但包括解决肿瘤异质性、限制脱靶效应和改进给药方法在内的障碍仍然是临床应用的主要障碍。为了为个性化医疗策略提供信息,未来的研究应集中于寻找预测性生物标志物并进行彻底的临床前验证。通过整合新兴疗法和解决这些局限性,这项工作为推进OSCC的管理和改善患者预后提供了全面的基础。
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引用次数: 0
Ocular microvascular changes in COVID-19: role of hypoxia, D-dimer, IL-6 and systemic treatment. COVID-19眼微血管变化:缺氧、d -二聚体、IL-6和全身治疗的作用
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-05-26 DOI: 10.1007/s43440-025-00738-1
Magdalena Kal, Michał Brzdęk, Izabella Karska-Basta, Piotr Rzymski, Antonio Pinna, Mateusz Winiarczyk, Jerzy Mackiewicz, Dominik Odrobina, Dorota Zarębska-Michaluk

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been associated with endothelial dysfunction, which may also compromise the microcirculation within ocular tissues. This prospective study evaluated associations between radial peripapillary capillary (RPC) vessel density (VD) and systemic treatment, age, hypoxia, D-dimer, and interleukin-6 (IL-6) levels in patients recovering from coronavirus disease 2019 (COVID-19) related pneumonia.

Methods: Sixty-three individuals who were admitted to the hospital due to COVID-19 bilateral pneumonia underwent ophthalmic examination two months post-discharge. RPC VD was measured using optical coherence tomography angiography. Associations with age, arterial hypertension, and systemic treatment (dexamethasone, remdesivir, and oxygen therapy), oxygen saturation, D-dimer, and IL-6 levels were evaluated. The control group comprised 43 control participants with no history of COVID-19 who attended routine ophthalmic examinations.

Results: No ophthalmic abnormalities were detected. RPC VD did not differ significantly with hypertension or systemic treatment with dexamethasone and remdesivir. However, patients receiving oxygen therapy had higher RPC VD. A borderline inverse correlation was observed between inferior RPC VD and age. There were no correlations between RPC VD and oxygen saturation. Significant inverse correlations were found between nasal RPC and mean RPC with D-dimer levels and between inferior RPC VD and IL-6 levels. No significant differences in RPC parameters were observed when comparing the COVID-19 group with controls.

Conclusions: Hypertension or systemic treatment had no significant effect on RCP VD. However, VD in specific RPC areas correlated inversely with D-dimer and IL-6 levels, highlighting the need for monitoring peripapillary microvasculature for potential long-term ocular effects of COVID-19.

背景:严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)与内皮功能障碍有关,内皮功能障碍也可能损害眼组织内的微循环。这项前瞻性研究评估了2019冠状病毒病(COVID-19)相关肺炎恢复期患者桡动脉乳头周围毛细血管密度(RPC)与全身治疗、年龄、缺氧、d -二聚体和白细胞介素-6 (IL-6)水平之间的关系。方法:63例因COVID-19双侧肺炎入院的患者在出院2个月后进行眼科检查。使用光学相干断层扫描血管造影测量RPC VD。评估与年龄、动脉高血压、全身治疗(地塞米松、瑞德西韦和氧治疗)、血氧饱和度、d -二聚体和IL-6水平的关系。对照组包括43名没有COVID-19病史的对照组参与者,他们参加了常规眼科检查。结果:未见眼部异常。RPC VD与高血压或全身性地塞米松和瑞德西韦治疗无显著差异。然而,接受氧疗的患者有较高的RPC VD。下位RPC VD与年龄呈临界负相关。RPC VD与血氧饱和度无相关性。鼻腔RPC和平均RPC与d -二聚体水平呈显著负相关,下RPC VD与IL-6水平呈显著负相关。与对照组相比,COVID-19组RPC参数无显著差异。结论:高血压或全身治疗对RCP VD无显著影响。然而,特定RPC区域的VD与d -二聚体和IL-6水平呈负相关,这突出表明需要监测乳头周围微血管,以了解COVID-19对眼部的潜在长期影响。
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引用次数: 0
Biomarkers associated with antidepressant response and illness severity in major depressive disorder: a pilot study. 重度抑郁障碍中与抗抑郁反应和疾病严重程度相关的生物标志物:一项初步研究
IF 3.6 3区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-08-01 Epub Date: 2025-05-30 DOI: 10.1007/s43440-025-00743-4
Massimiliano Buoli, Cecilia Maria Esposito, Alessandro Ceresa, Martina Di Paolo, Francesca Legnani, Anna Pan, Luca Ferrari, Valentina Bollati, Paola Monti

Background: Major Depressive Disorder (MDD) is a prevalent condition characterized by alterations in different biological systems including inflammatory and antioxidant pathways. Antidepressants seem to rebalance biological abnormalities. In this short communication, we report differences in a set of biomarkers between drug-free patients and those who benefited from response to antidepressant monotherapy.

Methods: A sample of patients affected by MDD (N = 38) was recruited at the inpatient and outpatient clinic of Policlinico Hospital in Milan: 26 responders and 12 drug-free subjects. The two groups of patients were compared by χ2 tests and analyses of variance, respectively, for qualitative and continuous variables. Correlation analyses were performed to evaluate the relationship between rating scale scores (severity of MDD) and biological parameters.

Results: Drug-free patients (compared to the counterpart) had a higher number of previous suicide attempts (p < 0.01), lower levels of plasmatic proteins (p < 0.01), albumin (p = 0.02), and total cholesterol (p = 0.02), but higher plasma levels of dehydroepiandrosterone sulfate (DHEAs) (p = 0.02), adrenocorticotropic hormone (ACTH) (p < 0.01) and angiotensin converting enzyme (ACE) (p = 0.02).

Conclusions: The results of the present study suggest that the severity of MDD is associated with more prominent biological changes, and antidepressants might mitigate these abnormalities. Future studies with larger samples are needed to confirm these preliminary findings.

背景:重度抑郁障碍(MDD)是一种以不同生物系统的改变为特征的普遍疾病,包括炎症和抗氧化途径。抗抑郁药似乎可以重新平衡生理异常。在这篇简短的交流中,我们报告了无药患者和受益于抗抑郁单药治疗的患者之间一组生物标志物的差异。方法:选取米兰Policlinico医院住院和门诊的MDD患者38例,其中有应答者26例,无药物者12例。两组患者分别采用χ2检验和方差分析对定性变量和连续变量进行比较。进行相关分析以评估评定量表得分(重度抑郁症)与生物学参数之间的关系。结论:本研究的结果表明,重度抑郁症的严重程度与更显著的生物学变化有关,抗抑郁药可能减轻这些异常。未来需要更大样本的研究来证实这些初步发现。
{"title":"Biomarkers associated with antidepressant response and illness severity in major depressive disorder: a pilot study.","authors":"Massimiliano Buoli, Cecilia Maria Esposito, Alessandro Ceresa, Martina Di Paolo, Francesca Legnani, Anna Pan, Luca Ferrari, Valentina Bollati, Paola Monti","doi":"10.1007/s43440-025-00743-4","DOIUrl":"10.1007/s43440-025-00743-4","url":null,"abstract":"<p><strong>Background: </strong>Major Depressive Disorder (MDD) is a prevalent condition characterized by alterations in different biological systems including inflammatory and antioxidant pathways. Antidepressants seem to rebalance biological abnormalities. In this short communication, we report differences in a set of biomarkers between drug-free patients and those who benefited from response to antidepressant monotherapy.</p><p><strong>Methods: </strong>A sample of patients affected by MDD (N = 38) was recruited at the inpatient and outpatient clinic of Policlinico Hospital in Milan: 26 responders and 12 drug-free subjects. The two groups of patients were compared by χ2 tests and analyses of variance, respectively, for qualitative and continuous variables. Correlation analyses were performed to evaluate the relationship between rating scale scores (severity of MDD) and biological parameters.</p><p><strong>Results: </strong>Drug-free patients (compared to the counterpart) had a higher number of previous suicide attempts (p < 0.01), lower levels of plasmatic proteins (p < 0.01), albumin (p = 0.02), and total cholesterol (p = 0.02), but higher plasma levels of dehydroepiandrosterone sulfate (DHEAs) (p = 0.02), adrenocorticotropic hormone (ACTH) (p < 0.01) and angiotensin converting enzyme (ACE) (p = 0.02).</p><p><strong>Conclusions: </strong>The results of the present study suggest that the severity of MDD is associated with more prominent biological changes, and antidepressants might mitigate these abnormalities. Future studies with larger samples are needed to confirm these preliminary findings.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1119-1125"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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Pharmacological Reports
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