Pub Date : 2026-01-01DOI: 10.1016/j.crphar.2025.100249
Lisa Myrseth Hemmingsen , Nataša Škalko-Basnet
Chronic wounds remain a significant challenge for healthcare systems worldwide, placing a considerable burden on both patients and resources. Their management is further complicated by the persistence of biofilm-forming bacteria and an escalating problem of antimicrobial resistance, both of which restrict the effectiveness of conventional therapies. Antimicrobial compounds with a rapid onset of action and activity that is not solely dependent on bacterial metabolism represent promising alternatives for bacterial and biofilm eradication. Among these, membrane-active antimicrobials (MAAs), including antimicrobial peptides, peptidomimetics, and other membrane-disrupting compounds, constitute a particularly interesting group of agents. Recent investigations have revealed diverse mechanisms through which MAAs compromise biofilm integrity, ranging from permeabilization of bacterial membranes to interference with quorum sensing and extracellular polymeric substances. Furthermore, pharmaceutical innovations such as nanoparticle-based carriers, hydrogel matrices, and scaffold-based delivery systems have shown potential to enhance MAA stability, optimize and prolong release profiles, improve antimicrobial and anti-biofilm efficacy, increase tissue penetration, and mitigate cytotoxicity concerns. By integrating insights from microbiology, materials science, and drug development, this short review aims to outline the challenges posed by biofilms in chronic wounds, appraise the antimicrobial and anti-biofilm activity of MAAs, and discuss how advanced delivery strategies might expand their clinical efficacy.
{"title":"Breaking biofilm barriers in skin wounds: Membrane-Active antimicrobials in an era of resistance","authors":"Lisa Myrseth Hemmingsen , Nataša Škalko-Basnet","doi":"10.1016/j.crphar.2025.100249","DOIUrl":"10.1016/j.crphar.2025.100249","url":null,"abstract":"<div><div>Chronic wounds remain a significant challenge for healthcare systems worldwide, placing a considerable burden on both patients and resources. Their management is further complicated by the persistence of biofilm-forming bacteria and an escalating problem of antimicrobial resistance, both of which restrict the effectiveness of conventional therapies. Antimicrobial compounds with a rapid onset of action and activity that is not solely dependent on bacterial metabolism represent promising alternatives for bacterial and biofilm eradication. Among these, membrane-active antimicrobials (MAAs), including antimicrobial peptides, peptidomimetics, and other membrane-disrupting compounds, constitute a particularly interesting group of agents. Recent investigations have revealed diverse mechanisms through which MAAs compromise biofilm integrity, ranging from permeabilization of bacterial membranes to interference with quorum sensing and extracellular polymeric substances. Furthermore, pharmaceutical innovations such as nanoparticle-based carriers, hydrogel matrices, and scaffold-based delivery systems have shown potential to enhance MAA stability, optimize and prolong release profiles, improve antimicrobial and anti-biofilm efficacy, increase tissue penetration, and mitigate cytotoxicity concerns. By integrating insights from microbiology, materials science, and drug development, this short review aims to outline the challenges posed by biofilms in chronic wounds, appraise the antimicrobial and anti-biofilm activity of MAAs, and discuss how advanced delivery strategies might expand their clinical efficacy.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"10 ","pages":"Article 100249"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145939369","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}
Adelmidrol is a bioactive semi-synthetic compound with significant therapeutic potential, particularly in resolving inflammation since inflammation plays a key role in the pathogenesis of several diseases. The mechanisms of action of adelmidrol are multifaceted, involving interactions with specific receptors like the PPAR-γ and modulation of signaling pathways associated with inflammation. Adelmidrol demonstrates efficacy in conditions such as inflammatory bowel disease, colon inflammation, and urothelial inflammation by regulating the level of pro-inflammatory cytokines. In dermatological conditions like atopic and allergic dermatitis, adelmidrol plays a key role in modulating immune responses and enhancing skin barrier function by reducing inflammation while offering an alternative to conventional therapies. Additionally, adelmidrol plays a critical role in wound healing and diabetic foot ulcers by facilitating cell migration and proliferation, thus accelerating wound closure and reducing infection risk. Adelmidrol has been shown to reduce joint inflammation and improve functionality, making it a candidate for adjunct therapy in musculoskeletal disorders like osteoarthritis. The compound also addresses pulmonary conditions, such as pulmonary fibrosis, by mitigating inflammatory responses and improving respiratory function. Furthermore, applications of adelmidrol in liver diseases, including liver ischemia and non-alcoholic steatohepatitis (NASH), highlight its potential in resolving hepatic inflammation. This review emphasizes the therapeutic promise of adelmidrol across various inflammatory diseases, advocating for further clinical studies to establish its full potential and optimize its clinical use all the while providing an overview of the properties, mechanisms of action, and therapeutic applications of adelmidrol.
{"title":"Therapeutic potential, pharmacological role and molecular mechanisms of adelmidrol, an analogue of palmitoylethanolamide","authors":"Bushra Zia , Abdulrahman Alkaabi , Niraj Kumar Jha , Sameer Mirza , Sandeep B Subramanya , Shreesh Ojha","doi":"10.1016/j.crphar.2026.100250","DOIUrl":"10.1016/j.crphar.2026.100250","url":null,"abstract":"<div><div>Adelmidrol is a bioactive semi-synthetic compound with significant therapeutic potential, particularly in resolving inflammation since inflammation plays a key role in the pathogenesis of several diseases. The mechanisms of action of adelmidrol are multifaceted, involving interactions with specific receptors like the PPAR-γ and modulation of signaling pathways associated with inflammation. Adelmidrol demonstrates efficacy in conditions such as inflammatory bowel disease, colon inflammation, and urothelial inflammation by regulating the level of pro-inflammatory cytokines. In dermatological conditions like atopic and allergic dermatitis, adelmidrol plays a key role in modulating immune responses and enhancing skin barrier function by reducing inflammation while offering an alternative to conventional therapies. Additionally, adelmidrol plays a critical role in wound healing and diabetic foot ulcers by facilitating cell migration and proliferation, thus accelerating wound closure and reducing infection risk. Adelmidrol has been shown to reduce joint inflammation and improve functionality, making it a candidate for adjunct therapy in musculoskeletal disorders like osteoarthritis. The compound also addresses pulmonary conditions, such as pulmonary fibrosis, by mitigating inflammatory responses and improving respiratory function. Furthermore, applications of adelmidrol in liver diseases, including liver ischemia and non-alcoholic steatohepatitis (NASH), highlight its potential in resolving hepatic inflammation. This review emphasizes the therapeutic promise of adelmidrol across various inflammatory diseases, advocating for further clinical studies to establish its full potential and optimize its clinical use all the while providing an overview of the properties, mechanisms of action, and therapeutic applications of adelmidrol.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"10 ","pages":"Article 100250"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146034792","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 : 2025-12-04DOI: 10.1016/j.crphar.2025.100242
Murtaza Haidary , Yahya Samadi , Zakaria Rezai , Atiqullah Sadaqat , Mohammad Ali Ahmadi , Jamshid Gholami , Mohammad Mahdi Mohammadi , Mohammad Taqi Shojae
Introduction
Nicotine withdrawal during adolescence induces severe neurobehavioral disturbances and neurochemical alterations, including anxiety, depression, affective dysregulation, oxidative stress, and neuroinflammation. Current therapeutic options for managing nicotine dependence remain suboptimal. This study investigated the neuroprotective potential of naringenin (NG) in alleviating behavioral and biochemical sequelae of nicotine withdrawal in adolescent rats.
Materials and methods
Male adolescent Wistar rats were allocated into eight groups and subjected to nicotine exposure (1 mg/kg) and NG treatment (50 or 100 mg/kg) across nicotine exposure and withdrawal phases. Behavioral assays (OFT, EPM, FST) were employed to evaluate anxiety- and depression-like behaviors. Neurochemical assessments of dopamine, serotonin, their metabolites (DOPAC, 5-HIAA), MAO-A activity, oxidative stress markers (MDA, Nit), antioxidant enzymes (SOD, CAT, TT), and neuroinflammatory/neurodegenerative biomarkers (GFAP, IL-10, BDNF, NSE) were conducted in prefrontal cortex (PFC) homogenates.
Results
Nicotine withdrawal significantly induced anxiety- and depression-like behaviors, disrupted monoaminergic balance, elevated MAO-A activity, and triggered oxidative and neuroinflammatory responses in the PFC. NG administration, particularly at 100 mg/kg across both phases, significantly ameliorated behavioral impairments, restored neurotransmitter homeostasis, inhibited MAO-A, suppressed lipid peroxidation and nitrosative stress, enhanced antioxidant defenses, reduced GFAP and NSE expression, and restored IL-10 and BDNF levels.
Conclusion
NG exerts anxiolytic, antidepressant, antioxidant, and anti-inflammatory effects, likely via modulation of monoaminergic pathways and suppression of neuroinflammation and oxidative stress. These findings underscore the potential of NG as a promising candidate for mitigating neuropathological effects associated with nicotine withdrawal-induced neuropathology, particularly during adolescence.
{"title":"Neuroprotective effects of naringenin on nicotine-induced anxiety and depression: Involvement of monoaminergic systems, oxidative stress, and neuroinflammation on male rats","authors":"Murtaza Haidary , Yahya Samadi , Zakaria Rezai , Atiqullah Sadaqat , Mohammad Ali Ahmadi , Jamshid Gholami , Mohammad Mahdi Mohammadi , Mohammad Taqi Shojae","doi":"10.1016/j.crphar.2025.100242","DOIUrl":"10.1016/j.crphar.2025.100242","url":null,"abstract":"<div><h3>Introduction</h3><div>Nicotine withdrawal during adolescence induces severe neurobehavioral disturbances and neurochemical alterations, including anxiety, depression, affective dysregulation, oxidative stress, and neuroinflammation. Current therapeutic options for managing nicotine dependence remain suboptimal. This study investigated the neuroprotective potential of naringenin (NG) in alleviating behavioral and biochemical sequelae of nicotine withdrawal in adolescent rats.</div></div><div><h3>Materials and methods</h3><div>Male adolescent Wistar rats were allocated into eight groups and subjected to nicotine exposure (1 mg/kg) and NG treatment (50 or 100 mg/kg) across nicotine exposure and withdrawal phases. Behavioral assays (OFT, EPM, FST) were employed to evaluate anxiety- and depression-like behaviors. Neurochemical assessments of dopamine, serotonin, their metabolites (DOPAC, 5-HIAA), MAO-A activity, oxidative stress markers (MDA, Nit), antioxidant enzymes (SOD, CAT, TT), and neuroinflammatory/neurodegenerative biomarkers (GFAP, IL-10, BDNF, NSE) were conducted in prefrontal cortex (PFC) homogenates.</div></div><div><h3>Results</h3><div>Nicotine withdrawal significantly induced anxiety- and depression-like behaviors, disrupted monoaminergic balance, elevated MAO-A activity, and triggered oxidative and neuroinflammatory responses in the PFC. NG administration, particularly at 100 mg/kg across both phases, significantly ameliorated behavioral impairments, restored neurotransmitter homeostasis, inhibited MAO-A, suppressed lipid peroxidation and nitrosative stress, enhanced antioxidant defenses, reduced GFAP and NSE expression, and restored IL-10 and BDNF levels.</div></div><div><h3>Conclusion</h3><div>NG exerts anxiolytic, antidepressant, antioxidant, and anti-inflammatory effects, likely via modulation of monoaminergic pathways and suppression of neuroinflammation and oxidative stress. These findings underscore the potential of NG as a promising candidate for mitigating neuropathological effects associated with nicotine withdrawal-induced neuropathology, particularly during adolescence.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"10 ","pages":"Article 100242"},"PeriodicalIF":0.0,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145705700","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}
Ovarian cancer (OC) remains one of the most lethal gynecological malignancies worldwide. The long non-coding RNA MEG3 (Maternally Expressed Gene 3), located on chromosome 14q32.3, has been identified as a tumor suppressor in various cancers. This study investigated the impact of siRNA-mediated MEG3 silencing in the context of dendrosomal nanocurcumin (DNC) and Oxaliplatin (OXA) treatments on ovarian cancer cell lines, focusing on the expression of genes associated with apoptosis and metastasis, including Bcl-2, BAX, MMP-2, and MMP-9.
Methods
Cell viability was assessed using the MTT assay; apoptosis and cell cycle progression were evaluated via flow cytometry and Annexin V-FLUOS staining. Cell migration and invasion were examined using the transwell assay, and gene expression levels were quantified by real-time PCR.
Results
MEG3 expression significantly increased in both cell lines upon DNC and OXA treatment in a time-dependent manner, with the most pronounced effect in OVCAR3 cells (P < 0.01–0.001). MEG3 silencing significantly attenuated the anticancer efficacy of both agents. Notably, MMP-2 expression increased in DNC (P < 0.01) and combination therapy (P < 0.001), while MMP-9 was upregulated following OXA treatment (P < 0.01) after MEG3 knockdown.
Conclusion
These results suggest that MEG3 knockdown impairs the anti-metastatic properties of DNC and OXA by modulating MMP-2 and MMP-9 expression. The combination of DNC and OXA holds promise as an effective therapeutic strategy in OC, and MEG3 may serve as a potential biomarker and therapeutic target, particularly in drug-resistant ovarian cancer.
{"title":"Synergistic effect of oxaliplatin and nanocurcumin in dendrosomal carrier to inhibits ovarian cancer cells invasion and metastasis through the long non-coding RNA MEG3","authors":"Elahe Seyed Hosseini , Marziyeh Alizadeh Zarei , Zahra Shabani , Hamed Haddad Kashani , Hossein Nikzad","doi":"10.1016/j.crphar.2025.100243","DOIUrl":"10.1016/j.crphar.2025.100243","url":null,"abstract":"<div><h3>Background</h3><div>Ovarian cancer (OC) remains one of the most lethal gynecological malignancies worldwide. The long non-coding RNA MEG3 (Maternally Expressed Gene 3), located on chromosome 14q32.3, has been identified as a tumor suppressor in various cancers. This study investigated the impact of siRNA-mediated MEG3 silencing in the context of dendrosomal nanocurcumin (DNC) and Oxaliplatin (OXA) treatments on ovarian cancer cell lines, focusing on the expression of genes associated with apoptosis and metastasis, including Bcl-2, BAX, MMP-2, and MMP-9.</div></div><div><h3>Methods</h3><div>Cell viability was assessed using the MTT assay; apoptosis and cell cycle progression were evaluated via flow cytometry and Annexin V-FLUOS staining. Cell migration and invasion were examined using the transwell assay, and gene expression levels were quantified by real-time PCR.</div></div><div><h3>Results</h3><div>MEG3 expression significantly increased in both cell lines upon DNC and OXA treatment in a time-dependent manner, with the most pronounced effect in OVCAR3 cells (P < 0.01–0.001). MEG3 silencing significantly attenuated the anticancer efficacy of both agents. Notably, MMP-2 expression increased in DNC (P < 0.01) and combination therapy (P < 0.001), while MMP-9 was upregulated following OXA treatment (P < 0.01) after MEG3 knockdown.</div></div><div><h3>Conclusion</h3><div>These results suggest that MEG3 knockdown impairs the anti-metastatic properties of DNC and OXA by modulating MMP-2 and MMP-9 expression. The combination of DNC and OXA holds promise as an effective therapeutic strategy in OC, and MEG3 may serve as a potential biomarker and therapeutic target, particularly in drug-resistant ovarian cancer.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"10 ","pages":"Article 100243"},"PeriodicalIF":0.0,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145747033","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}
Telomeres, the repetitive DNA–protein complexes capping eukaryotic chromosomes, preserve genomic stability and regulate cellular replicative capacity. Progressive telomere shortening, coupled with diminished telomerase activity, is a hallmark of aging and contributes to cellular senescence, tissue degeneration, and the onset of age-related diseases. Conversely, telomerase overactivation in malignant cells enables uncontrolled proliferation, positioning telomere biology as a dual therapeutic target in longevity and oncology. Plant-derived compounds possess diverse structural classes such as polyphenols, flavonoids, triterpenoid saponins, polysaccharides, lignans, alkaloids, carotenoids, amino acids, and fatty acids that can modulate telomere length and telomerase activity via multiple molecular pathways. These include antioxidant and anti-inflammatory actions, regulation of key genes such as hTERT, SIRT1, and c-Myc, modulation of PI3K/Akt, JAK/STAT, and ERK signaling, and stabilization or destabilization of G-quadruplex DNA structures. Compounds such as resveratrol, epigallocatechin gallate, astragaloside IV, cycloastragenol, and ginsenoside Rg1 have demonstrated telomerase activation or inhibition in a context-dependent manner, influenced by concentration, cell type, and disease state. This review categorizes plant-derived positive and negative telomere/telomerase modulators, detailing their sources, mechanisms of action, experimental evidence, and the formulation challenges that hinder clinical translation, such as low bioavailability, instability, and variability in phytochemical content. By integrating molecular insights with pharmacological perspectives, this review highlights the potential of plant-derived agents as multi-target interventions in aging and cancer. Advancing this field will require rigorous pharmacokinetic profiling, standardized preparations, and longitudinal clinical studies to bridge the gap between laboratory findings and real-world therapeutic outcomes.
{"title":"Targeting telomere dynamics with plant-derived compounds: Molecular strategies against aging","authors":"Raushanara Akter, Adwiza Chakraborty Bishakha, Raisha Rajib, Asef Raj, Mashwiyat Samrin Roja, Fouzia Noor","doi":"10.1016/j.crphar.2025.100238","DOIUrl":"10.1016/j.crphar.2025.100238","url":null,"abstract":"<div><div>Telomeres, the repetitive DNA–protein complexes capping eukaryotic chromosomes, preserve genomic stability and regulate cellular replicative capacity. Progressive telomere shortening, coupled with diminished telomerase activity, is a hallmark of aging and contributes to cellular senescence, tissue degeneration, and the onset of age-related diseases. Conversely, telomerase overactivation in malignant cells enables uncontrolled proliferation, positioning telomere biology as a dual therapeutic target in longevity and oncology. Plant-derived compounds possess diverse structural classes such as polyphenols, flavonoids, triterpenoid saponins, polysaccharides, lignans, alkaloids, carotenoids, amino acids, and fatty acids that can modulate telomere length and telomerase activity via multiple molecular pathways. These include antioxidant and anti-inflammatory actions, regulation of key genes such as hTERT, SIRT1, and c-Myc, modulation of PI3K/Akt, JAK/STAT, and ERK signaling, and stabilization or destabilization of G-quadruplex DNA structures. Compounds such as resveratrol, epigallocatechin gallate, astragaloside IV, cycloastragenol, and ginsenoside Rg1 have demonstrated telomerase activation or inhibition in a context-dependent manner, influenced by concentration, cell type, and disease state. This review categorizes plant-derived positive and negative telomere/telomerase modulators, detailing their sources, mechanisms of action, experimental evidence, and the formulation challenges that hinder clinical translation, such as low bioavailability, instability, and variability in phytochemical content. By integrating molecular insights with pharmacological perspectives, this review highlights the potential of plant-derived agents as multi-target interventions in aging and cancer. Advancing this field will require rigorous pharmacokinetic profiling, standardized preparations, and longitudinal clinical studies to bridge the gap between laboratory findings and real-world therapeutic outcomes.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100238"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145516511","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.2025.100215
Fiammetta Iannuzzo , Gianpaolo Antonio Basile , Domenica Campolo , Giovanni Genovese , Gianluca Pandolfo , Loretta Giunta , Domenica Ruggeri , Antonino Di Benedetto , Antonio Bruno
{"title":"Corrigendum to “Metabolic and clinical effect of alpha-lipoic acid administration in schizophrenic subjects stabilized with atypical antipsychotics: A 12-week, open-label, uncontrolled study” [Curr. Res. Pharmacol. Drug Discov. 3 (2022) 100116]","authors":"Fiammetta Iannuzzo , Gianpaolo Antonio Basile , Domenica Campolo , Giovanni Genovese , Gianluca Pandolfo , Loretta Giunta , Domenica Ruggeri , Antonino Di Benedetto , Antonio Bruno","doi":"10.1016/j.crphar.2025.100215","DOIUrl":"10.1016/j.crphar.2025.100215","url":null,"abstract":"","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100215"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600711","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.2025.100240
Dylan Le Jan , Sandrine Destrumelle , Chantal Thorin , Jean-Claude Desfontis , Eric Betti , Mohamed Yassine Mallem
Background
Obesity impairs cardiovascular health through endothelial dysfunction, which is exacerbated by high-fat high-sugar (HFHS) diets through mechanisms involving chronic inflammation, oxidative stress, and insulin resistance. Nutritional interventions, specifically vitamin D (VD) and omega-3 fatty acids (ω3), have emerged as potential therapies to improve endothelial function and mitigate cardiovascular risks associated with obesity.
Objective
This study investigated the effects of VD, ω3 and their combination on endothelial dysfunction induced by an HFHS diet in Wistar rats.
Methods
Sixty-four male Wistar rats were fed either a Standard (S) or HFHS diet for 26 weeks. After 13 weeks, rats were supplemented with VD (600 IU/kg/day), ω3 (300 mg/kg/day), both (VD/ω3), or a control (C) for an additional 13 weeks. Endothelial function was assessed using aortic ring assays, focusing on acetylcholine (ACh)-mediated endothelium-dependent vasorelaxation, phenylephrine (Phe)-mediated vasoconstriction, and insulin responsiveness.
Results
VD and/or ω3 supplementation effectively improved ACh-mediated vasorelaxation and counteracted HFHS-induced endothelial dysfunction. VD enhanced insulin-mediated vasorelaxation, while ω3 showed a non-significant trend towards improved Phe-mediated vasoconstriction.
Conclusion
VD and ω3 supplementation, alone or in combination, significantly improved endothelial function and mitigated the adverse effects of an HFHS diet. The combination did not show clear additive effects. These findings suggest their potential as therapeutic strategies for managing obesity-related cardiovascular issues.
{"title":"Therapeutic effects of vitamin D and omega-3 supplementation on HFHS diet-induced endothelial dysfunction in Wistar rats","authors":"Dylan Le Jan , Sandrine Destrumelle , Chantal Thorin , Jean-Claude Desfontis , Eric Betti , Mohamed Yassine Mallem","doi":"10.1016/j.crphar.2025.100240","DOIUrl":"10.1016/j.crphar.2025.100240","url":null,"abstract":"<div><h3>Background</h3><div>Obesity impairs cardiovascular health through endothelial dysfunction, which is exacerbated by high-fat high-sugar (HFHS) diets through mechanisms involving chronic inflammation, oxidative stress, and insulin resistance. Nutritional interventions, specifically vitamin D (VD) and omega-3 fatty acids (ω3), have emerged as potential therapies to improve endothelial function and mitigate cardiovascular risks associated with obesity.</div></div><div><h3>Objective</h3><div>This study investigated the effects of VD, ω3 and their combination on endothelial dysfunction induced by an HFHS diet in Wistar rats.</div></div><div><h3>Methods</h3><div>Sixty-four male Wistar rats were fed either a Standard (S) or HFHS diet for 26 weeks. After 13 weeks, rats were supplemented with VD (600 IU/kg/day), ω3 (300 mg/kg/day), both (VD/ω3), or a control (C) for an additional 13 weeks. Endothelial function was assessed using aortic ring assays, focusing on acetylcholine (ACh)-mediated endothelium-dependent vasorelaxation, phenylephrine (Phe)-mediated vasoconstriction, and insulin responsiveness.</div></div><div><h3>Results</h3><div>VD and/or ω3 supplementation effectively improved ACh-mediated vasorelaxation and counteracted HFHS-induced endothelial dysfunction. VD enhanced insulin-mediated vasorelaxation, while ω3 showed a non-significant trend towards improved Phe-mediated vasoconstriction.</div></div><div><h3>Conclusion</h3><div>VD and ω3 supplementation, alone or in combination, significantly improved endothelial function and mitigated the adverse effects of an HFHS diet. The combination did not show clear additive effects. These findings suggest their potential as therapeutic strategies for managing obesity-related cardiovascular issues.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100240"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145681173","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.2024.100212
Jing Zhang , Zequn Wang , Xihua Wei , Mengyuan Han , Ribai Yan , Lijie Ma , Yan Pan
Non-small-cell lung cancer (NSCLC) represents a predominant histological subtype of lung cancer, characterized by high incidence and mortality rates. Despite significant advancements in therapeutic strategies and a deeper understanding of targeted therapies in recent years, tumor resistance remains an inevitable challenge, leading to poor prognostic outcomes. Several studies have indicated that sphingosine kinase 1 (SPHK1) plays a regulatory role in epidermal growth factor receptor (EGFR) signaling, and its elevated expression may be associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Furthermore, the catalytic product of SPHK1, sphingosine 1-phosphate (S1P), along with its receptor, sphingosine 1-phosphate receptor 3 (S1PR3), plays a regulatory role in the function of the EGFR. However, the specific effects of the SPHK1/S1P/S1PR3 axis on EGFR in NSCLC, as well as the combined effects of SPHK1/S1P/S1PR3 inhibitors with the EGFR-TKI gefitinib, remain to be elucidated. In the present study, we investigated the correlation between SPHK1 expression levels and the survival rates of NSCLC patients, the relationship between SPHK1 or S1PR3 and EGFR, and the impact of SPHK1 expression on the half-maximal inhibitory concentration (IC50) of gefitinib in NSCLC. In A549 cells, the phosphorylation of EGFR was significantly reduced following SPHK1 knockdown. Utilizing SPHK1/S1P/S1PR3 inhibitors, namely PF543, TY52156, and FTY720, we established that the SPHK1/S1P/S1PR3 axis modulates EGFR activation in NSCLC. Furthermore, these signaling inhibitors enhanced the anti-proliferative efficacy of the EGFR-TKI gefitinib. RNA sequencing analysis revealed substantial alterations in 85 differentially expressed genes in NSCLC cells treated with the combination of FTY720 and gefitinib. These genes were predominantly associated with pathways such as axon guidance, microRNAs in cancer, and the JAK-STAT signaling pathway, among others. Overall, targeting the SPHK1/S1P/S1PR3 signaling pathway represents a promising therapeutic strategy to enhance gefitinib sensitivity in NSCLC.
{"title":"The suppression of the SPHK1/S1P/S1PR3 signaling pathway diminishes EGFR activation and increases the sensitivity of non-small cell lung cancer to gefitinib","authors":"Jing Zhang , Zequn Wang , Xihua Wei , Mengyuan Han , Ribai Yan , Lijie Ma , Yan Pan","doi":"10.1016/j.crphar.2024.100212","DOIUrl":"10.1016/j.crphar.2024.100212","url":null,"abstract":"<div><div>Non-small-cell lung cancer (NSCLC) represents a predominant histological subtype of lung cancer, characterized by high incidence and mortality rates. Despite significant advancements in therapeutic strategies and a deeper understanding of targeted therapies in recent years, tumor resistance remains an inevitable challenge, leading to poor prognostic outcomes. Several studies have indicated that sphingosine kinase 1 (SPHK1) plays a regulatory role in epidermal growth factor receptor (EGFR) signaling, and its elevated expression may be associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Furthermore, the catalytic product of SPHK1, sphingosine 1-phosphate (S1P), along with its receptor, sphingosine 1-phosphate receptor 3 (S1PR3), plays a regulatory role in the function of the EGFR. However, the specific effects of the SPHK1/S1P/S1PR3 axis on EGFR in NSCLC, as well as the combined effects of SPHK1/S1P/S1PR3 inhibitors with the EGFR-TKI gefitinib, remain to be elucidated. In the present study, we investigated the correlation between SPHK1 expression levels and the survival rates of NSCLC patients, the relationship between SPHK1 or S1PR3 and EGFR, and the impact of SPHK1 expression on the half-maximal inhibitory concentration (IC<sub>50</sub>) of gefitinib in NSCLC. In A549 cells, the phosphorylation of EGFR was significantly reduced following SPHK1 knockdown. Utilizing SPHK1/S1P/S1PR3 inhibitors, namely PF543, TY52156, and FTY720, we established that the SPHK1/S1P/S1PR3 axis modulates EGFR activation in NSCLC. Furthermore, these signaling inhibitors enhanced the anti-proliferative efficacy of the EGFR-TKI gefitinib. RNA sequencing analysis revealed substantial alterations in 85 differentially expressed genes in NSCLC cells treated with the combination of FTY720 and gefitinib. These genes were predominantly associated with pathways such as axon guidance, microRNAs in cancer, and the JAK-STAT signaling pathway, among others. Overall, targeting the SPHK1/S1P/S1PR3 signaling pathway represents a promising therapeutic strategy to enhance gefitinib sensitivity in NSCLC.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100212"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078650","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}
Prostate cancer (PCa) is a leading global health burden, with a particularly high prevalence in South Africa. Despite therapeutic advancements, chemoresistance remains a major challenge, limiting the efficacy of docetaxel and contributing to treatment failure and disease progression. Multidrug resistance (MDR), primarily mediated by ATP-binding cassette (ABC) transporters such as ABCC1 and ABCC10, has been implicated in reduced chemotherapy effectiveness. This study aimed to evaluate the association between ABCC1 and ABCC10 expression levels and docetaxel treatment response in PCa patients. A retrospective case-control study was conducted using pre-treated formalin-fixed paraffin-embedded (FFPE) tissue biopsies from PCa patients. Patients were classified into good responders (cases) and poor responders (cases) based on treatment outcomes. For each patient, tumour and adjacent normal sections were excised from FFPE samples, with normal sections serving as the control group. RNA was extracted and subjected to quantitative real-time PCR (qRT-PCR) to assess ABCC1 and ABCC10 expression levels. ABCC1 and ABCC10 were significantly upregulated in tumour sections of poor responders, whereas good responders exhibited downregulated expression in tumour sections. Importantly, normal tissue sections (controls) displayed significantly lower expression levels of both transporter genes compared to tumour sections. The overexpression of ABCC1 and ABCC10 in tumour tissues, particularly in poor responders, suggests their potential role in mediating docetaxel resistance. These findings highlight ABCC1 and ABCC10 as potential predictive biomarkers for docetaxel treatment response in PCa, warranting further investigation in prospective clinical studies.
{"title":"ABCC1 and ABCC10 as predictive biomarkers of docetaxel treatment response in prostate cancer","authors":"Nandi Ngesi , Beynon Abrahams , Aubrey Shoko , Mamello Sekhoacha","doi":"10.1016/j.crphar.2025.100216","DOIUrl":"10.1016/j.crphar.2025.100216","url":null,"abstract":"<div><div>Prostate cancer (PCa) is a leading global health burden, with a particularly high prevalence in South Africa. Despite therapeutic advancements, chemoresistance remains a major challenge, limiting the efficacy of docetaxel and contributing to treatment failure and disease progression. Multidrug resistance (MDR), primarily mediated by ATP-binding cassette (ABC) transporters such as ABCC1 and ABCC10, has been implicated in reduced chemotherapy effectiveness. This study aimed to evaluate the association between ABCC1 and ABCC10 expression levels and docetaxel treatment response in PCa patients. A retrospective case-control study was conducted using pre-treated formalin-fixed paraffin-embedded (FFPE) tissue biopsies from PCa patients. Patients were classified into good responders (cases) and poor responders (cases) based on treatment outcomes. For each patient, tumour and adjacent normal sections were excised from FFPE samples, with normal sections serving as the control group. RNA was extracted and subjected to quantitative real-time PCR (qRT-PCR) to assess ABCC1 and ABCC10 expression levels. ABCC1 and ABCC10 were significantly upregulated in tumour sections of poor responders, whereas good responders exhibited downregulated expression in tumour sections. Importantly, normal tissue sections (controls) displayed significantly lower expression levels of both transporter genes compared to tumour sections. The overexpression of ABCC1 and ABCC10 in tumour tissues, particularly in poor responders, suggests their potential role in mediating docetaxel resistance. These findings highlight ABCC1 and ABCC10 as potential predictive biomarkers for docetaxel treatment response in PCa, warranting further investigation in prospective clinical studies.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"8 ","pages":"Article 100216"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705523","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.2025.100233
Dana F. AlKharboush , Frank Kozielski , Geoffrey Wells , Exequiel O.J. Porta
Three decades after its introduction, fragment-based drug (or lead) discovery (FBDD or FBLD) has become a mature and powerful strategy for generating novel leads, offering distinct advantages for challenging or previously “undruggable” targets where traditional screening (e.g., high throughput screening) often fails. The FBDD approach identifies low molecular weight fragments (MW < 300 Da) that bind weakly to a target; these interactions are detected using highly sensitive biophysical methods such as NMR, X-ray crystallography, and SPR. These initial hits are then optimised into potent leads through structure-guided strategies, including fragment growing, linking, or merging. This graphical review illustrates the modern FBDD workflow, highlighting the critical integration of experimental and computational methods. We discuss how innovations in library design, hybrid screening platforms, and the application of AI/ML are accelerating discovery cycles and improving hit validation. The power of this approach is demonstrated through case studies of FDA-approved drugs, including Vemurafenib and Venetoclax, which progressed from simple fragments to transformative medicines. Finally, we provide an outlook on the future of FBDD as it continues to evolve with emerging technologies to push the boundaries of drug discovery.
{"title":"Fragment-based drug discovery: A graphical review","authors":"Dana F. AlKharboush , Frank Kozielski , Geoffrey Wells , Exequiel O.J. Porta","doi":"10.1016/j.crphar.2025.100233","DOIUrl":"10.1016/j.crphar.2025.100233","url":null,"abstract":"<div><div>Three decades after its introduction, fragment-based drug (or lead) discovery (FBDD or FBLD) has become a mature and powerful strategy for generating novel leads, offering distinct advantages for challenging or previously “undruggable” targets where traditional screening (e.g., high throughput screening) often fails. The FBDD approach identifies low molecular weight fragments (MW < 300 Da) that bind weakly to a target; these interactions are detected using highly sensitive biophysical methods such as NMR, X-ray crystallography, and SPR. These initial hits are then optimised into potent leads through structure-guided strategies, including fragment growing, linking, or merging. This graphical review illustrates the modern FBDD workflow, highlighting the critical integration of experimental and computational methods. We discuss how innovations in library design, hybrid screening platforms, and the application of AI/ML are accelerating discovery cycles and improving hit validation. The power of this approach is demonstrated through case studies of FDA-approved drugs, including Vemurafenib and Venetoclax, which progressed from simple fragments to transformative medicines. Finally, we provide an outlook on the future of FBDD as it continues to evolve with emerging technologies to push the boundaries of drug discovery.</div></div>","PeriodicalId":10877,"journal":{"name":"Current Research in Pharmacology and Drug Discovery","volume":"9 ","pages":"Article 100233"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145044499","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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