Drug combinations have shown promise in suppressing drug resistance, improving drug efficacy, and reducing side effects in anticancer therapy. Considering that the anticancer activity of melatonin may be due to its antiproliferative, antioxidant, and immunomodulatory activities, the combined administration of this endogenous indoleamine with anticancer drugs has been extensively explored. This review provides an overview of the advances in the last five years in the anticancer activity of melatonin in combination with synthetic drugs and natural products. Papers on this topic were searched in PubMed, Google Scholar, Cochrane, and Scopus within the period 2018–2024. A total of 47 papers were retrieved showing a synergistic antitumor effect of melatonin combined with different drugs in the treatment of breast, colorectal, prostate, gastric, thyroid, and pancreatic cancer, as well as in head and neck squamous cell carcinoma, melanoma, and glioblastoma. The evidence gathered in this review will contribute to our knowledge of the use of melatonin. In addition, it may allow us to develop novel approaches to the treatment of cancer to be evaluated in preclinical and/or clinical trials.
{"title":"Melatonin combined with antineoplastic drugs or natural products for cancer treatment: An update","authors":"Cristina Trejo-Solís , Irma Susana Rojas-Tomé , Helgi Jung-Cook , Francisca Palomares-Alonso","doi":"10.1016/j.crphar.2025.100239","DOIUrl":"10.1016/j.crphar.2025.100239","url":null,"abstract":"<div><div>Drug combinations have shown promise in suppressing drug resistance, improving drug efficacy, and reducing side effects in anticancer therapy. Considering that the anticancer activity of melatonin may be due to its antiproliferative, antioxidant, and immunomodulatory activities, the combined administration of this endogenous indoleamine with anticancer drugs has been extensively explored. This review provides an overview of the advances in the last five years in the anticancer activity of melatonin in combination with synthetic drugs and natural products. Papers on this topic were searched in PubMed, Google Scholar, Cochrane, and Scopus within the period 2018–2024. A total of 47 papers were retrieved showing a synergistic antitumor effect of melatonin combined with different drugs in the treatment of breast, colorectal, prostate, gastric, thyroid, and pancreatic cancer, as well as in head and neck squamous cell carcinoma, melanoma, and glioblastoma. The evidence gathered in this review will contribute to our knowledge of the use of melatonin. In addition, it may allow us to develop novel approaches to the treatment of cancer to be evaluated in preclinical and/or clinical trials.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100239"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Asprosin, a novel adipokine released under fasting conditions, may play a significant role in the pathophysiology of type 2 diabetes mellitus (T2DM). The objective of this study is to investigate the effects of metformin on serum asprosin levels and FBN1 gene expression in white adipose tissue in male rats.
Methods
Thirty-two male Wistar rats were randomly and equally divided into four groups (n = 8): 1. Control Group (CON): Received standard food; 2. Non-Diabetic Metformin Group (CON + MET): Received standard food and were treated with metformin (400 mg/kg/day) for four weeks; 3. Diabetic Group (DM): Induced with T2DM; and 4. Diabetic Metformin Group (DM + MET): Induced with T2DM and treated with metformin (400 mg/kg/day) for four weeks. Finally, serum asprosin levels, lipid profiles, fasting glucose, and insulin concentrations were measured. The expression level of the FBN1 gene in white adipose tissue was quantified using quantitative real-time polymerase chain reaction (qRT-PCR).
Results
Serum asprosin levels were significantly higher in the DM group compared to both the CON and CON + MET groups (P < 0.0001). However, serum asprosin levels were significantly lower in the DM + MET group than in the DM group (P = 0.0003). Additionally, the FBN1 gene expression level in white adipose tissue was significantly higher in the DM group compared to the CON group (P = 0.0053), while FBN1 gene expression was significantly lower in the DM + MET group than in the DM group (P < 0.0001). Furthermore, lipid profile, insulin resistance, and fasting blood sugar improved in the CON + MET and DM + MET groups compared to the CON and DM groups, respectively.
Discussion
Our findings in diabetic male rats reveal that metformin treatment significantly downregulates FBN1 gene expression and reduces serum asprosin levels, suggesting a potential mechanism for its therapeutic benefits beyond improving insulin sensitivity.
{"title":"Metformin's impact on asprosin and FBN1 expression: Potential mechanisms beyond insulin sensitivity in type 2 diabetes in rats","authors":"Ali Dashtkar , Mansour Karajibani , Mohsen Saravani , Roya zanganeh , Hamed Fanaei","doi":"10.1016/j.crphar.2024.100207","DOIUrl":"10.1016/j.crphar.2024.100207","url":null,"abstract":"<div><h3>Background</h3><div>Asprosin, a novel adipokine released under fasting conditions, may play a significant role in the pathophysiology of type 2 diabetes mellitus (T2DM). The objective of this study is to investigate the effects of metformin on serum asprosin levels and FBN1 gene expression in white adipose tissue in male rats.</div></div><div><h3>Methods</h3><div>Thirty-two male Wistar rats were randomly and equally divided into four groups (n = 8): 1. Control Group (CON): Received standard food; 2. Non-Diabetic Metformin Group (CON + MET): Received standard food and were treated with metformin (400 mg/kg/day) for four weeks; 3. Diabetic Group (DM): Induced with T2DM; and 4. Diabetic Metformin Group (DM + MET): Induced with T2DM and treated with metformin (400 mg/kg/day) for four weeks. Finally, serum asprosin levels, lipid profiles, fasting glucose, and insulin concentrations were measured. The expression level of the FBN1 gene in white adipose tissue was quantified using quantitative real-time polymerase chain reaction (qRT-PCR).</div></div><div><h3>Results</h3><div>Serum asprosin levels were significantly higher in the DM group compared to both the CON and CON + MET groups (P < 0.0001). However, serum asprosin levels were significantly lower in the DM + MET group than in the DM group (P = 0.0003). Additionally, the FBN1 gene expression level in white adipose tissue was significantly higher in the DM group compared to the CON group (P = 0.0053), while FBN1 gene expression was significantly lower in the DM + MET group than in the DM group (P < 0.0001). Furthermore, lipid profile, insulin resistance, and fasting blood sugar improved in the CON + MET and DM + MET groups compared to the CON and DM groups, respectively.</div></div><div><h3>Discussion</h3><div>Our findings in diabetic male rats reveal that metformin treatment significantly downregulates FBN1 gene expression and reduces serum asprosin levels, suggesting a potential mechanism for its therapeutic benefits beyond improving insulin sensitivity.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100207"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11721834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crphar.2025.100220
Medha Satti , Kavita Prasad , Yash Patel , Demi Poulathas , Lawrence Walker , Esha Paghdal , Samuel Gunderson , Lei Yu
U1 Adaptor is a novel gene-silencing technology, offering an innovative approach to target genes in the CNS for the treatment of diseases. Intrathecal delivery is a medically viable route of administration of CNS-bound nucleic acid drugs; therefore, it is important to investigate U1 Adaptor distribution after intrathecal drug delivery. We investigated the distribution patterns of U1 Adaptor upon intrathecal bolus administration in mice. It readily distributes to CNS tissues, including the lumbar and the cervical spinal cord, and the cerebellum. Over time, the U1 Adaptor also accumulates in the periphery, both in the liver and the kidneys, while plasma levels are undetectable. Our findings provide useful information for future in-depth pharmacokinetic modeling of U1 Adaptor distribution upon intrathecal administration.
{"title":"Tissue distribution pharmacokinetics of intrathecal U1 adaptor oligonucleotide in mice","authors":"Medha Satti , Kavita Prasad , Yash Patel , Demi Poulathas , Lawrence Walker , Esha Paghdal , Samuel Gunderson , Lei Yu","doi":"10.1016/j.crphar.2025.100220","DOIUrl":"10.1016/j.crphar.2025.100220","url":null,"abstract":"<div><div>U1 Adaptor is a novel gene-silencing technology, offering an innovative approach to target genes in the CNS for the treatment of diseases. Intrathecal delivery is a medically viable route of administration of CNS-bound nucleic acid drugs; therefore, it is important to investigate U1 Adaptor distribution after intrathecal drug delivery. We investigated the distribution patterns of U1 Adaptor upon intrathecal bolus administration in mice. It readily distributes to CNS tissues, including the lumbar and the cervical spinal cord, and the cerebellum. Over time, the U1 Adaptor also accumulates in the periphery, both in the liver and the kidneys, while plasma levels are undetectable. Our findings provide useful information for future in-depth pharmacokinetic modeling of U1 Adaptor distribution upon intrathecal administration.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100220"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143851555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This review highlights the current status of cyclodextrin-based formulations tested in human participants, highlighting ongoing clinical research in this area. It provides a comprehensive link between the structure, properties, and clinical applications of these formulations, bridging the gap between medical theory and practical use. The aim of this work is to support the future commercialization of cyclodextrin-based therapies for patient care. Additionally, it emphasizes the need for expanded clinical investigations on cyclodextrin-based formulations, particularly cyclodextrin-based polymers, to pave the way for their successful introduction to the market. This is related to the potential of cyclodextrin-based polymers as advanced drug delivery systems, improving the therapeutic efficacy of numerous drugs. Expanding clinical trials will contribute to the optimization of cyclodextrin-based polymer synthesis, boosting their effectiveness as nanocarriers and facilitating the discovery of new disease treatments.
This review also explores the potential of artificial intelligence (AI) to support clinical and medical solutions.
{"title":"Cyclodextrin-based therapeutics delivery systems: A review of current clinical trials","authors":"Gjylije Hoti , Neha Bajwa , Fabrizio Caldera , Preet Amol Singh , Ibrahim Hussein , Claudio Cecone , Adrián Matencio , Rita Spagnolo , Monica Argenziano , Roberta Cavalli , Jitender Madan , Francesco Trotta","doi":"10.1016/j.crphar.2025.100232","DOIUrl":"10.1016/j.crphar.2025.100232","url":null,"abstract":"<div><div>This review highlights the current status of cyclodextrin-based formulations tested in human participants, highlighting ongoing clinical research in this area. It provides a comprehensive link between the structure, properties, and clinical applications of these formulations, bridging the gap between medical theory and practical use. The aim of this work is to support the future commercialization of cyclodextrin-based therapies for patient care. Additionally, it emphasizes the need for expanded clinical investigations on cyclodextrin-based formulations, particularly cyclodextrin-based polymers, to pave the way for their successful introduction to the market. This is related to the potential of cyclodextrin-based polymers as advanced drug delivery systems, improving the therapeutic efficacy of numerous drugs. Expanding clinical trials will contribute to the optimization of cyclodextrin-based polymer synthesis, boosting their effectiveness as nanocarriers and facilitating the discovery of new disease treatments.</div><div>This review also explores the potential of artificial intelligence (AI) to support clinical and medical solutions.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100232"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145018491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Flavonoids are hydroxylated polyphenols that are abundantly produced by plants as secondary metabolites. These flavonoids hold vast therapeutic potential as they possess numerous medicinal benefits encompassing anti-inflammatory, anti-oxidative, anticancer and antiviral properties. Flavonoids render anti-inflammatory effect either by activating antioxidant pathways or by inhibiting enzymatic secretions involved in inflammatory reactions. Flavonoids like quercetin targets inflammation by modulating expression of cytokines and pro-inflammatory molecules and by inhibiting pro-inflammatory enzymes. Mode of action, absorption and bioavailability of flavonoids greatly affect their biological activity. On-going research is focussing on isolation, synthesis of flavonoid analogs and effect of flavonoids on human health by manifestation of different techniques and animal models. Unravelling the anti-inflammatory potential of flavonoids can manifest better treatment options against variety of diseases and metabolic syndromes. Additionally, enhanced bioavailability of flavonoids can result in superior pharmaceutical activities.
{"title":"Anti-inflammatory potential of quercetin: From chemistry and mechanistic insight to nanoformulations","authors":"Diwakar Aggarwal , Mayank Chaudhary , Sachin Kumar Mandotra , Hardeep Singh Tuli , Ritu Chauhan , Naveen Chandra Joshi , Damandeep Kaur , Laurent Dufossé , Abhishek Chauhan","doi":"10.1016/j.crphar.2025.100217","DOIUrl":"10.1016/j.crphar.2025.100217","url":null,"abstract":"<div><div>Flavonoids are hydroxylated polyphenols that are abundantly produced by plants as secondary metabolites. These flavonoids hold vast therapeutic potential as they possess numerous medicinal benefits encompassing anti-inflammatory, anti-oxidative, anticancer and antiviral properties. Flavonoids render anti-inflammatory effect either by activating antioxidant pathways or by inhibiting enzymatic secretions involved in inflammatory reactions. Flavonoids like quercetin targets inflammation by modulating expression of cytokines and pro-inflammatory molecules and by inhibiting pro-inflammatory enzymes. Mode of action, absorption and bioavailability of flavonoids greatly affect their biological activity. On-going research is focussing on isolation, synthesis of flavonoid analogs and effect of flavonoids on human health by manifestation of different techniques and animal models. Unravelling the anti-inflammatory potential of flavonoids can manifest better treatment options against variety of diseases and metabolic syndromes. Additionally, enhanced bioavailability of flavonoids can result in superior pharmaceutical activities.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100217"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crphar.2025.100230
Luis Sendra , Gladys G. Olivera-Pasquini , Enrique G. Zucchet , Fabiana D.V. Genvigir , María Isabel Beneyto , Julio Hernández-Jaras , María José Herrero , Salvador F. Aliño
Background
Pharmacogenetic variability has been reported to influence the efficacy and safety of immunosuppressive therapies in early stages of kidney transplantation. This study investigates long-term associations between pharmacogene variants and clinical outcomes in a cohort of kidney transplant recipients over a 12-year follow-up.
Materials and methods
We analyzed 37 SNPs from 14 genes related to drug metabolism and transport in 79 kidney transplant patients. Clinical parameters, including survival, renal function, tumor occurrence, and pharmacokinetics of tacrolimus, were evaluated. Logistic regression and Kaplan-Meier analyses assessed associations between gene variants and clinical outcomes.
Results
Variants in metabolizer (CYP3A5, CYP2B6) and transporter genes (ABCB1, ABCC2) were associated with 12-year survival. Increased tumor risk correlated with ABCC2 variants in donors and decreased risk with CYP2B6 rs3745274 in recipients. Renal function was influenced by variants in ABCB1, ABCC2, CYP3A5, CYP3A4, and CYP2B6. Tacrolimus dose-dependent concentration was affected by variants in CYP3A4, CYP3A5, CYP2C19, ABCB1, and SLCO1B1. Increased nephrotoxicity risk was associated with CYP2C19 rs4244285 and reduced by SLCO1B1 rs2306283 AA and AG variants. Gene variant interactions between metabolizer and transporter genes were also associated with altered risk of events incidence.
Discussion
Our findings support that pharmacogene variants influence transplant outcomes. Notable associations include survival related to ABCB1 and ABCC2 variants, tumor occurrence linked to CYP2B6 rs3745274, and renal function affected by multiple pharmacogenes. Variants in CYP2C19 and SLCO1B1 significantly impacted tacrolimus pharmacokinetics and nephrotoxicity risk. These results underline the importance of pharmacogenetic testing for personalized management in kidney transplantation, although further validation in larger cohorts is necessary.
{"title":"Pharmacogenetics association with long-term clinical evolution in a kidney transplant patients cohort","authors":"Luis Sendra , Gladys G. Olivera-Pasquini , Enrique G. Zucchet , Fabiana D.V. Genvigir , María Isabel Beneyto , Julio Hernández-Jaras , María José Herrero , Salvador F. Aliño","doi":"10.1016/j.crphar.2025.100230","DOIUrl":"10.1016/j.crphar.2025.100230","url":null,"abstract":"<div><h3>Background</h3><div>Pharmacogenetic variability has been reported to influence the efficacy and safety of immunosuppressive therapies in early stages of kidney transplantation. This study investigates long-term associations between pharmacogene variants and clinical outcomes in a cohort of kidney transplant recipients over a 12-year follow-up.</div></div><div><h3>Materials and methods</h3><div>We analyzed 37 SNPs from 14 genes related to drug metabolism and transport in 79 kidney transplant patients. Clinical parameters, including survival, renal function, tumor occurrence, and pharmacokinetics of tacrolimus, were evaluated. Logistic regression and Kaplan-Meier analyses assessed associations between gene variants and clinical outcomes.</div></div><div><h3>Results</h3><div>Variants in metabolizer (CYP3A5, CYP2B6) and transporter genes (ABCB1, ABCC2) were associated with 12-year survival. Increased tumor risk correlated with ABCC2 variants in donors and decreased risk with CYP2B6 rs3745274 in recipients. Renal function was influenced by variants in ABCB1, ABCC2, CYP3A5, CYP3A4, and CYP2B6. Tacrolimus dose-dependent concentration was affected by variants in CYP3A4, CYP3A5, CYP2C19, ABCB1, and SLCO1B1. Increased nephrotoxicity risk was associated with CYP2C19 rs4244285 and reduced by SLCO1B1 rs2306283 AA and AG variants. Gene variant interactions between metabolizer and transporter genes were also associated with altered risk of events incidence.</div></div><div><h3>Discussion</h3><div>Our findings support that pharmacogene variants influence transplant outcomes. Notable associations include survival related to ABCB1 and ABCC2 variants, tumor occurrence linked to CYP2B6 rs3745274, and renal function affected by multiple pharmacogenes. Variants in CYP2C19 and SLCO1B1 significantly impacted tacrolimus pharmacokinetics and nephrotoxicity risk. These results underline the importance of pharmacogenetic testing for personalized management in kidney transplantation, although further validation in larger cohorts is necessary.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100230"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144712926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crphar.2025.100241
Hsuan-Yin Tung , Yi-Ling Ye , Chi-Maw Lin , Li-Shian Shi
Arecoline, which is a primary alkaloid in areca nuts, contributes in key ways to the development of oral submucous fibrosis and the subsequent oral cancer through the induction of oxidative stress, promotion of fibrosis, and activation of oncogenic signaling. Salvianolic acid B (SAB) is the most abundant water-soluble phenolic compound found in Salvia miltiorrhiza Bunge. SAB appears to have the potential to mitigate the effects of arecoline. However, the interaction between SAB and arecoline in oral cancer has been less frequently discussed. Therefore, we conducted this study in which SCC-4 tongue cancer cells were treated with arecoline alone or in combination with SAB. The effects on collagen contraction, cell migration, reactive oxygen species (ROS) production, and transcriptomic alterations were assessed. Arecoline increased collagen contraction, ROS accumulation, and the activation of tumor-promoting pathways, including TGF-β/Smad, EGFR, MAPK, and ferroptosis. In contrast, SAB effectively decreased collagen contraction, reduced cell migration, and attenuated oxidative stress in a dose-dependent manner. Moreover, in the presence of arecoline, SAB supplementation reversed fibrosis-related processes, modulated metabolic activity, and enhanced DNA repair mechanisms, thereby counteracting arecoline-induced oncogenic effects. Therefore, SAB, through its ability to reduce oxidative stress, fibrosis, and metabolic dysregulation, is a promising therapeutic candidate for mitigating arecoline-induced tumor progression. Our study offers novel insights into the role of SAB in protecting against the pathophysiology of oral cancer and highlights its potential as a natural compound for the prevention and treatment of this disease.
{"title":"Salvianolic acid B decreases oxidative stress and alleviates the tumor-promoting effects of arecoline in oral cancer","authors":"Hsuan-Yin Tung , Yi-Ling Ye , Chi-Maw Lin , Li-Shian Shi","doi":"10.1016/j.crphar.2025.100241","DOIUrl":"10.1016/j.crphar.2025.100241","url":null,"abstract":"<div><div>Arecoline, which is a primary alkaloid in areca nuts, contributes in key ways to the development of oral submucous fibrosis and the subsequent oral cancer through the induction of oxidative stress, promotion of fibrosis, and activation of oncogenic signaling. Salvianolic acid B (SAB) is the most abundant water-soluble phenolic compound found in <em>Salvia miltiorrhiza</em> Bunge. SAB appears to have the potential to mitigate the effects of arecoline. However, the interaction between SAB and arecoline in oral cancer has been less frequently discussed. Therefore, we conducted this study in which SCC-4 tongue cancer cells were treated with arecoline alone or in combination with SAB. The effects on collagen contraction, cell migration, reactive oxygen species (ROS) production, and transcriptomic alterations were assessed. Arecoline increased collagen contraction, ROS accumulation, and the activation of tumor-promoting pathways, including TGF-β/Smad, EGFR, MAPK, and ferroptosis. In contrast, SAB effectively decreased collagen contraction, reduced cell migration, and attenuated oxidative stress in a dose-dependent manner. Moreover, in the presence of arecoline, SAB supplementation reversed fibrosis-related processes, modulated metabolic activity, and enhanced DNA repair mechanisms, thereby counteracting arecoline-induced oncogenic effects. Therefore, SAB, through its ability to reduce oxidative stress, fibrosis, and metabolic dysregulation, is a promising therapeutic candidate for mitigating arecoline-induced tumor progression. Our study offers novel insights into the role of SAB in protecting against the pathophysiology of oral cancer and highlights its potential as a natural compound for the prevention and treatment of this disease.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100241"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crphar.2025.100237
Szabolcs Hambalkó , Csilla Pelyhe , Csenger Kovácsházi , Bence Kenyeres , Bernadett Kiss , Bence Ágg , Tamás G. Gergely , Bennet Y. Weber , András Makkos , Gábor B. Brenner , Tímea Komlódi , László Tretter , Csaba Horváth , Izabela Jarabicová , Adriana Adameová , Anikó Görbe , Paola Poggi , Alexandros Chatgilialoglu , Ildikó Horváth , Domokos Máthé , Zoltán Giricz
Background
Obesity is a major risk factor for the development of cardiovascular disease. However, recent research shows that moderate obesity reduces the risk of developing cardiovascular disease. We evidenced before that MAO-B inhibitor selegiline reduced visceral adiposity.
Aim
Therefore, our aim was to investigate cardiac effects of selegiline in moderate obesity in rats treated with a high-fat diet (HFD).
Key findings
We demonstrated that HFD improved cardiac contractility parameters, which were reversed by selegiline. Enhanced contractility might be attributed to an increased sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a) expression and phospholamban pentamerization. Selegiline reduced SERCA2a expression in HFD. HFD increased Tumor necrosis factor and Nuclear factor-kappa B expression which were not affected by selegiline. HFD induced proapoptotic processes, which were restored by selegiline.
Conclusion
In conclusion, moderate obesity improves cardiac function through Ca2+ homeostasis and inflammatory processes and MAO-B inhibition reverses these effects.
{"title":"MAO-B inhibition by selegiline blunts cardiac functions improved by high-fat diet: Role of inflammation, apoptosis, and calcium-handling","authors":"Szabolcs Hambalkó , Csilla Pelyhe , Csenger Kovácsházi , Bence Kenyeres , Bernadett Kiss , Bence Ágg , Tamás G. Gergely , Bennet Y. Weber , András Makkos , Gábor B. Brenner , Tímea Komlódi , László Tretter , Csaba Horváth , Izabela Jarabicová , Adriana Adameová , Anikó Görbe , Paola Poggi , Alexandros Chatgilialoglu , Ildikó Horváth , Domokos Máthé , Zoltán Giricz","doi":"10.1016/j.crphar.2025.100237","DOIUrl":"10.1016/j.crphar.2025.100237","url":null,"abstract":"<div><h3>Background</h3><div>Obesity is a major risk factor for the development of cardiovascular disease. However, recent research shows that moderate obesity reduces the risk of developing cardiovascular disease. We evidenced before that MAO-B inhibitor selegiline reduced visceral adiposity.</div></div><div><h3>Aim</h3><div>Therefore, our aim was to investigate cardiac effects of selegiline in moderate obesity in rats treated with a high-fat diet (HFD).</div></div><div><h3>Key findings</h3><div>We demonstrated that HFD improved cardiac contractility parameters, which were reversed by selegiline. Enhanced contractility might be attributed to an increased sarcoplasmic/endoplasmic reticulum Ca<sup>2+</sup>-ATPase (SERCA2a) expression and phospholamban pentamerization. Selegiline reduced SERCA2a expression in HFD. HFD increased Tumor necrosis factor and Nuclear factor-kappa B expression which were not affected by selegiline. HFD induced proapoptotic processes, which were restored by selegiline.</div></div><div><h3>Conclusion</h3><div>In conclusion, moderate obesity improves cardiac function through Ca<sup>2+</sup> homeostasis and inflammatory processes and MAO-B inhibition reverses these effects.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100237"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-01DOI: 10.1016/j.crphar.2025.100214
Elaina Seemann, Trevor Beeler, Mohammed Alfarra, Mark Cosio, Charles Chan, Peyton Grant, Yingzi Chang
Background
Nebivolol is a β-adrenergic receptor antagonist that has intrinsic activity on β3-adrenergic receptors (β3-ARs). Previous studies suggest that nebivolol inhibits bFGF-induced vascular smooth muscle cell (VSMC) proliferation and migration and vascular injury-induced neointima formation through activation of β3-ARs. However, our recently published data shown that activation of β3-ARs produced the opposite results, suggesting that the mechanisms of nebivolol-mediated effects are not fully understood. The current project was to study the mechanisms of nebivolol’s effects on bFGF-induced VSMC proliferation and migration by comparing to the selective β3-AR agonist, CL316,243.
Methods
VSMCs isolated from Sprague Dawley rat aortas were pretreated with nebivolol or CL316,243 followed by stimulation with bFGF. Cell proliferation and migration and phosphorylation of ERK and AKT were measured.
Results
We found that pretreatment of VSMCs with nebivolol produced biphasic effects on bFGF-induced VSMC proliferation, manifested as potentiation at lower concentrations and inhibition at the higher concentration. The effects of low concentrations of nebivolol on bFGF-induced VSMC proliferation was blocked by the selective β3-AR antagonist, SR59230A. Nebivolol inhibited bFGF-induced cell migration at all concentrations tested. In addition, only higher concentrations of nebivolol significantly inhibited bFGF-induced AKT phosphorylation but not ERK phosphorylation whereas CL316,243 at all concentrations tested significantly enhanced bFGF-induced VSMC proliferation and migration and higher concentrations of CL316,243 not only enhanced bFGF-induced AKT phosphorylation but also ERK phosphorylation.
Conclusion
Our data suggest that the effect of nebivolol on bFGF-induced cell proliferation is concentration-dependent. The enhancement on bFGF-induced cell proliferation at lower concentrations appears to be mainly mediated by activation of β3-ARs but the inhibitory effects on bFGF-mediated cell proliferation as well as migration may occur through different mechanisms. AKT signaling is only involved in high concentrations of nebivolol-mediated effects.
{"title":"Mechanisms of nebivolol-mediated effects on bFGF-induced vascular smooth muscle cell proliferation and migration","authors":"Elaina Seemann, Trevor Beeler, Mohammed Alfarra, Mark Cosio, Charles Chan, Peyton Grant, Yingzi Chang","doi":"10.1016/j.crphar.2025.100214","DOIUrl":"10.1016/j.crphar.2025.100214","url":null,"abstract":"<div><h3>Background</h3><div>Nebivolol is a β-adrenergic receptor antagonist that has intrinsic activity on β<sub>3</sub>-adrenergic receptors (β<sub>3</sub>-ARs). Previous studies suggest that nebivolol inhibits bFGF-induced vascular smooth muscle cell (VSMC) proliferation and migration and vascular injury-induced neointima formation through activation of β<sub>3</sub>-ARs. However, our recently published data shown that activation of β<sub>3</sub>-ARs produced the opposite results, suggesting that the mechanisms of nebivolol-mediated effects are not fully understood. The current project was to study the mechanisms of nebivolol’s effects on bFGF-induced VSMC proliferation and migration by comparing to the selective β<sub>3</sub>-AR agonist, CL316,243.</div></div><div><h3>Methods</h3><div>VSMCs isolated from Sprague Dawley rat aortas were pretreated with nebivolol or CL316,243 followed by stimulation with bFGF. Cell proliferation and migration and phosphorylation of ERK and AKT were measured.</div></div><div><h3>Results</h3><div>We found that pretreatment of VSMCs with nebivolol produced biphasic effects on bFGF-induced VSMC proliferation, manifested as potentiation at lower concentrations and inhibition at the higher concentration. The effects of low concentrations of nebivolol on bFGF-induced VSMC proliferation was blocked by the selective β<sub>3</sub>-AR antagonist, SR59230A. Nebivolol inhibited bFGF-induced cell migration at all concentrations tested. In addition, only higher concentrations of nebivolol significantly inhibited bFGF-induced AKT phosphorylation but not ERK phosphorylation whereas CL316,243 at all concentrations tested significantly enhanced bFGF-induced VSMC proliferation and migration and higher concentrations of CL316,243 not only enhanced bFGF-induced AKT phosphorylation but also ERK phosphorylation.</div></div><div><h3>Conclusion</h3><div>Our data suggest that the effect of nebivolol on bFGF-induced cell proliferation is concentration-dependent. The enhancement on bFGF-induced cell proliferation at lower concentrations appears to be mainly mediated by activation of β<sub>3</sub>-ARs but the inhibitory effects on bFGF-mediated cell proliferation as well as migration may occur through different mechanisms. AKT signaling is only involved in high concentrations of nebivolol-mediated effects.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100214"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143487234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The repeated dressing changes, especially for infected wounds and those with high exudate, and applying drugs daily, are huge demands in wound management. Sustained and regulated medication release of BCS II/IV antibiotics improves chronic wound therapy. The poor solubility and absorption of BCS-class medicines makes it challenging at target site. This work seeks to build 3D nano scaffolds for administering ciprofloxacin, a BCS II/IV class medication, using biocompatible sulphonated polyether ether ketone mat produced by electrospinning, which is flexible. We demonstrated a reliable method to prevent burst drug release and maintain it for three weeks, with good biocompatibility, minimal cytotoxicity, and excellent tensile strength characterizing sulphonated polyether ether ketone. Nanofibers improve medication interaction and delivery due to their high specific surface area ratio. In vitro and in vivo experiments were used to define and study ciprofloxacin release from 30 % w/v sulphonated polyether ether ketone nanofibers. The SPEEK polymer/mat was analysed using 1H- NMR, FESEM, FTIR, TGA, and EDAX for structural and morphological characteristics. The UV spectroscopy showed that the nanofibrous SPEEK released 90 % ciprofloxacin over 21 days by non-Fickian diffusion (supported by mathematical modelling). Both direct and indirect MTT experiments at 1st, 3rd, and 7th days reveal compatibility with RAW 264.7 cell lines. Live-dead staining and cell adhesion investigations, support adherent cells and growth; scratch assay display migration in electrospun scaffold exhibits wound healing behaviour. In vivo investigations on Balb/C mice demonstrated that SPEEK-CF impregnated healed wounds from 3rd day and preventing infection till 14th day and confirmed by histopathology. This nanofibrous mat is suitable for sustained drug delivery.
{"title":"BCS II/IV antibiotics blended with SPEEK nanofibrous mat as an alternative for recurrent wound care: An in vitro and in vivo assessment","authors":"Himabindu Padinjarathil , Carmelo Drago , Sandro Dattilo , Libera Vitiello , Kaarthick Raaja Venkatachalam , Thirugnasambandam G. Manivasagam , Prasanna Ramani","doi":"10.1016/j.crphar.2025.100235","DOIUrl":"10.1016/j.crphar.2025.100235","url":null,"abstract":"<div><div>The repeated dressing changes, especially for infected wounds and those with high exudate, and applying drugs daily, are huge demands in wound management. Sustained and regulated medication release of BCS II/IV antibiotics improves chronic wound therapy. The poor solubility and absorption of BCS-class medicines makes it challenging at target site. This work seeks to build 3D nano scaffolds for administering ciprofloxacin, a BCS II/IV class medication, using biocompatible sulphonated polyether ether ketone mat produced by electrospinning, which is flexible. We demonstrated a reliable method to prevent burst drug release and maintain it for three weeks, with good biocompatibility, minimal cytotoxicity, and excellent tensile strength characterizing sulphonated polyether ether ketone. Nanofibers improve medication interaction and delivery due to their high specific surface area ratio. <em>In vitro</em> and <em>in vivo</em> experiments were used to define and study ciprofloxacin release from 30 % w/v sulphonated polyether ether ketone nanofibers. The SPEEK polymer/mat was analysed using <sup>1</sup>H- NMR, FESEM, FTIR, TGA, and EDAX for structural and morphological characteristics. The UV spectroscopy showed that the nanofibrous SPEEK released 90 % ciprofloxacin over 21 days by non-Fickian diffusion (supported by mathematical modelling). Both direct and indirect MTT experiments at 1st, 3rd, and 7th days reveal compatibility with RAW 264.7 cell lines. Live-dead staining and cell adhesion investigations, support adherent cells and growth; scratch assay display migration in electrospun scaffold exhibits wound healing behaviour. <em>In vivo</em> investigations on Balb/C mice demonstrated that SPEEK-CF impregnated healed wounds from 3rd day and preventing infection till 14th day and confirmed by histopathology. This nanofibrous mat is suitable for sustained drug delivery.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100235"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145412769","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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