Anna Klimont, M. Ruciński, N. Sawicka-Gutaj, Marta Szyszka, Małgorzata Blatkiewicz, Tomasz Wierzbicki, Marek Karczewski, M. Janicka-Jedyńska, M. Ruchała, Hanna Komarowska
The aim of the study was to evaluate the diagnostic and prognostic significance of leptin receptor isoforms in adrenal tumors. In a single-center study, 96 patients (19 with adrenal cortical carcinoma and 77 with benign tumors) underwent an adrenalectomy. A total of 14 unaffected adrenal gland tissues from kidney donors were used as controls. Fasting blood samples were collected for laboratory tests, and mRNA expressions of leptin receptor isoforms were assessed by RT-qPCR. The study analyzed correlations between mRNA expressions and clinical data and measured NCI-H295R cell proliferation via a real-time cell analyzer. All adrenal lesions expressed leptin receptor isoforms. Significantly lower LepR1 expression was observed in carcinoma tissues than in adenomas and controls (p = 0.016). Expressions of LepR3&LepR6 were correlated with overall survival (p = 0.036), while LepR2&LepR4 and LepR5 expressions were inversely related to morning serum cortisol levels (p = 0.041). Leptin reduced NCI-H295R cell proliferation (p < 0.0001). The study highlights the diagnostic and prognostic significance of leptin receptor isoforms in adrenal tumors. Specifically, LepR1 may serve as a diagnostic marker for carcinomas, while LepR3&LepR6 have potential use as prognostic markers.
{"title":"Role of Different Variants of Leptin Receptor in Human Adrenal Tumor Types","authors":"Anna Klimont, M. Ruciński, N. Sawicka-Gutaj, Marta Szyszka, Małgorzata Blatkiewicz, Tomasz Wierzbicki, Marek Karczewski, M. Janicka-Jedyńska, M. Ruchała, Hanna Komarowska","doi":"10.3390/ijms25168682","DOIUrl":"https://doi.org/10.3390/ijms25168682","url":null,"abstract":"The aim of the study was to evaluate the diagnostic and prognostic significance of leptin receptor isoforms in adrenal tumors. In a single-center study, 96 patients (19 with adrenal cortical carcinoma and 77 with benign tumors) underwent an adrenalectomy. A total of 14 unaffected adrenal gland tissues from kidney donors were used as controls. Fasting blood samples were collected for laboratory tests, and mRNA expressions of leptin receptor isoforms were assessed by RT-qPCR. The study analyzed correlations between mRNA expressions and clinical data and measured NCI-H295R cell proliferation via a real-time cell analyzer. All adrenal lesions expressed leptin receptor isoforms. Significantly lower LepR1 expression was observed in carcinoma tissues than in adenomas and controls (p = 0.016). Expressions of LepR3&LepR6 were correlated with overall survival (p = 0.036), while LepR2&LepR4 and LepR5 expressions were inversely related to morning serum cortisol levels (p = 0.041). Leptin reduced NCI-H295R cell proliferation (p < 0.0001). The study highlights the diagnostic and prognostic significance of leptin receptor isoforms in adrenal tumors. Specifically, LepR1 may serve as a diagnostic marker for carcinomas, while LepR3&LepR6 have potential use as prognostic markers.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Orzechowska-Wylęgała, Adam Wylęgała, J. Z. Fiolka, Z. Czuba, Katarzyna Kryszan, Michał Toborek
Dentofacial inflammation resulting from untreated dental caries is a serious disease that can spread to deeper tissues of the neck and face. This study aimed to analyze salivary cytokine profiles as potential biomarkers of acute odontogenic infections in children. The study group consisted of 28 children aged 3–17 years old with acute dentofacial infections (DI) and a control group (caries experience, CE) of 52 children aged 4–17 years old with uncomplicated dental caries. The cytokine profile was analyzed using the Bio-Plex Pro Human Cytokine 27-Plex kit in the saliva of children in both groups. The levels of IL-4, IL-15, FGF-2, G-CSF, and PDGF-BB were significantly increased in children with dentofacial infections compared to the control group. In contrast, the levels of other cytokines, such as IL-2, IL-7, IL-9, IL-13, GM-CSF, and IFN-γ, did not show statistically significant differences between these two groups. IL-4, IL-15, FGF-2, G-CSF, and PDGF-BB may serve as potential selective biomarkers of inflammation of the oral cavity in children. These biomarkers can be useful in identifying and monitoring the progress and treatment of bacterial infections resulting in dentofacial inflammation.
{"title":"Selected Saliva-Derived Cytokines and Growth Factors Are Elevated in Pediatric Dentofacial Inflammation","authors":"B. Orzechowska-Wylęgała, Adam Wylęgała, J. Z. Fiolka, Z. Czuba, Katarzyna Kryszan, Michał Toborek","doi":"10.3390/ijms25168680","DOIUrl":"https://doi.org/10.3390/ijms25168680","url":null,"abstract":"Dentofacial inflammation resulting from untreated dental caries is a serious disease that can spread to deeper tissues of the neck and face. This study aimed to analyze salivary cytokine profiles as potential biomarkers of acute odontogenic infections in children. The study group consisted of 28 children aged 3–17 years old with acute dentofacial infections (DI) and a control group (caries experience, CE) of 52 children aged 4–17 years old with uncomplicated dental caries. The cytokine profile was analyzed using the Bio-Plex Pro Human Cytokine 27-Plex kit in the saliva of children in both groups. The levels of IL-4, IL-15, FGF-2, G-CSF, and PDGF-BB were significantly increased in children with dentofacial infections compared to the control group. In contrast, the levels of other cytokines, such as IL-2, IL-7, IL-9, IL-13, GM-CSF, and IFN-γ, did not show statistically significant differences between these two groups. IL-4, IL-15, FGF-2, G-CSF, and PDGF-BB may serve as potential selective biomarkers of inflammation of the oral cavity in children. These biomarkers can be useful in identifying and monitoring the progress and treatment of bacterial infections resulting in dentofacial inflammation.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923484","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaoli Zhou, Yuhang Xu, Cheng Fang, Chutian Ye, Weiming Liang, Zhexia Fan, Xuerong Ma, Aijun Liu, Xiquan Zhang, Qingbin Luo
Light is a key environmental factor regulating reproduction in avians. However, the mechanism of light intensity regulating ovarian development is still unclear. In this study, 5-week-old (5 wk) partridge broiler breeders were randomly divided into a low-light-intensity group (LL group) and a natural-light-intensity group (NL group) (n = 100). In the rearing period (5 wk to 22 wk), the light intensity of the LL group and NL group were 0.41 ± 0.05 lux and 45.39 ± 1.09 lux, and in the laying period (23 wk to 32 wk) they were 23.92 ± 0.06 lux and 66.93 ± 0.76 lux, respectively. Samples were collected on 22 wk and 32 wk. The results showed that the LL group had a later age at first egg and a longer laying period than the NL group. Serum P4 and LH levels in the LL group were higher than in the NL group on 22 wk (p < 0.05). On 32 wk, P4, E2, LH and FSH levels in the LL group were lower than in the NL group (p < 0.05). Ovarian transcriptomics and metabolomics identified 128 differentially expressed genes (DEGs) and 467 differential metabolites (DMs) on 22 wk; 155 DEGs and 531 DMs on 32 wk between two groups. An enrichment analysis of these DEGs and DMs identified key signaling pathways, including steroid hormone biosynthesis, neuroactive ligand-receptor interaction. In these pathways, genes such as CYP21A1, SSTR2, and NPY may regulate the synthesis of metabolites, including tryptamine, triglycerides, and phenylalanine. These genes and metabolites may play a dominant role in the light-intensity regulation of ovarian development and laying performance in broiler breeders.
{"title":"Integrated Transcriptomic–Metabolomic Analysis Reveals the Effect of Different Light Intensities on Ovarian Development in Chickens","authors":"Xiaoli Zhou, Yuhang Xu, Cheng Fang, Chutian Ye, Weiming Liang, Zhexia Fan, Xuerong Ma, Aijun Liu, Xiquan Zhang, Qingbin Luo","doi":"10.3390/ijms25168704","DOIUrl":"https://doi.org/10.3390/ijms25168704","url":null,"abstract":"Light is a key environmental factor regulating reproduction in avians. However, the mechanism of light intensity regulating ovarian development is still unclear. In this study, 5-week-old (5 wk) partridge broiler breeders were randomly divided into a low-light-intensity group (LL group) and a natural-light-intensity group (NL group) (n = 100). In the rearing period (5 wk to 22 wk), the light intensity of the LL group and NL group were 0.41 ± 0.05 lux and 45.39 ± 1.09 lux, and in the laying period (23 wk to 32 wk) they were 23.92 ± 0.06 lux and 66.93 ± 0.76 lux, respectively. Samples were collected on 22 wk and 32 wk. The results showed that the LL group had a later age at first egg and a longer laying period than the NL group. Serum P4 and LH levels in the LL group were higher than in the NL group on 22 wk (p < 0.05). On 32 wk, P4, E2, LH and FSH levels in the LL group were lower than in the NL group (p < 0.05). Ovarian transcriptomics and metabolomics identified 128 differentially expressed genes (DEGs) and 467 differential metabolites (DMs) on 22 wk; 155 DEGs and 531 DMs on 32 wk between two groups. An enrichment analysis of these DEGs and DMs identified key signaling pathways, including steroid hormone biosynthesis, neuroactive ligand-receptor interaction. In these pathways, genes such as CYP21A1, SSTR2, and NPY may regulate the synthesis of metabolites, including tryptamine, triglycerides, and phenylalanine. These genes and metabolites may play a dominant role in the light-intensity regulation of ovarian development and laying performance in broiler breeders.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141921572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Pavlova, A. E. Shulgina, S. M. Zakian, E. V. Dementyeva
Hypertrophic cardiomyopathy (HCM) is a cardiovascular pathology that is caused by variants in genes encoding sarcomere-associated proteins. However, the clinical significance of numerous variants in HCM-associated genes is still unknown. CRISPR/Cas9 is a tool of nucleotide sequence editing that allows for the unraveling of different biological tasks. In this study, introducing a mutation with CRISPR/Cas9 into induced pluripotent stem cells (iPSCs) of a healthy donor and the directed differentiation of the isogenic iPSC lines into cardiomyocytes were used to assess the pathogenicity of a variant of unknown significance, p.M659I (c.1977G > A) in MYH7, which was found previously in an HCM patient. Using two single-stranded donor oligonucleotides with and without the p.M659I (c.1977G > A) mutation, together with CRISPR/Cas9, an iPSC line heterozygous at the p.M659I (c.1977G > A) variant in MYH7 was generated. No CRISPR/Cas9 off-target activity was observed. The iPSC line with the introduced p.M659I (c.1977G > A) mutation in MYH7 retained its pluripotent state and normal karyotype. Compared to the isogenic control, cardiomyocytes derived from the iPSCs with the introduced p.M659I (c.1977G > A) mutation in MYH7 recapitulated known HCM features: enlarged size, elevated diastolic calcium level, changes in the expression of HCM-related genes, and disrupted energy metabolism. These findings indicate the pathogenicity of the variant.
{"title":"Studying Pathogenetic Contribution of a Variant of Unknown Significance, p.M659I (c.1977G > A) in MYH7, to the Development of Hypertrophic Cardiomyopathy Using CRISPR/Cas9-Engineered Isogenic Induced Pluripotent Stem Cells","authors":"S. Pavlova, A. E. Shulgina, S. M. Zakian, E. V. Dementyeva","doi":"10.3390/ijms25168695","DOIUrl":"https://doi.org/10.3390/ijms25168695","url":null,"abstract":"Hypertrophic cardiomyopathy (HCM) is a cardiovascular pathology that is caused by variants in genes encoding sarcomere-associated proteins. However, the clinical significance of numerous variants in HCM-associated genes is still unknown. CRISPR/Cas9 is a tool of nucleotide sequence editing that allows for the unraveling of different biological tasks. In this study, introducing a mutation with CRISPR/Cas9 into induced pluripotent stem cells (iPSCs) of a healthy donor and the directed differentiation of the isogenic iPSC lines into cardiomyocytes were used to assess the pathogenicity of a variant of unknown significance, p.M659I (c.1977G > A) in MYH7, which was found previously in an HCM patient. Using two single-stranded donor oligonucleotides with and without the p.M659I (c.1977G > A) mutation, together with CRISPR/Cas9, an iPSC line heterozygous at the p.M659I (c.1977G > A) variant in MYH7 was generated. No CRISPR/Cas9 off-target activity was observed. The iPSC line with the introduced p.M659I (c.1977G > A) mutation in MYH7 retained its pluripotent state and normal karyotype. Compared to the isogenic control, cardiomyocytes derived from the iPSCs with the introduced p.M659I (c.1977G > A) mutation in MYH7 recapitulated known HCM features: enlarged size, elevated diastolic calcium level, changes in the expression of HCM-related genes, and disrupted energy metabolism. These findings indicate the pathogenicity of the variant.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Assim Hayderi, Mulugeta Melkie Zegeye, Sare Meydan, A. Sirsjö, A. K. Kumawat, L. Ljungberg
Laminins are essential components of the basement membranes, expressed in a tissue- and cell-specific manner under physiological conditions. During inflammatory circumstances, such as atherosclerosis, alterations in laminin composition within vessels have been observed. Our study aimed to assess the influence of tumor necrosis factor-alpha (TNF), a proinflammatory cytokine abundantly found in atherosclerotic lesions, on endothelial laminin gene expression and the effects of laminin-332 (LN332) on endothelial cells’ behavior. We also evaluated the expression of LN332-encoding genes in human carotid atherosclerotic plaques. Our findings demonstrate that TNF induces upregulation of LAMB3 and LAMC2, which, along with LAMA3, encode the LN332 isoform. Endothelial cells cultured on recombinant LN332 exhibit decreased claudin-5 expression and display a loosely connected phenotype, with an elevated expression of chemokines and leukocyte adhesion molecules, enhancing their attractiveness and adhesion to leukocytes in vitro. Furthermore, LAMB3 and LAMC2 are upregulated in human carotid plaques and show a positive correlation with TNF expression. In summary, TNF stimulates the expression of LN332-encoding genes in human endothelial cells and LN332 promotes an endothelial phenotype characterized by compromised junctional integrity and increased leukocyte interaction. These findings highlight the importance of basement membrane proteins for endothelial integrity and the potential role of LN332 in atherosclerosis.
{"title":"TNF Induces Laminin-332-Encoding Genes in Endothelial Cells and Laminin-332 Promotes an Atherogenic Endothelial Phenotype","authors":"Assim Hayderi, Mulugeta Melkie Zegeye, Sare Meydan, A. Sirsjö, A. K. Kumawat, L. Ljungberg","doi":"10.3390/ijms25168699","DOIUrl":"https://doi.org/10.3390/ijms25168699","url":null,"abstract":"Laminins are essential components of the basement membranes, expressed in a tissue- and cell-specific manner under physiological conditions. During inflammatory circumstances, such as atherosclerosis, alterations in laminin composition within vessels have been observed. Our study aimed to assess the influence of tumor necrosis factor-alpha (TNF), a proinflammatory cytokine abundantly found in atherosclerotic lesions, on endothelial laminin gene expression and the effects of laminin-332 (LN332) on endothelial cells’ behavior. We also evaluated the expression of LN332-encoding genes in human carotid atherosclerotic plaques. Our findings demonstrate that TNF induces upregulation of LAMB3 and LAMC2, which, along with LAMA3, encode the LN332 isoform. Endothelial cells cultured on recombinant LN332 exhibit decreased claudin-5 expression and display a loosely connected phenotype, with an elevated expression of chemokines and leukocyte adhesion molecules, enhancing their attractiveness and adhesion to leukocytes in vitro. Furthermore, LAMB3 and LAMC2 are upregulated in human carotid plaques and show a positive correlation with TNF expression. In summary, TNF stimulates the expression of LN332-encoding genes in human endothelial cells and LN332 promotes an endothelial phenotype characterized by compromised junctional integrity and increased leukocyte interaction. These findings highlight the importance of basement membrane proteins for endothelial integrity and the potential role of LN332 in atherosclerosis.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrea Howard, A. Carroll-Portillo, Joe Alcock, Henry C. Lin
As knowledge of the gut microbiome has expanded our understanding of the symbiotic and dysbiotic relationships between the human host and its microbial constituents, the influence of gastrointestinal (GI) microbes both locally and beyond the intestine has become evident. Shifts in bacterial populations have now been associated with several conditions including Crohn’s disease (CD), Ulcerative Colitis (UC), irritable bowel syndrome (IBS), Alzheimer’s disease, Parkinson’s Disease, liver diseases, obesity, metabolic syndrome, anxiety, depression, and cancers. As the bacteria in our gut thrive on the food we eat, diet plays a critical role in the functional aspects of our gut microbiome, influencing not only health but also the development of disease. While the bacterial microbiome in the context of disease is well studied, the associated gut phageome—bacteriophages living amongst and within our bacterial microbiome—is less well understood. With growing evidence that fluctuations in the phageome also correlate with dysbiosis, how diet influences this population needs to be better understood. This review surveys the current understanding of the effects of diet on the gut phageome.
{"title":"Dietary Effects on the Gut Phageome","authors":"Andrea Howard, A. Carroll-Portillo, Joe Alcock, Henry C. Lin","doi":"10.3390/ijms25168690","DOIUrl":"https://doi.org/10.3390/ijms25168690","url":null,"abstract":"As knowledge of the gut microbiome has expanded our understanding of the symbiotic and dysbiotic relationships between the human host and its microbial constituents, the influence of gastrointestinal (GI) microbes both locally and beyond the intestine has become evident. Shifts in bacterial populations have now been associated with several conditions including Crohn’s disease (CD), Ulcerative Colitis (UC), irritable bowel syndrome (IBS), Alzheimer’s disease, Parkinson’s Disease, liver diseases, obesity, metabolic syndrome, anxiety, depression, and cancers. As the bacteria in our gut thrive on the food we eat, diet plays a critical role in the functional aspects of our gut microbiome, influencing not only health but also the development of disease. While the bacterial microbiome in the context of disease is well studied, the associated gut phageome—bacteriophages living amongst and within our bacterial microbiome—is less well understood. With growing evidence that fluctuations in the phageome also correlate with dysbiosis, how diet influences this population needs to be better understood. This review surveys the current understanding of the effects of diet on the gut phageome.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
O. Vashchenko, Volodymyr P. Berest, Liliia V. Sviechnikova, N. Kutsevol, N. Kasian, Dmitry S. Sofronov, Oleksii Skorokhod
Gramicidin S (GS), one of the first discovered antimicrobial peptides, still shows strong antibiotic activity after decades of clinical use, with no evidence of resistance. The relatively high hemolytic activity and narrow therapeutic window of GS limit its use in topical applications. Encapsulation and targeted delivery may be the way to develop the internal administration of this drug. The lipid composition of membranes and non-covalent interactions affect GS’s affinity for and partitioning into lipid bilayers as monomers or oligomers, which are crucial for GS activity. Using both differential scanning calorimetry (DSC) and FTIR methods, the impact of GS on dipalmitoylphosphatidylcholine (DPPC) membranes was tested. Additionally, the combined effect of GS and cholesterol on membrane characteristics was observed; while dipalmitoylphosphatydylglycerol (DPPG) and cerebrosides did not affect GS binding to DPPC membranes, cholesterol significantly altered the membrane, with 30% mol concentration being most effective in enhancing GS binding. The effect of star-like dextran-polyacrylamide D-g-PAA(PE) on GS binding to the membrane was tested, revealing that it interacted with GS in the membrane and significantly increased the proportion of GS oligomers. Instead, calcium ions affected GS binding to the membrane differently, with independent binding of calcium and GS and no interaction between them. This study shows how GS interactions with lipid membranes can be effectively modulated, potentially leading to new formulations for internal GS administration. Modified liposomes or polymer nanocarriers for targeted GS delivery could be used to treat protein misfolding disorders and inflammatory conditions associated with free-radical processes in cell membranes.
{"title":"Modifying Membranotropic Action of Antimicrobial Peptide Gramicidin S by Star-like Polyacrylamide and Lipid Composition of Nanocontainers","authors":"O. Vashchenko, Volodymyr P. Berest, Liliia V. Sviechnikova, N. Kutsevol, N. Kasian, Dmitry S. Sofronov, Oleksii Skorokhod","doi":"10.3390/ijms25168691","DOIUrl":"https://doi.org/10.3390/ijms25168691","url":null,"abstract":"Gramicidin S (GS), one of the first discovered antimicrobial peptides, still shows strong antibiotic activity after decades of clinical use, with no evidence of resistance. The relatively high hemolytic activity and narrow therapeutic window of GS limit its use in topical applications. Encapsulation and targeted delivery may be the way to develop the internal administration of this drug. The lipid composition of membranes and non-covalent interactions affect GS’s affinity for and partitioning into lipid bilayers as monomers or oligomers, which are crucial for GS activity. Using both differential scanning calorimetry (DSC) and FTIR methods, the impact of GS on dipalmitoylphosphatidylcholine (DPPC) membranes was tested. Additionally, the combined effect of GS and cholesterol on membrane characteristics was observed; while dipalmitoylphosphatydylglycerol (DPPG) and cerebrosides did not affect GS binding to DPPC membranes, cholesterol significantly altered the membrane, with 30% mol concentration being most effective in enhancing GS binding. The effect of star-like dextran-polyacrylamide D-g-PAA(PE) on GS binding to the membrane was tested, revealing that it interacted with GS in the membrane and significantly increased the proportion of GS oligomers. Instead, calcium ions affected GS binding to the membrane differently, with independent binding of calcium and GS and no interaction between them. This study shows how GS interactions with lipid membranes can be effectively modulated, potentially leading to new formulations for internal GS administration. Modified liposomes or polymer nanocarriers for targeted GS delivery could be used to treat protein misfolding disorders and inflammatory conditions associated with free-radical processes in cell membranes.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Pružinská, M. Chrastina, S. Khademnematolahi, Veronika Vyletelová, Lívia Gajdošová, Lucia Pastvová, F. Dráfi, S. Poništ, Ľ. Pašková, Jarmila Kucharská, Z. Sumbalová, J. Muchová, Silvia Martiniaková, K. Bauerová
This in vivo study performed in rat adjuvant arthritis aims to advance the understanding of astaxanthin’s therapeutic properties for the possible treatment of rheumatoid arthritis (RA) in monotherapy and along with the standard RA treatment, methotrexate (MTX), in combination therapy. The main goal was to elucidate astaxanthin’s full therapeutic potential, evaluate its dose dependency, and compare its effects in monotherapy with other carotenoids such as β-carotene and β-cryptoxanthin (KXAN). Moreover, potential differences in therapeutic activity caused by using different sources of astaxanthin, synthetic (ASYN) versus isolated from Blakeslea trispora (ASTAP), were evaluated using one-way ANOVA (Tukey-Kramer post hoc test). KXAN was the most effective in reducing plasma MMP-9 levels in monotherapy, significantly better than MTX, and in reducing hind paw swelling. The differences in the action of ASTAP and ASYN have been observed across various biometric, anti-inflammatory, and antioxidative parameters. In combined therapy with MTX, the ASYN + MTX combination proved to be better. These findings, especially the significant anti-arthritic effect of KXAN and ASYN + MTX, could be the basis for further preclinical studies.
{"title":"Astaxanthin, Compared to Other Carotenoids, Increases the Efficacy of Methotrexate in Rat Adjuvant Arthritis","authors":"K. Pružinská, M. Chrastina, S. Khademnematolahi, Veronika Vyletelová, Lívia Gajdošová, Lucia Pastvová, F. Dráfi, S. Poništ, Ľ. Pašková, Jarmila Kucharská, Z. Sumbalová, J. Muchová, Silvia Martiniaková, K. Bauerová","doi":"10.3390/ijms25168710","DOIUrl":"https://doi.org/10.3390/ijms25168710","url":null,"abstract":"This in vivo study performed in rat adjuvant arthritis aims to advance the understanding of astaxanthin’s therapeutic properties for the possible treatment of rheumatoid arthritis (RA) in monotherapy and along with the standard RA treatment, methotrexate (MTX), in combination therapy. The main goal was to elucidate astaxanthin’s full therapeutic potential, evaluate its dose dependency, and compare its effects in monotherapy with other carotenoids such as β-carotene and β-cryptoxanthin (KXAN). Moreover, potential differences in therapeutic activity caused by using different sources of astaxanthin, synthetic (ASYN) versus isolated from Blakeslea trispora (ASTAP), were evaluated using one-way ANOVA (Tukey-Kramer post hoc test). KXAN was the most effective in reducing plasma MMP-9 levels in monotherapy, significantly better than MTX, and in reducing hind paw swelling. The differences in the action of ASTAP and ASYN have been observed across various biometric, anti-inflammatory, and antioxidative parameters. In combined therapy with MTX, the ASYN + MTX combination proved to be better. These findings, especially the significant anti-arthritic effect of KXAN and ASYN + MTX, could be the basis for further preclinical studies.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients’ quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.
{"title":"Three Years On: The Role of Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria (PNH) since Its Initial Approval","authors":"R. Horneff, Barbara Czech, M. Yeh, Elena Surova","doi":"10.3390/ijms25168698","DOIUrl":"https://doi.org/10.3390/ijms25168698","url":null,"abstract":"Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients’ quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141921176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yoojin Choi, Isa Samad, Harshini Chakravarthy, Joanne A. Matsubara, David J. Granville, Sonia N. Yeung
Pterygium is often associated with chronic ultraviolet (UV) radiation exposure and characterized by the overgrowth of conjunctiva and extracellular matrix (ECM) remodeling. Notably, several studies in the skin have demonstrated that chronic UV radiation can upregulate Granzyme B (GrB) expression and increase ECM degradation. The aim of this study was to compare GrB expression between pterygium and healthy controls and to further link this GrB expression to mast cells. Post-mortem pterygium tissues and conjunctival tissues from age-matched controls were used to assess GrB expression via immunofluorescence and microscopy. We found a significantly higher density of GrB+ cells from pterygium specimens compared to healthy controls. Furthermore, many of the GrB+ cells in pterygium specimens co-expressed tryptase, a mast cell marker. These findings suggest a role for conjunctival mast cell-secreted GrB in the pathogenesis of pterygium and highlight GrB as a possible therapeutic target in delaying or halting pterygium progression.
翼状胬肉通常与长期紫外线（UV）照射有关，其特点是结膜过度生长和细胞外基质（ECM）重塑。值得注意的是，几项皮肤研究表明，慢性紫外线辐射可上调颗粒酶 B（GrB）的表达并增加 ECM 降解。本研究的目的是比较翼状胬肉和健康对照组的 GrB 表达，并进一步将 GrB 表达与肥大细胞联系起来。通过免疫荧光和显微镜检查，我们使用死后翼状胬肉组织和年龄匹配的对照组结膜组织来评估 GrB 的表达。我们发现，与健康对照组相比，翼状胬肉标本中的 GrB+ 细胞密度明显更高。此外，翼状胬肉标本中的许多 GrB+ 细胞同时表达一种肥大细胞标记物--胰蛋白酶。这些发现表明结膜肥大细胞分泌的 GrB 在翼状胬肉的发病机制中扮演了重要角色，并强调 GrB 可能是延缓或阻止翼状胬肉发展的治疗靶点。
{"title":"Granzyme B Expression in Conjunctiva of Patients with Pterygium","authors":"Yoojin Choi, Isa Samad, Harshini Chakravarthy, Joanne A. Matsubara, David J. Granville, Sonia N. Yeung","doi":"10.3390/ijms25168679","DOIUrl":"https://doi.org/10.3390/ijms25168679","url":null,"abstract":"Pterygium is often associated with chronic ultraviolet (UV) radiation exposure and characterized by the overgrowth of conjunctiva and extracellular matrix (ECM) remodeling. Notably, several studies in the skin have demonstrated that chronic UV radiation can upregulate Granzyme B (GrB) expression and increase ECM degradation. The aim of this study was to compare GrB expression between pterygium and healthy controls and to further link this GrB expression to mast cells. Post-mortem pterygium tissues and conjunctival tissues from age-matched controls were used to assess GrB expression via immunofluorescence and microscopy. We found a significantly higher density of GrB+ cells from pterygium specimens compared to healthy controls. Furthermore, many of the GrB+ cells in pterygium specimens co-expressed tryptase, a mast cell marker. These findings suggest a role for conjunctival mast cell-secreted GrB in the pathogenesis of pterygium and highlight GrB as a possible therapeutic target in delaying or halting pterygium progression.","PeriodicalId":49179,"journal":{"name":"International Journal of Molecular Sciences","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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