Gloria Ciniero, Tiago Marques Pedro, Charles Dumontet, Ahmed H Elmenoufy, Frederick G West, Michael Weinfeld, Francesco Gentile, Jack A Tuszynski, Emeline Cros-Perrial, Lars Petter Jordheim
{"title":"The synergy between alkylating agents and ERCC1-XPF inhibitors is p53 dependent.","authors":"Gloria Ciniero, Tiago Marques Pedro, Charles Dumontet, Ahmed H Elmenoufy, Frederick G West, Michael Weinfeld, Francesco Gentile, Jack A Tuszynski, Emeline Cros-Perrial, Lars Petter Jordheim","doi":"10.1111/fcp.13043","DOIUrl":"https://doi.org/10.1111/fcp.13043","url":null,"abstract":"<p><strong>Background: </strong>DNA repair plays a major role in maintaining genomic stability, thus limiting the transformation of normal cells into cancer cells. However, in cancer patients treated with DNA-targeting drugs, DNA repair can decrease efficacy by removing the damage generated by such molecules that is needed to induce pharmacological activity. Inhibiting DNA repair thus represents an interesting approach to potentiating the activity of chemotherapy in this setting.</p><p><strong>Objectives: </strong>Here, we continue the characterization of an inhibitor of the interaction between Excision Repair Cross-Complementing Rrodent repair deficiency complementation group 1 (ERCC1) and Xeroderma Pigmentousum group F (XPF) (B9), two key proteins of nucleotide excision repair.</p><p><strong>Methods: </strong>We used various cell lines and co-incubation studies for the determination of cell survival and DNA repair capacities.</p><p><strong>Results: </strong>We show that it is synergistic with other platinum derivatives than previously described, and that synergy is lacking in cells not expressing ERCC1 or XPF. Finally, a series of experiments show that potentiation is observed only in cells expressing wild-type p53.</p><p><strong>Conclusion: </strong>Our results confirm the mechanism of action of our ERCC1-XPF inhibitor and give important additional data on this approach to enhance the activity of already existing cancer drugs.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Capivasertib augments chemotherapy via Akt inhibition in preclinical small cell lung cancer models.","authors":"Cheng Long, Hui Shen, Hui Li, Lan Han","doi":"10.1111/fcp.13042","DOIUrl":"https://doi.org/10.1111/fcp.13042","url":null,"abstract":"<p><strong>Background: </strong>Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer for which platinum-based chemotherapy is the standard of care. Despite an initial response to this therapy, patients eventually develop resistance to the chemotherapy.</p><p><strong>Objectives: </strong>To investigate the potential of capivasertib, an approved drug for advanced breast cancer, to enhance the efficacy of cisplatin in preclinical SCLC models and explore the underlying mechanisms.</p><p><strong>Methods: </strong>SCLC cell lines were treated with capivasertib and cisplatin, alone or in combination, to assess cell viability, proliferation, colony formation, and apoptosis. Next, capivasertib's effects, alone and combined with cisplatin, were evaluated in an SCLC mouse model. Mechanistic studies focused on Akt and MYC signaling, with constitutively active Akt overexpression used to assess its role.</p><p><strong>Results: </strong>Capivasertib is active against a panel of SCLC cell lines regardless of cellular origin and genetic profiling with IC50 at a clinically achievable range. Particularly, capivasertib inhibits proliferation and anchorage-independent colony formation and induces apoptosis in SCLC cells. It significantly augments cisplatin's inhibitory effects in all tested cell lines. Importantly, capivasertib at a non-toxic dose is effective in delaying SCLC growth in mice and its combination with cisplatin achieves nearly complete tumor growth inhibition. Mechanistic studies confirm that capivasertib inhibits Akt and MYC signaling, and furthermore, that overexpression of constitutively active Akt reversed anti-SCLC activity of capivasertib.</p><p><strong>Conclusion: </strong>Our work is the first to reveal that Akt inhibition can augment chemotherapy in SCLC, and capivasertib is a useful addition to the treatment armamentarium for SCLC.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"New ways to repurpose salmeterol in an animal model of fibromyalgia.","authors":"Mena Z Shafiek, Hala F Zaki, Ahmed F Mohamed","doi":"10.1111/fcp.13041","DOIUrl":"https://doi.org/10.1111/fcp.13041","url":null,"abstract":"<p><strong>Background: </strong>Fibromyalgia (FM) is a syndrome of pervasive chronic pain accompanied by low mood, sleep disorders, and cognitive decline. The dysfunction of central pain processing systems along with neurotransmitter disturbances are possible contributing mechanisms. Genetic polymorphism of the 𝛽2 adrenergic receptors is reported in FM patients. It is reported that chronic β2 agonists administration is effective for neuropathic pain alleviation. No current information, however, exists on their potential to alleviate nociplastic pain, such as FM. Therefore, the purpose of the current study is to examine salmeterol's potential antiallodynic effects in experimentally produced FM and explore some of the possible contributing mechanisms.</p><p><strong>Methods: </strong>Thirty rats are allocated into three groups (n = 10): a normal group, a reserpine group that received reserpine (1 mg/kg; s.c.) for 3 days, and a reserpine + salmeterol group that received salmeterol (1 mg/kg; i.p.) for 21 consecutive days following last reserpine injection.</p><p><strong>Results: </strong>Reserpine administration resulted in behavioral and biochemical changes consistent with FM, including thermal and mechanical hyperalgesia, depressive behavior, and motor incoordination. This is coupled with disturbed spinal monoamine levels, depressed cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, disturbed mitochondrial function/dynamics, and compromised blood-nerve barrier integrity. Treatment with salmeterol conceivably reversed these effects.</p><p><strong>Conclusion: </strong>β2 receptor agonists such as salmeterol could be regarded as a promising strategy for the management of FM.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142575847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wei-Zhe Liang, Kai-Wei Hsieh, Zong-Da Yang, Gwo-Ching Sun
{"title":"Induction of Ca<sup>2+</sup> signaling and cytotoxic responses of human lung fibroblasts upon an antihistamine drug oxatomide treatment and evaluating the protective effects of Ca<sup>2+</sup> chelating.","authors":"Wei-Zhe Liang, Kai-Wei Hsieh, Zong-Da Yang, Gwo-Ching Sun","doi":"10.1111/fcp.13040","DOIUrl":"https://doi.org/10.1111/fcp.13040","url":null,"abstract":"<p><strong>Background: </strong>Oxatomide, an antihistamine drug of the diphenylmethylpiperazine family, has anti-inflammatory effects in airway disease. Because oxatomide was shown to cause diverse physiological responses in several cell models, the impact of oxatomide on Ca<sup>2+</sup> signaling and its related physiological effects has not been explored in IMR-90 human fetal lung fibroblasts.</p><p><strong>Objectives: </strong>This study assessed the effect of oxatomide on cell viability and intracellular free Ca<sup>2+</sup> concentrations ([Ca<sup>2+</sup>]<sub>i</sub>) and examined whether oxatomide-induced cytotoxicity through Ca<sup>2+</sup> signaling in IMR-90 cells.</p><p><strong>Methods: </strong>Cell viability was measured by the cell proliferation reagent (WST-1). [Ca<sup>2+</sup>]<sub>i</sub> was measured by the Ca<sup>2+</sup>-sensitive fluorescent dye fura-2.</p><p><strong>Results: </strong>Oxatomide (10-40 μM) concentration dependently reduced cell viability and induced [Ca<sup>2+</sup>]<sub>i</sub> rises in IMR-90 cells. This cytotoxic effect was reversed by chelation of cytosolic Ca<sup>2+</sup> with BAPTA-AM. In terms of Ca<sup>2+</sup> signaling, oxatomide-caused Ca<sup>2+</sup> entry was inhibited by modulators of store-operated Ca<sup>2+</sup> channels (2-APB and SKF96365) and protein kinase C (PKC) inhibitor (GF109203X). Furthermore, oxatomide-induced Ca<sup>2+</sup> influx was confirmed by Mn<sup>2+</sup>-induced quench of fura-2 fluorescence. In a Ca<sup>2+</sup>-free medium, preincubation with the endoplasmic reticulum Ca<sup>2+</sup> pump inhibitor thapsigargin inhibited oxatomide-evoked [Ca<sup>2+</sup>]<sub>i</sub> rises. Conversely, treatment with oxatomide abolished thapsigargin-induced [Ca<sup>2+</sup>]<sub>i</sub> rises. Inhibition of phospholipase C (PLC) with U73122 also inhibited oxatomide-caused [Ca<sup>2+</sup>]<sub>i</sub> rises.</p><p><strong>Conclusion: </strong>In IMR-90 cells, oxatomide-induced cytotoxicity by preceding [Ca<sup>2+</sup>]<sub>i</sub> rises involving PKC-sensitive store-operated Ca<sup>2+</sup> entry and PLC-dependent Ca<sup>2+</sup> release from the endoplasmic reticulum. BAPTA-AM, with its Ca<sup>2+</sup> chelating effects, may be a potential compound for preventing oxatomide-induced cytotoxicity.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Nociceptive TRP channels function as molecular target for several antifungal drugs","authors":"Shota Okabe, Kenji Takahashi, Miho Hashimoto, Toshio Ohta","doi":"10.1111/fcp.13039","DOIUrl":"10.1111/fcp.13039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background/objectives</h3>\u0000 \u0000 <p>Topically applied antifungal agents can induce adverse effects, such as pain and irritation. The transient receptor potential (TRP) channels—TRPA1 and TRPV1—mainly expressed in sensory neurons, act as sensors for detecting irritants. This study aims to evaluate the involvement of nociceptive channels in topical antifungal-induced pain and irritation. We tested nine topical antifungals belonging five classes: isoconazole, econazole, miconazole, clotrimazole, and ketoconazole as imidazoles; liranaftate as a thiocarbamate; terbinafine as an allylamine; amorolfine as a morpholine; and butenafine as a benzylamine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Intracellular calcium concentrations ([Ca<sup>2+</sup>]<sub>i</sub>) and membrane currents in response to antifungals were measured to estimate channel activity using heterologously expressing cells and isolated mouse sensory neurons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In mouse TRPA1-expressing cells, all the tested drugs induced an increase in [Ca<sup>2+</sup>]<sub>i</sub>, which was abrogated or reduced by a TRPA1 blocker. Although many drugs evoked the TRPA1-nonspecific [Ca<sup>2+</sup>]<sub>i</sub> response at high concentrations, responses to clotrimazole, ketoconazole, and liranaftate were TRPA1 specific and elicited current responses in TRPA1-expressing cells. In mouse TRPV1-expressing cells, clotrimazole and ketoconazole elicited [Ca<sup>2+</sup>]<sub>i</sub> and current responses. In mouse sensory neurons, liranaftate-induced increase in [Ca<sup>2+</sup>]<sub>i</sub> was abrogated by a TRPA1 blocker and <i>Trpa1</i> deletion. Responses to ketoconazole were inhibited by TRPA1 and TRPV1 blockers and by the genetic deletion of either channel.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These results suggest that topical antifungal-induced pain and irritation are attributable to the activation of nociceptive TRPA1 and/or TRPV1 channel/s. Consequently, caution should be exercised in the use of topical antifungals with symptoms of pain.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1178-1189"},"PeriodicalIF":2.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/fcp.13039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142463158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alfredo Augusto Vasconcelos-Silva, Suliana Mesquita Paula, Karine Lima-Silva, Kalinne Kelly Lima de Gadelha, Rodrigo José Bezerra de Siqueira, Armenio Aguiar Dos Santos, Saad Lahlou, Ricardo de Freitas Lima, Pedro Jorge Caldas Magalhães
{"title":"In vitro evidence that the vasorelaxant effects of 2-nitro-1-phenyl-1-propanol on rat coronary arteries involve cyclic nucleotide pathways.","authors":"Alfredo Augusto Vasconcelos-Silva, Suliana Mesquita Paula, Karine Lima-Silva, Kalinne Kelly Lima de Gadelha, Rodrigo José Bezerra de Siqueira, Armenio Aguiar Dos Santos, Saad Lahlou, Ricardo de Freitas Lima, Pedro Jorge Caldas Magalhães","doi":"10.1111/fcp.13038","DOIUrl":"https://doi.org/10.1111/fcp.13038","url":null,"abstract":"<p><p>The synthetic nitro-alcohol 2-nitro-1-phenyl-1-propanol (NPP) has endothelium-independent relaxing properties in isolated preparations of rat aorta and mesenteric artery. In this study, we investigated whether the vasodilator effects occur in coronary vessels and explored whether hyperpolarization is involved in the underlying mechanism of NPP-induced smooth muscle relaxation. The relaxing responses were studied in isolated preparations of the left anterior descending coronary (ADC) and the septal coronary (SC) arteries, which had been previously maintained under sustained contraction induced by the thromboxane A<sub>2</sub> analogue U-46619. Administered cumulatively, NPP elicited concentration-dependent vasorelaxation with similar potency in both vessels. The relaxant effect remained unaffected by the nitric oxide synthase inhibitor L-NAME, the protein kinase C inhibitor bisindolylmaleimide IV and the Rho-associated protein kinase inhibitor Y-27632. However, it was significantly diminished by the adenylyl cyclase inhibitor MDL-12,330A, the guanylyl cyclase inhibitor ODQ, as well as the K<sup>+</sup> channel inhibitors tetraethylammonium and CsCl. In ADC preparations impaled with intracellular micropipettes, NPP hyperpolarized the vascular preparation. When the isolated preparation was precontracted by 5-hydroxytryptamine or 80 mM KCl, NPP-induced relaxation with lower pharmacological potency compared to the vessels contracted by U-46619. In conclusion, NPP exhibits vasorelaxant effects on rat coronary arteries, likely involving pathways that include cyclic nucleotide production and membrane hyperpolarization.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lucas Silva de Baco, Laura Cé da Silva, Luis Carlos Moreira Antunes, Marina Venzon Antunes, Rafael Linden, Mauber Eduardo Schultz Moreira, Ricardo Bolsson Radins, Sarayane Araújo Brandão Maranhão, Sylvio Elvis da Silva Barbosa, Lucimara Volpato, Lauren Razzera Stefanon, Natália Brucker
{"title":"Evaluation of chemotherapy toxicities in patients receiving treatment for gastrointestinal cancers and therapeutic monitoring of 5-fluorouracil as a clinical support tool","authors":"Lucas Silva de Baco, Laura Cé da Silva, Luis Carlos Moreira Antunes, Marina Venzon Antunes, Rafael Linden, Mauber Eduardo Schultz Moreira, Ricardo Bolsson Radins, Sarayane Araújo Brandão Maranhão, Sylvio Elvis da Silva Barbosa, Lucimara Volpato, Lauren Razzera Stefanon, Natália Brucker","doi":"10.1111/fcp.13037","DOIUrl":"10.1111/fcp.13037","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>5-Fluorouracil (5-FU) is essential in treating gastrointestinal cancers, but some patients show severe toxicity. The toxicity is exposure-related, which is linked to the enzyme dihydropyrimidine dehydrogenase (DPD) decoded by the DPYD gene. This study aimed to evaluate the possible toxicity related to 5-FU plasma levels, DPYD genotyping, and DPD phenotyping.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Forty-seven gastrointestinal cancer patients receiving 5-FU were included in this study. 5-FU plasma levels and DPD phenotyping were analyzed by UPLC-MS/MS. DPYD genotyping was also assessed. The Common Terminology Criteria for Adverse Events (CTCAE) was used to classify the toxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>For hematological toxicity, 27.65% showed neutropenia, 78.72% anemia, and 29.78% thrombocytopenia. The area under the curve (AUC) of 5-FU calculated from the plasma was evaluated for three treatment cycles, and we observed that at the initial cycle, 48.93% were underexposed and 10.63% were overexposed, with a total of 59.56% of patients outside the therapeutic range. In the DPYD genotyping, 97.87% of patients had a wild-type genotype, and 2.12% had c.1236G>A mutation (E412E, rs56038477). A total of 82.97% of patients showed a phenotype compatible with normal DPD activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest that the evaluation of DPYD genotyping and DPD phenotyping in the Brazilian population still requires further study. Moreover, the analysis of the plasma AUC of 5-FU could contribute to clinical routine, being a very useful tool, especially for identifying patients outside the therapeutic range and thus guiding more individualized doses, or even in the intervention of possible toxicities related to overexposure.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1190-1202"},"PeriodicalIF":2.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142284312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marija Marinko, Ivan Stojanovic, Predrag Milojevic, Dragoslav Nenezic, Vladimir Kanjuh, Qin Yang, Guo-Wei He, Aleksandra Novakovic
{"title":"Involvement of different K+ channel subtypes in hydrogen sulfide-induced vasorelaxation of human internal mammary artery","authors":"Marija Marinko, Ivan Stojanovic, Predrag Milojevic, Dragoslav Nenezic, Vladimir Kanjuh, Qin Yang, Guo-Wei He, Aleksandra Novakovic","doi":"10.1111/fcp.13036","DOIUrl":"10.1111/fcp.13036","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Changes in K<sup>+</sup> channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K<sup>+</sup> channels. Their involvement in hydrogen sulfide (H<sub>2</sub>S)-mediated vasorelaxation is still unclear, and data about human vessels are limited.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To determine the role of K<sup>+</sup> channel subtypes in the vasorelaxant mechanism of H<sub>2</sub>S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NaHS (1 × 10<sup>−6</sup>–3 × 10<sup>−3</sup> mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K<sup>+</sup>. Among K<sup>+</sup> channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (<i>P</i> < 0.01), whereas in the presence of apamin/1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) combination, the HIMA relaxation was partially reduced (<i>P</i> < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L-NAME and KT5823, and by cyclo-oxygenase inhibitor, indomethacin (<i>P</i> < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM-34 and glibenclamide caused further decrease in NaHS-induced vasorelaxation (<i>P</i> < 0.01), while iberiotoxin, 4-AP, and margatoxin were without additional effect (<i>P</i> > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (<i>P</i> < 0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our results demonstrated that H<sub>2</sub>S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H<sub>2</sub>S included direct or indirect opening of different K<sup>+</sup> channel subtypes, K<sub>ATP</sub>, BK<sub>Ca</sub>, SK<sub>Ca</sub>/IK<sub>Ca</sub>, and K<sub>V</sub> (subtype K<sub>V</sub>1.3), in addition to NO pathway activation and interference with extracellular Ca<sup>2+</sup> influx.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1155-1167"},"PeriodicalIF":2.1,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yomna M. Tamim, Mohamed L. Soliman, Moataz M. Sayed, Muhammad S. Abdul-Rasheed, Ahmed A. Nagy, Ahmed M. Abdellah, Ahmed H. Osman, Amel F. M. Ismail
{"title":"Acetazolamide suppresses the progression of hepatocellular carcinoma induced by diethylnitrosamine in Wistar albino rats","authors":"Yomna M. Tamim, Mohamed L. Soliman, Moataz M. Sayed, Muhammad S. Abdul-Rasheed, Ahmed A. Nagy, Ahmed M. Abdellah, Ahmed H. Osman, Amel F. M. Ismail","doi":"10.1111/fcp.13032","DOIUrl":"10.1111/fcp.13032","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) continues to be the most prevalent type of liver cancer worldwide. Diethylnitrosamine (DEN)-induced HCC is an extensively used hepatic cancer model in experimental animals. Acetazolamide (AZA) is a carbonic anhydrase enzyme inhibitor. This study aimed to assess the therapeutic mechanism of AZA against DEN-induced HCC. Thirty male <i>Wistar</i> albino rats were divided equally into three groups. Group I (C): control group, Group II (HCC): DEN-induced HCC, and Group III (HCC/AZA): AZA-treated HCC. Verification of the HCC induced by DEN was confirmed by elevated liver enzymes' activities, and increased α-fetoprotein (AFP) levels, as well as distinct liver architecture changes. On the other hand, the AZA-treated HCC group experienced decreases in the activities of serum liver enzymes and AFP levels, as well as, regulated liver architecture. Additionally, it downregulated p-p38 MAPK/p-JNK1/JNK2/p-C-Jun/p-NF-κB p65 protein expressions. Moreover, it ameliorated autophagy by controlling the expression of the p-AMPK/p-mTOR1/LC3 I/II proteins. Furthermore, it downregulated the relative gene expressions of carbonic anhydrase-IX (CAIX) and hexokinase-II (HKII). Histopathological examination of AZA-treated HCC liver tissues supported these findings. Conclusion: AZA provides a new dimension in ameliorating experimentally induced HCC through regulation of hepatic biomarkers, antioxidant status, inflammatory markers, and autophagy, mediated by amelioration of CAIX and HKII gene expressions.</p>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1045-1058"},"PeriodicalIF":2.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tainá Larissa Lubschinski, Luiz Antonio Escorteganha Pollo, Paula Giarola Fragoso de Oliveira, Luigi Arruda Nardino, Eduarda Talita Bramorski Mohr, Ziliani da Silva Buss, Louis Pergaud Sandjo, Maique Weber Biavatti, Felipe Perozzo Daltoé, Eduardo Monguilhott Dalmarco
{"title":"Preclinical evidence of the anti-inflammatory effect and toxicological safety of aryl-cyclohexanone in vivo","authors":"Tainá Larissa Lubschinski, Luiz Antonio Escorteganha Pollo, Paula Giarola Fragoso de Oliveira, Luigi Arruda Nardino, Eduarda Talita Bramorski Mohr, Ziliani da Silva Buss, Louis Pergaud Sandjo, Maique Weber Biavatti, Felipe Perozzo Daltoé, Eduardo Monguilhott Dalmarco","doi":"10.1111/fcp.13035","DOIUrl":"10.1111/fcp.13035","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Respiratory distress syndrome is a complex inflammatory condition defined by the presence of acute hypoxemia and cellular infiltration with diffuse alveolar injury following a tissue injury, such as acute lung injury. The inflammatory process involved in this pathology is a defense mechanism of the body against infectious agents and/or tissue injuries. However, when the condition is not reversed, it becomes a significant cause of tissue damage, sometimes leading to loss of function of the affected organ. Therefore, it is essential to understand the mechanisms underlying inflammation, as well as the development of new therapeutic agents that reduce inflammatory damage in these cases. Aryl-cyclohexanone derivatives have previously shown significant anti-inflammatory activity linked to an immunomodulatory capacity in vitro and may be good candidates for therapies in which inflammation plays a central role.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Was evaluated the anti-inflammatory capacity of a synthesized molecule aryl-cyclohexanone in the murine model of lipopolysaccharide (LPS)-induced acute lung injury. The assessment of acute oral toxicity follows the Organization for Economic Co-operation and Development (OECD) guideline 423.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The results demonstrated that the studied molecule protects against LPS-induced inflammation. We observed a decrease in the migration of total and differential leukocytes to the bronchoalveolar lavage fluid (BALF), in addition to a reduction in exudation, myeloperoxidase (MPO) activity, nitric oxide metabolites, and the secretion of pro-inflammatory cytokines (alpha tumor necrosis factors [TNF-α], interleukin-6 [IL-6], interferon-gamma [IFN-γ], and monocyte chemoattractant protein-1 [MCP-1]). Finally, aryl cyclohexanone did not show signs of acute oral toxicity (OECD 423).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results prove our hypothesis that aryl-cyclohexanone is a promising molecule for developing a new, safe anti-inflammatory drug.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12657,"journal":{"name":"Fundamental & Clinical Pharmacology","volume":"38 6","pages":"1103-1115"},"PeriodicalIF":2.1,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}