Pharmacological Reports最新文献

{"title":"Unveiling hidden risks: pharmacogenetic insights from a cross-sectional study of statin therapy in the Indian population.","authors":"Shaik Mohammad Naushad, Palani Kumar Palanichamy, Jagadeesh Babu Sreemanthula, Yadam Reddy Kanaka Durga Devi, Palakonda Gopi, Tajamul Hussain, Vijay Kumar Kutala","doi":"10.1007/s43440-025-00746-1","DOIUrl":"10.1007/s43440-025-00746-1","url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Materials and methods: </strong>Whole exome sequencing was performed in 2180 subjects, and the variant data were segregated further into diplotypes and phenotypes.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1040-1049"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249142","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}

{"title":"Involvement of TRPV1 and MOR-NMDAR complex on the antiallodynic effect of LMH-2, a sigma-1 receptor antagonist, in mouse model of diabetic neuropathy - a behavioral approach.","authors":"Rosa Ventura-Martínez, Guadalupe Esther Ángeles-López, Tania Domínguez-Páez, Gabriel Navarrete-Vázquez, Wendy Arratia-Damián, Maria Eva González-Trujano, Myrna Déciga-Campos","doi":"10.1007/s43440-025-00727-4","DOIUrl":"10.1007/s43440-025-00727-4","url":null,"abstract":"<p><strong>Background: </strong>Recently, the antinociceptive effect of LMH-2, a σ1 receptor antagonist, has been reported in diabetic mice with neuropathic pain. However, the mechanism by which this effect is produced is not completely clear. In this study, we explored the involvement of TRPV1 and the MOR-NMDAR complex in the antiallodynic effect of LMH-2 in hyperglycemic mice with neuropathic pain.</p><p><strong>Methods: </strong>Hyperglycemia was induced in mice by administering streptozotocin-nicotinamide. Four weeks later, once neuropathic pain was established, the antiallodynic effect of LMH-2 (56.2 mg/kg) was evaluated using the up-down method with the von Frey filaments, both in the absence and the presence of capsazepine (8 mg/kg, ip), naloxone (NLX, 1 mg/kg, ip), NMDA (0.4 nM/10 µL, it), or their co-administration (NLX-NMDA). Gabapentin was used as positive control.</p><p><strong>Results: </strong>Pretreatment with NLX did not alter the antiallodynic effect of LMH-2 in the up-down method with the von Frey filaments in hyperglycemic mice, whereas NMDA significantly reduced it. The addition of NLX to NMDA (NLX-NMDA) did not modify the effect of NMDA alone on the antiallodynic activity of LMH-2. Additionally, capsazepine completely blocked the antinociceptive effect of LMH-2 in hyperglycemic mice. Molecular docking analysis suggested a potential interaction between LMH-2 and TRPV1. Moreover, a higher dose of LMH-2 did not cause mortality or damage in healthy mice.</p><p><strong>Conclusion: </strong>These results suggest the potential utility of LMH-2 in the treatment of diabetic neuropathy and highlight a key role for TRPV1 in LMH-2's antiallodynic mechanism, along with a possible, albeit limited, interaction with the MOR/NMDA complex.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1011-1023"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144064184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Empiric and targeted antibiotic therapy for bloodstream infections in internal medicine patients in Poland: a three-year analysis in a single centre using the AWaRe classification.","authors":"Piotr Piekiełko, Dariusz A Hareza, Ewa Stawowczyk, Estera Jachowicz-Matczak, Jadwiga Wójkowska-Mach","doi":"10.1007/s43440-025-00753-2","DOIUrl":"10.1007/s43440-025-00753-2","url":null,"abstract":"<p><strong>Background: </strong>Bloodstream infection (BSI), defined as bacteraemia accompanied by sepsis or septic shock, is a frequent cause of hospitalization in departments of internal medicine (DIM). This study aimed to characterize the epidemiology, microbiological profile, and antibiotic treatment patterns of BSIs in a DIM setting in 2021-2023 in Polish hospital.</p><p><strong>Methods: </strong>A three-year, single-centre retrospective analysis was conducted at a DIM in Southern Poland. Medical records from 2021 to 2023 were reviewed for patients diagnosed with sepsis (ICD-10 codes A40-A41) with microbiological confirmation. Antibiotic use was assessed using Days of Therapy (DOT) and Length of Therapy (LOT). Empiric and targeted therapies were classified according to the WHO AWaRe (Access, Watch, Reserve) framework.</p><p><strong>Results: </strong>A total of 124 BSI cases were identified, with an incidence rate of 5.8%. Community-acquired BSIs accounted for 84.3% of cases, while 15.7% were hospital-acquired. The predominant pathogens were Escherichia coli and Staphylococcus aureus. The median LOT for empiric therapy was 3 days (IQR 2-4), with third-generation cephalosporins being the most frequently used agents (78 patients; 43.3%, 228 DOTs; 43.9%). Targeted therapy had a median LOT of 8 days (IQR 5-10), most commonly involving penicillins (33 patients; 28.4%, 291 DOTs; 34.5%). Access group antibiotics were significantly more prevalent in targeted therapy compared to empiric therapy (p < 0.001).</p><p><strong>Conclusions: </strong>Microbiological confirmation of BSI facilitates a safe de-escalation from broad-spectrum empiric antibiotics to narrow-spectrum targeted therapy, supporting antimicrobial stewardship in internal medicine settings.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1100-1108"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241269/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Residence time in drug discovery: current insights and future perspectives.","authors":"Szymon K Kordylewski, Ryszard Bugno, Sabina Podlewska","doi":"10.1007/s43440-025-00748-z","DOIUrl":"10.1007/s43440-025-00748-z","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"851-873"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144249141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adolescent cannabidiol treatment produces antidepressant-like effects without compromising long-term cognition in rats.","authors":"Laura Gálvez-Melero, Itziar Beruete-Fresnillo, Sandra Ledesma-Corvi, M Julia García-Fuster","doi":"10.1007/s43440-025-00750-5","DOIUrl":"10.1007/s43440-025-00750-5","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Overall, our data suggest that adolescent cannabidiol treatment produces dose-dependent antidepressant-like effects of moderate magnitude without compromising long-term cognition in rats.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"999-1010"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combined effects of HCRTR1/2 gene variants and non-genetic factors on sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia.","authors":"Zhuoling Zheng, Faling Xue, Haini Wang, Qingling Gu, Rong Hu, Xiaoyan Li, Min Huang, Wenqi Huang, Zhongxing Wang, Jiali Li","doi":"10.1007/s43440-025-00740-7","DOIUrl":"10.1007/s43440-025-00740-7","url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>Genetic variants of HCRTR1 and HCRTR2 may affect sleep-wake transition and hemodynamic stability during propofol, dexmedetomidine, and remifentanil anesthesia.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"1050-1062"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174493","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}

{"title":"Naltrexone dose-selectively modulates goal-directed behavior and the hypothalamic proteome in rats.","authors":"Natalia Malikowska-Racia, Przemysław Mielczarek, Piotr Popik","doi":"10.1007/s43440-025-00735-4","DOIUrl":"10.1007/s43440-025-00735-4","url":null,"abstract":"<p><strong>Background: </strong>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).</p><p><strong>Methods: </strong>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).</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"983-998"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144161058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory lung diseases: a clinical and scientific review of the latest advances and challenges.","authors":"Ahmed A Katamesh, Khaled Almansour, Shimaa M Hassoun, Ossama M Sayed, Mohammed Khaled Bin Break, Randa Mohammed Zaki, Obaid Afzal, Amr Radwan","doi":"10.1007/s43440-025-00749-y","DOIUrl":"10.1007/s43440-025-00749-y","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"889-906"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144286109","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}

{"title":"Emerging role of neural stem/progenitor cell secretome in brain inflammatory response modulation.","authors":"Krzysztof Łukowicz, Beata Grygier, Agnieszka Basta-Kaim","doi":"10.1007/s43440-025-00733-6","DOIUrl":"10.1007/s43440-025-00733-6","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"907-920"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12241244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144094537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel receptor tyrosine kinase-targeted strategies to overcome resistance in oral squamous cell carcinoma.","authors":"Shahryar Irannejadrankouhi, Hassan Mivehchi, Aisan Eskandari-Yaghbastlo, Seyedeh Tabasom Nejati, Sahand Emrahoglu, Fatemeh Azarang, Abbas Nikroo, Mohsen Nabi-Afjadi","doi":"10.1007/s43440-025-00745-2","DOIUrl":"10.1007/s43440-025-00745-2","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":19947,"journal":{"name":"Pharmacological Reports","volume":" ","pages":"962-982"},"PeriodicalIF":3.6,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144226188","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}