International Journal of Molecular Sciences

12 pages, 4920 KiB

Open AccessArticle

The Complete Mitochondrial Genome of the Siberian Scoter Melanitta stejnegeri and Its Phylogenetic Relationship in Anseriformes

by Huimin Chen, Yaqin Chen, Zhenqi Wang, Dawei Wu, Pan Chen and Yanhong Chen

Int. J. Mol. Sci. 2024, 25(18), 10181; https://doi.org/10.3390/ijms251810181 (registering DOI) - 22 Sep 2024

Abstract

The Siberian Scoter (Melanitta stejnegeri) is a medium sea duck distinct from M. deglandi due to the absence of hybridization and differences in morphological characteristics. However, knowledge of its phylogenetic relationships within Anseriformes is limited due to a lack of molecular [...] Read more.

The Siberian Scoter (Melanitta stejnegeri) is a medium sea duck distinct from M. deglandi due to the absence of hybridization and differences in morphological characteristics. However, knowledge of its phylogenetic relationships within Anseriformes is limited due to a lack of molecular data. In this study, the complete mitogenome of M. stejnegeri was firstly sequenced, then annotated and used to reconstruct the phylogenetic relationships of 76 Anseriformes species. The complete mitogenome of M. stejnegeri is 16,631 bp and encodes 37 typical genes: 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, and 1 non-coding control region. Its mitogenome organization is similar to that of other Anseriformes species. The phylogenetic relationships within the genus Melanitta are initially clarified, with M. americana at the base. M. stejnegeri and M. deglandi are sister groups, clustering with M. fusca and M. perspicillata in order. Phylogenetic analysis suggests that Mareca falcata and M. strepera are sister groups, differing from previous studies. Results firstly indicate that Clangula hyemalis and Somateria mollissima are sister groups, suggesting a potentially skewed phylogenetic relationship may have been overlooked in earlier analyses relying solely on mitochondrial genomes. Our results provide new mitogenome data to support further phylogenetic and taxonomic studies of Anseriformes. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

24 pages, 547 KiB

Open AccessArticle

Investigating the Link between STAT4 Genetic Variants, STAT4 Protein Concentrations, and Laryngeal Squamous Cell Carcinoma: A Comprehensive Analysis of Clinical Manifestations

by Enrika Pileckaite, Alvita Vilkeviciute, Loresa Kriauciuniene, Vykintas Liutkevicius and Rasa Liutkeviciene

Int. J. Mol. Sci. 2024, 25(18), 10180; https://doi.org/10.3390/ijms251810180 (registering DOI) - 22 Sep 2024

Abstract

According to recent research, inflammatory STAT4 and its protein impact may be important factors in developing cancerous diseases. Still unanalyzed is this effect in patients with laryngeal squamous cell carcinoma (LSCC). In the present study, we evaluated four single nucleotide variants (SNVs) of [...] Read more.

According to recent research, inflammatory STAT4 and its protein impact may be important factors in developing cancerous diseases. Still unanalyzed is this effect in patients with laryngeal squamous cell carcinoma (LSCC). In the present study, we evaluated four single nucleotide variants (SNVs) of STAT4 (rs10181656, rs7574865, rs7601754, and rs10168266) and STAT4 serum levels to determine their link between LSCC development and its clinical manifestations. A total of 632 men (324 LSCC patients and 338 healthy individuals) were involved in this study. The genotyping was carried out using real-time PCR. Additionally, we measured 80 study subjects’ (40 LSCC patients and 40 control subjects) STAT4 protein concentrations using an enzyme-linked immunosorbent assay (ELISA). In our study, the T allele of STAT4 rs7574865 significantly increases the likelihood of LSCC occurrence by 1.4-fold. Additionally, this SNV is associated with higher odds of early-stage disease, T1 size LSCC development, absence of metastasis to neck lymph nodes, and well-differentiated carcinoma. The G allele of rs10181656 is significantly associated with various clinical characteristics of LSCC, increasing the odds of early- and advanced-stage disease by 2.8-fold and 1.9-fold, respectively. Additionally, this allele is linked to an increased likelihood of developing tumors of different sizes and non-metastasized LSCC, as well as poorly differentiated carcinoma, highlighting its potential impact on the development and features of LSCC. Conclusion: The analysis of the STAT4 rs7574865 SNV revealed that the G allele is linked to a more favorable prognosis in LSCC. Additionally, it is hypothesized that the G allele of rs10181656 may be associated with the occurrence of LSCC but may not serve as a sensitive prognostic biomarker for distinguishing between disease stages, cell differentiation, or tumor size. Full article

(This article belongs to the Special Issue Pathogenesis and Therapy of Oral Carcinogenesis, 2nd Edition)

► Show Figures

Figure 1

24 pages, 5867 KiB

Open AccessArticle

Aerobic Exercise Training Protects Against Insulin Resistance, Despite Low-Sodium Diet-Induced Increased Inflammation and Visceral Adiposity

by Vanessa Del Bianco, Guilherme da Silva Ferreira, Ana Paula Garcia Bochi, Paula Ramos Pinto, Letícia Gomes Rodrigues, Luzia Naoko Shinohara Furukawa, Maristela Mitiko Okamoto, Jaíne Alves Almeida, Lizandre Keren Ramos da Silveira, Aritania Sousa Santos, Kely Cristina Soares Bispo, Vera Luiza Capelozzi, Maria Lucia Correa-Giannella, Alexandre Alves da Silva, Ana Paula Pereira Velosa, Edna Regina Nakandakare, Ubiratan Fabres Machado, Walcy Paganelli Rosolia Teodoro, Marisa Passarelli and Sergio Catanozi

Int. J. Mol. Sci. 2024, 25(18), 10179; https://doi.org/10.3390/ijms251810179 (registering DOI) - 22 Sep 2024

Abstract

Dietary sodium restriction increases plasma triglycerides (TG) and total cholesterol (TC) concentrations as well as causing insulin resistance and stimulation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. Stimulation of the angiotensin II type-1 receptor (AT1) is associated with insulin resistance, [...] Read more.

Dietary sodium restriction increases plasma triglycerides (TG) and total cholesterol (TC) concentrations as well as causing insulin resistance and stimulation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. Stimulation of the angiotensin II type-1 receptor (AT1) is associated with insulin resistance, inflammation, and the inhibition of adipogenesis. The current study investigated whether aerobic exercise training (AET) mitigates or inhibits the adverse effects of dietary sodium restriction on adiposity, inflammation, and insulin sensitivity in periepididymal adipose tissue. LDL receptor knockout mice were fed either a normal-sodium (NS; 1.27% NaCl) or a low-sodium (LS; 0.15% NaCl) diet and were either subjected to AET for 90 days or kept sedentary. Body mass, blood pressure (BP), hematocrit, plasma TC, TG, glucose and 24-hour urinary sodium (U_Na) concentrations, insulin sensitivity, lipoprotein profile, histopathological analyses, and gene and protein expression were determined. The results were evaluated using two-way ANOVA. Differences were not observed in BP, hematocrit, diet consumption, and TC. The LS diet was found to enhance body mass, insulin resistance, plasma glucose, TG, LDL-C, and VLDL-TG and reduce U_Na, HDL-C, and HDL-TG, showing a pro-atherogenic lipid profile. In periepididymal adipose tissue, the LS diet increased tissue mass, TG, TC, AT1 receptor, pro-inflammatory macro-phages contents, and the area of adipocytes; contrarily, the LS diet decreased anti-inflammatory macrophages, protein contents and the transcription of genes related to insulin sensitivity. The AET prevented insulin resistance, but did not protect against dyslipidemia, adipose tissue pro-inflammatory profile, increased tissue mass, AT1 receptor expression, TG, and TC induced by the LS diet. Full article

(This article belongs to the Special Issue New Insights into Adipose Tissue Metabolic Function and Dysfunction, 3rd Edition)

► Show Figures

Figure 1

19 pages, 1527 KiB

Open AccessArticle

Exploring Taxonomic and Genetic Relationships in the Pinus mugo Complex Using Genome Skimming Data

by Joanna Sikora and Konrad Celiński

Int. J. Mol. Sci. 2024, 25(18), 10178; https://doi.org/10.3390/ijms251810178 (registering DOI) - 22 Sep 2024

Abstract

Genome skimming is a novel approach that enables obtaining large-scale genomic information based on high-copy DNA fractions from shallow whole-genome sequencing. The simplicity of this method, low analysis costs, and large amounts of generated data have made it widely used in plant research, [...] Read more.

Genome skimming is a novel approach that enables obtaining large-scale genomic information based on high-copy DNA fractions from shallow whole-genome sequencing. The simplicity of this method, low analysis costs, and large amounts of generated data have made it widely used in plant research, including species identification, especially in the case of protected or endangered taxa. This task is particularly difficult in the case of closely related taxa. The Pinus mugo complex includes several dozen closely related taxa occurring in the most important mountain ranges in Europe. The taxonomic rank, origin, or distribution of many of these taxa have been debated for years. In this study, we used genome skimming and multilocus DNA barcoding approaches to obtain different sequence data sets and also to determine their genetic diversity and suitability for distinguishing closely related taxa in the Pinus mugo complex. We generated seven different data sets, which were then analyzed using three discrimination methods, i.e., tree based, distance based, and assembling species by automatic partitioning. Genetic diversity among populations and taxa was also investigated using haplotype network analysis and principal coordinate analysis. The proposed data set based on divergence hotspots is even twenty-times more variable than the other analyzed sets and improves the phylogenetic resolution of the Pinus mugo complex. In light of the obtained results, Pinus × rhaetica does not belong to the Pinus mugo complex and should not be identified with either Pinus uliginosa or Pinus rotundata. It seems to represent a fixed hybrid or introgressant between Pinus sylvestris and Pinus mugo. In turn, Pinus mugo and Pinus uncinata apparently played an important role in the origins of Pinus uliginosa and Pinus rotundata. Full article

(This article belongs to the Special Issue Plant Biodiversity and Molecular Marker Technology: Discovery and Application of DNA Polymorphisms)

23 pages, 2660 KiB

Open AccessReview

Statins in Mitigating Anticancer Treatment-Related Cardiovascular Disease

by Rong Jiang, Lian Lou, Wen Shi, Yuxiao Chen, Zhaoming Fu, Shuo Liu, Thida Sok, Zhihang Li, Xuan Zhang and Jian Yang

Int. J. Mol. Sci. 2024, 25(18), 10177; https://doi.org/10.3390/ijms251810177 (registering DOI) - 22 Sep 2024

Abstract

Certain anticancer therapies inevitably increase the risk of cardiovascular events, now the second leading cause of death among cancer patients. This underscores the critical need for developing effective drugs or regimens for cardiovascular protection. Statins possess properties such as antioxidative stress, anti-inflammatory effects, [...] Read more.

Certain anticancer therapies inevitably increase the risk of cardiovascular events, now the second leading cause of death among cancer patients. This underscores the critical need for developing effective drugs or regimens for cardiovascular protection. Statins possess properties such as antioxidative stress, anti-inflammatory effects, antifibrotic activity, endothelial protection, and immune modulation. These pathological processes are central to the cardiotoxicity associated with anticancer treatment. There is prospective clinical evidence confirming the protective role of statins in chemotherapy-induced cardiotoxicity. Numerous preclinical studies have demonstrated that statins can ameliorate heart and endothelial damage caused by radiotherapy, although clinical studies are scarce. In the animal models of trastuzumab-induced cardiomyopathy, statins provide protection through anti-inflammatory, antioxidant, and antifibrotic mechanisms. In animal and cell models, statins can mitigate inflammation, endothelial damage, and cardiac injury induced by immune checkpoint inhibitors. Chimeric antigen receptor (CAR)-T cell therapy-induced cardiotoxicity and immune effector cell-associated neurotoxicity syndrome are associated with uncontrolled inflammation and immune activation. Due to their anti-inflammatory and immunomodulatory effects, statins have been used to manage CAR-T cell therapy-induced immune effector cell-associated neurotoxicity syndrome in a clinical trial. However, direct evidence proving that statins can mitigate CAR-T cell therapy-induced cardiotoxicity is still lacking. This review summarizes the possible mechanisms of anticancer therapy-induced cardiotoxicity and the potential mechanisms by which statins may reduce related cardiac damage. We also discuss the current status of research on the protective effect of statins in anticancer treatment-related cardiovascular disease and provide directions for future research. Additionally, we propose further studies on using statins for the prevention of cardiovascular disease in anticancer treatment. Full article

(This article belongs to the Section Molecular Pharmacology)

► Show Figures

Figure 1

14 pages, 2561 KiB

Open AccessArticle

BMP4 and Temozolomide Synergize in the Majority of Patient-Derived Glioblastoma Cultures

by Iris S. C. Verploegh, Andrea Conidi, Hoesna El Hassnaoui, Floor A. M. Verhoeven, Anne L. Korporaal, Ioannis Ntafoulis, Mirjam C. G. N. van den Hout, Rutger W. W. Brouwer, Martine L. M. Lamfers, Wilfred F. J. van IJcken, Danny Huylebroeck and Sieger Leenstra

Int. J. Mol. Sci. 2024, 25(18), 10176; https://doi.org/10.3390/ijms251810176 (registering DOI) - 22 Sep 2024

Abstract

One of the main causes of poor prognoses in patient with glioblastoma (GBM) is drug resistance to current standard treatment, which includes chemoradiation and adjuvant temozolomide (TMZ). In addition, the concept of cancer stem cells provides new insights into therapy resistance and management [...] Read more.

One of the main causes of poor prognoses in patient with glioblastoma (GBM) is drug resistance to current standard treatment, which includes chemoradiation and adjuvant temozolomide (TMZ). In addition, the concept of cancer stem cells provides new insights into therapy resistance and management also in GBM and glioblastoma stem cell-like cells (GSCs), which might contribute to therapy resistance. Bone morphogenetic protein-4 (BMP4) stimulates astroglial differentiation of GSCs and thereby reduces their self-renewal capacity. Exposure of GSCs to BMP4 may also sensitize these cells to TMZ. A recent phase I trial has shown that local delivery of BMP4 is safe, but a large variation in survival is seen in these treated patients and in features of their cultured tumors. We wanted to combine TMZ and BMP4 (TMZ + BMP4) therapy and assess the inter-tumoral variability in response to TMZ + BMP4 in patient-derived GBM cultures. A phase II trial could then benefit a larger group of patients than those treated with BMP4 only. We first show that simultaneous treatment with TMZ + BMP4 is more effective than sequential treatment. Second, when applying our optimized treatment protocol, 70% of a total of 20 GBM cultures displayed TMZ + BMP4 synergy. This combination induces cellular apoptosis and does not inhibit cell proliferation. Comparative bulk RNA-sequencing indicates that treatment with TMZ + BMP4 eventually results in decreased MAPK signaling, in line with previous evidence that increased MAPK signaling is associated with resistance to TMZ. Based on these results, we advocate further clinical trial research to test patient benefit and validate pathophysiological hypothesis. Full article

(This article belongs to the Special Issue Biomechanics and Molecular Research on Glioblastoma)

► Show Figures

Figure 1

27 pages, 4259 KiB

Open AccessArticle

Novel Drug-like HsrA Inhibitors Exhibit Potent Narrow-Spectrum Antimicrobial Activities against Helicobacter pylori

by Javier Casado, Irene Olivan-Muro, Sonia Algarate, Eduardo Chueca, Sandra Salillas, Adrián Velázquez-Campoy, Elena Piazuelo, María F. Fillat, Javier Sancho, Ángel Lanas and Andrés González

Int. J. Mol. Sci. 2024, 25(18), 10175; https://doi.org/10.3390/ijms251810175 (registering DOI) - 22 Sep 2024

Abstract

Helicobacter pylori infection constitutes a silent pandemic of global concern. In the last decades, the alarming increase in multidrug resistance evolved by this pathogen has led to a marked drop in the eradication rates of traditional therapies worldwide. By using a high-throughput screening [...] Read more.

Helicobacter pylori infection constitutes a silent pandemic of global concern. In the last decades, the alarming increase in multidrug resistance evolved by this pathogen has led to a marked drop in the eradication rates of traditional therapies worldwide. By using a high-throughput screening strategy, in combination with in vitro DNA binding assays and antibacterial activity testing, we identified a battery of novel drug-like HsrA inhibitors with MIC values ranging from 0.031 to 4 mg/L against several antibiotic-resistant strains of H. pylori, and minor effects against both Gram-negative and Gram-positive species of human microbiota. The most potent anti-H. pylori candidate demonstrated a high therapeutic index, an additive effect in combination with metronidazole and clarithromycin as well as a strong antimicrobial action against Campylobacter jejuni, another clinically relevant pathogen of phylum Campylobacterota. Transcriptomic analysis suggests that the in vivo inhibition of HsrA triggers lethal global disturbances in H. pylori physiology including the arrest of protein biosynthesis, malfunction of respiratory chain, detriment in ATP generation, and oxidative stress. The novel drug-like HsrA inhibitors described here constitute valuable candidates to a new family of narrow-spectrum antibiotics that allow overcoming the current resistome, protecting from dysbiosis, and increasing therapeutic options for novel personalized treatments against H. pylori. Full article

(This article belongs to the Special Issue Recent Advances in the Pathogenesis, Treatment and Development of New Drugs against Helicobacter pylori and Campylobacter jejuni)

► Show Figures

Figure 1

31 pages, 1994 KiB

Open AccessReview

Graphene-Oxide Peptide-Containing Materials for Biomedical Applications

by Andreea Gostaviceanu, Simona Gavrilaş, Lucian Copolovici and Dana Maria Copolovici

Int. J. Mol. Sci. 2024, 25(18), 10174; https://doi.org/10.3390/ijms251810174 (registering DOI) - 22 Sep 2024

Abstract

This review explores the application of graphene-based materials (GBMs) in biomedicine, focusing on graphene oxide (GO) and its interactions with peptides and proteins. GO, a versatile nanomaterial with oxygen-containing functional groups, holds significant potential for biomedical applications but faces challenges related to toxicity [...] Read more.

This review explores the application of graphene-based materials (GBMs) in biomedicine, focusing on graphene oxide (GO) and its interactions with peptides and proteins. GO, a versatile nanomaterial with oxygen-containing functional groups, holds significant potential for biomedical applications but faces challenges related to toxicity and environmental impact. Peptides and proteins can be functionalized on GO surfaces through various methods, including non-covalent interactions such as π–π stacking, electrostatic forces, hydrophobic interactions, hydrogen bonding, and van der Waals forces, as well as covalent bonding through reactions involving amide bond formation, esterification, thiol chemistry, and click chemistry. These approaches enhance GO’s functionality in several key areas: biosensing for sensitive biomarker detection, theranostic imaging that integrates diagnostics and therapy for real-time treatment monitoring, and targeted cancer therapy where GO can deliver drugs directly to tumor sites while being tracked by imaging techniques like MRI and photoacoustic imaging. Additionally, GO-based scaffolds are advancing tissue engineering and aiding tissues’ bone, muscle, and nerve tissue regeneration, while their antimicrobial properties are improving infection-resistant medical devices. Despite its potential, addressing challenges related to stability and scalability is essential to fully harness the benefits of GBMs in healthcare. Full article

(This article belongs to the Special Issue The Applicability of Graphene-Based Materials in the Pharmaceutical, Biological and Biomedical Sectors)

► Show Figures

Figure 1

22 pages, 802 KiB

Open AccessReview

Advances in the Insulin–Heart Axis: Current Therapies and Future Directions

by Alfredo Caturano, Erica Vetrano, Raffaele Galiero, Celestino Sardu, Luca Rinaldi, Vincenzo Russo, Marcellino Monda, Raffaele Marfella and Ferdinando Carlo Sasso

Int. J. Mol. Sci. 2024, 25(18), 10173; https://doi.org/10.3390/ijms251810173 (registering DOI) - 22 Sep 2024

Abstract

The insulin–heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) [...] Read more.

The insulin–heart axis plays a pivotal role in the pathophysiology of cardiovascular disease (CVD) in insulin-resistant states, including type 2 diabetes mellitus. Insulin resistance disrupts glucose and lipid metabolism, leading to systemic inflammation, oxidative stress, and atherogenesis, which contribute to heart failure (HF) and other CVDs. This review was conducted by systematically searching PubMed, Scopus, and Web of Science databases for peer-reviewed studies published in the past decade, focusing on therapeutic interventions targeting the insulin–heart axis. Studies were selected based on their relevance to insulin resistance, cardiovascular outcomes, and the efficacy of pharmacologic treatments. Key findings from the review highlight the efficacy of lifestyle modifications, such as dietary changes and physical activity, which remain the cornerstone of managing insulin resistance and improving cardiovascular outcomes. Moreover, pharmacologic interventions, such as metformin, sodium–glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors, have shown efficacy in reducing cardiovascular risk by addressing metabolic dysfunction, reducing inflammation, and improving endothelial function. Furthermore, emerging treatments, such as angiotensin receptor–neprilysin inhibitors, and mechanical interventions like ventricular assist devices offer new avenues for managing HF in insulin-resistant patients. The potential of these therapies to improve left ventricular ejection fraction and reverse pathological cardiac remodeling highlights the importance of early intervention. However, challenges remain in optimizing treatment regimens and understanding the long-term cardiovascular effects of these agents. Future research should focus on personalized approaches that integrate lifestyle and pharmacologic therapies to effectively target the insulin–heart axis and mitigate the burden of cardiovascular complications in insulin-resistant populations. Full article

(This article belongs to the Special Issue Cardiovascular Disease and Diabetes: A New Challenge in Treatment and Management)

► Show Figures

Figure 1

11 pages, 1013 KiB

Open AccessCommunication

The VEGFA rs3025039 Variant Is a Risk Factor for Breast Cancer in Mexican Women

by Bricia M. Gutiérrez-Zepeda, Mariana M. Gómez-Del Toro, Diego J. Ortiz-Soto, Denisse S. Becerra-Loaiza, Angel F. Quiroz-Bolaños, Antonio Topete, Ramón A. Franco-Topete, Adrián Daneri-Navarro, Alicia Del Toro-Arreola and Antonio Quintero-Ramos

Int. J. Mol. Sci. 2024, 25(18), 10172; https://doi.org/10.3390/ijms251810172 (registering DOI) - 22 Sep 2024

Abstract

Breast cancer (BC) is the leading cause of death from tumors in women worldwide, influenced by various factors, including genetics. The T allele of the single nucleotide variant (SNV) rs3025039 at position +936 of the VEGFA gene has been reported to affect the [...] Read more.

Breast cancer (BC) is the leading cause of death from tumors in women worldwide, influenced by various factors, including genetics. The T allele of the single nucleotide variant (SNV) rs3025039 at position +936 of the VEGFA gene has been reported to affect the mRNA regulatory mechanisms, potentially altering VEGFA expression and increasing BC risk. This study aimed to investigate the association between rs3025039 and BC in Mexican women residing in Jalisco, Mexico. The study included 231 women with a confirmed diagnosis of BC and 201 healthy subjects as a reference group (RG). PCR–RFLP was employed for the genotyping of rs3025039, with the visualization of amplified products using polyacrylamide gel electrophoresis. Significant differences were observed in rs3025039 alleles and genotypes between BC cases and the RG (p = 0.0038). The frequency of the T allele and the CT genotype was higher in the BC group compared to the RG, with a significant difference (p = 0.0006). In conclusion, this research suggests that the SNV rs3025039 is associated with a higher risk of BC in Mexican women. These findings enhance our understanding of the genetic underpinnings of BC in this population, offering potential insights for future studies and interventions. Full article

(This article belongs to the Special Issue Role of Mutations and Polymorphisms in Various Diseases)

► Show Figures

Figure 1

13 pages, 4550 KiB

Open AccessArticle

Oleuropein Relieves Pancreatic Ischemia Reperfusion Injury in Rats by Suppressing Inflammation and Oxidative Stress through HMGB1/NF-κB Pathway

by Maged S. Abdel-Kader, Rehab F. Abdel-Rahman, Gamal A. Soliman, Hanan A. Ogaly, Mohammed A. Alamri and Abdulrahman G. Alharbi

Int. J. Mol. Sci. 2024, 25(18), 10171; https://doi.org/10.3390/ijms251810171 (registering DOI) - 22 Sep 2024

Abstract

Oleuropein (OLP) is a naturally occurring phenolic compound in olive plant with antioxidant and anti-inflammatory potential and can possibly be used in treating pancreatic injuries. This investigation aimed to follow the molecular mechanism behind the potential therapeutic effect of OLP against pancreatic injury [...] Read more.

Oleuropein (OLP) is a naturally occurring phenolic compound in olive plant with antioxidant and anti-inflammatory potential and can possibly be used in treating pancreatic injuries. This investigation aimed to follow the molecular mechanism behind the potential therapeutic effect of OLP against pancreatic injury persuaded by ischemia–reperfusion (I/R). Pancreatic I/R injury was induced by splenic artery occlusion for 60 min followed by reperfusion. Oral administration of OLP (10 and 20 mg/kg) for 2 days significantly alleviated I/R-persuaded oxidative damage and inflammatory responses in pancreatic tissue as indicated by the decreased malondialdehyde (MDA) content and increased glutathione peroxidase (GPx) activity, accompanied by the suppression of myeloperoxidase (MPO) activity and reduced levels of interleukin-1beta (IL-1β), nuclear factor kappa B (NF-κB), and tumor necrosis factor alpha (TNF-α) in pancreatic tissues. Furthermore, OLP treatment markedly restored the serum levels of amylase, trypsinogen-activated peptide (TAP), and lipase, with concurrent improvement in pancreatic histopathological alterations. Moreover, treatment with OLP regulated the pancreatic expression of inducible nitric oxide synthase (iNOS) and high-mobility group box 1 (HMGB1) relative to rats of the pancreatic IR group. Thus, OLP treatment significantly alleviates the I/R-induced pancreatic injury by inhibiting oxidative stress and inflammation in rats through downregulation of HMGB1 and its downstream NF-κB signaling pathway. Full article

(This article belongs to the Special Issue Anti-cancer, Anti-inflammatory, and Antioxidation Active Substances: 2nd Edition)

► Show Figures

Figure 1

18 pages, 72594 KiB

Open AccessArticle

Augmented Global Protein Acetylation Diminishes Cell Growth and Migration of Cholangiocarcinoma Cells

by Saowaluk Saisomboon, Ryusho Kariya, Panupong Mahalapbutr, Tonkla Insawang, Kanlayanee Sawanyawisuth, Ubon Cha’on, Thanyada Rungrotmongkol, Sopit Wongkham, Sarawut Jitrapakdee, Seiji Okada and Kulthida Vaeteewoottacharn

Int. J. Mol. Sci. 2024, 25(18), 10170; https://doi.org/10.3390/ijms251810170 (registering DOI) - 22 Sep 2024

Abstract

We have previously shown that the overexpression of acetyl-CoA carboxylase 1 (ACC1) was associated with the poor prognosis of cholangiocarcinoma (CCA) patients, and suppression of its expression in CCA cell lines deteriorated cell growth. The present study explored the mechanism by which ACC1 [...] Read more.

We have previously shown that the overexpression of acetyl-CoA carboxylase 1 (ACC1) was associated with the poor prognosis of cholangiocarcinoma (CCA) patients, and suppression of its expression in CCA cell lines deteriorated cell growth. The present study explored the mechanism by which ACC1 inhibition affects global protein acetylation, using genetic knockdown and pharmacological inhibition with an ACC1 inhibitor ND-646 as models. Both ACC1 knockdown and ACC1-inhibitor-treated cells displayed the hyperacetylation of proteins, accompanied by impaired growth and migration. The immunoprecipitation of hyperacetylated proteins using the anti-acetylated lysine antibody, followed by tandem mass spectrometry, identified three potential verification candidates, namely POTE ankyrin domain family member E, peroxisomal biogenesis factor 1, and heat shock protein 90 beta (HSP90B). HSP90 acetylation was the candidate selected for the verification of protein acetylation. To establish the effects of protein hyperacetylation, treatment with suberoylanilide hydroxamic acid (SAHA), a lysine deacetylase inhibitor, was conducted, and this served as an independent model. Decreased tumor growth but increased acetylated protein levels were observed in ACC1-KD xenograft tumors. Hyperacetylated-alleviated cell growth and migration were consistently observed in the SAHA-treated models. The molecular linkage between protein hyperacetylation and the AKT/GSK3β/Snail pathway was demonstrated. This study highlighted the importance of protein acetylation in CCA progression, suggesting that ACC1 and KDAC are potential targets for CCA treatment. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

► Show Figures

Figure 1

24 pages, 969 KiB

Open AccessReview

The Effects of Growth Hormone Treatment Beyond Growth Promotion in Patients with Genetic Syndromes: A Systematic Review of the Literature

by Anna Kucharska, Ewelina Witkowska-Sędek, Michał Erazmus, Dorota Artemniak-Wojtowicz, Maria Krajewska and Beata Pyrżak

Int. J. Mol. Sci. 2024, 25(18), 10169; https://doi.org/10.3390/ijms251810169 (registering DOI) - 22 Sep 2024

Abstract

Recombinant human growth hormone therapy (rhGH) has been widely accepted as the safe treatment for short stature in children with such genetic syndromes as Prader–Willi syndrome and Turner or Noonan syndrome. Some patients with short stature and rare genetic syndromes are treated with [...] Read more.

Recombinant human growth hormone therapy (rhGH) has been widely accepted as the safe treatment for short stature in children with such genetic syndromes as Prader–Willi syndrome and Turner or Noonan syndrome. Some patients with short stature and rare genetic syndromes are treated with rhGH as growth hormone-deficient individuals or as children born small for their gestational age. After years of experience with this therapy in syndromic short stature, it has been proved that there are some aspects of long-term rhGH treatment beyond growth promotion, which can justify rhGH use in these individuals. This paper summarizes the data of a literature review of the effects of rhGH treatment beyond growth promotion in selected genetic syndromes. We chose three of the most common syndromes, Prader–Willi, Turner, and Noonan, in which rhGH treatment is indicated, and three rarer syndromes, Silver–Russel, Kabuki, and Duchenne muscular dystrophy, in which rhGH treatment is not widely indicated. Many studies have shown a significant impact of rhGH therapy on body composition, resting energy expenditure, insulin sensitivity, muscle tonus, motor function, and mental and behavioral development. Growth promotion is undoubtedly the primary benefit of rhGH therapy; nevertheless, especially with genetic syndromes, the additional effects should also be considered as important indications for this treatment. Full article

(This article belongs to the Special Issue Growth Hormone and Human Disease)

► Show Figures

Figure 1

18 pages, 4329 KiB

Open AccessArticle

Polyethylene Micro/Nanoplastics Exposure Induces Epithelial–Mesenchymal Transition in Human Bronchial and Alveolar Epithelial Cells

by Alice Traversa, Emanuela Mari, Paola Pontecorvi, Giulia Gerini, Enrico Romano, Francesca Megiorni, Amedeo Amedei, Cinzia Marchese, Danilo Ranieri and Simona Ceccarelli

Int. J. Mol. Sci. 2024, 25(18), 10168; https://doi.org/10.3390/ijms251810168 (registering DOI) - 22 Sep 2024

Abstract

Micro/nanoplastics (MNPs), which are widely spread in the environment, have gained attention because of their ability to enter the human body mainly through ingestion, inhalation, and skin contact, thus representing a serious health threat. Several studies have reported the presence of MNPs in [...] Read more.

Micro/nanoplastics (MNPs), which are widely spread in the environment, have gained attention because of their ability to enter the human body mainly through ingestion, inhalation, and skin contact, thus representing a serious health threat. Several studies have reported the presence of MNPs in lung tissue and the potential role of MNP inhalation in triggering lung fibrosis and tumorigenesis. However, there is a paucity of knowledge regarding the cellular response to MNPs composed of polyethylene (PE), one of the most common plastic pollutants in the biosphere. In this study, we investigated the effects of low/high concentrations of PE MNPs on respiratory epithelial cell viability and migration/invasion abilities, using MTT, scratch, and transwell assays. Morphological and molecular changes were assessed via immunofluorescence, Western blot, and qRT-PCR. We demonstrated that acute exposure to PE MNPs does not induce cellular toxicity. Instead, cells displayed visible morphological changes also involving actin cytoskeleton reorganization. Our data underlined the role of epithelial–mesenchymal transition (EMT) in triggering this process. Moreover, a remarkable increase in migration potential was noticed, in absence of a significant alteration of the cell’s invasive capacity. The present study highlights the potential impact of PE MNPs inhalation on the human respiratory epithelium, suggesting a possible role in carcinogenesis. Full article

(This article belongs to the Special Issue Molecular Mechanism in Epithelial-Mesenchymal Transition (EMT) and Fibrosis: 2nd Edition)

► Show Figures

Figure 1

13 pages, 301 KiB

Open AccessReview

Sperm DNA Fragmentation: Unraveling Its Imperative Impact on Male Infertility Based on Recent Evidence

by Sofoklis Stavros, Anastasios Potiris, Ermioni Molopodi, Despoina Mavrogianni, Athanasios Zikopoulos, Konstantinos Louis, Theodoros Karampitsakos, Eleni Nazou, Dimdos Sioutis, Chrysi Christodoulaki, Charikleia Skentou, Angeliki Gerede, Athanasios Zachariou, Panagiotis Christopoulos, Periklis Panagopoulos, Ekaterini Domali and Peter Drakakis

Int. J. Mol. Sci. 2024, 25(18), 10167; https://doi.org/10.3390/ijms251810167 (registering DOI) - 22 Sep 2024

Abstract

Male factors may be present in up to 50–70% of infertile couples and the prevalence of male infertility accounts for 20–30% of infertility cases. Understanding the mechanisms and causes behind male infertility remains a challenge, but new diagnostic tools such as DNA fragmentation [...] Read more.

Male factors may be present in up to 50–70% of infertile couples and the prevalence of male infertility accounts for 20–30% of infertility cases. Understanding the mechanisms and causes behind male infertility remains a challenge, but new diagnostic tools such as DNA fragmentation might aid in cases where the routine semen analysis is insufficient. DNA fragmentation, which refers to damages or breaks of the genetic material of the spermatozoa, is considered one of the main causes of male infertility due to impaired functional capability of sperm. The aim of the present narrative review is to investigate and enlighten the potential correlation between DNA fragmentation and male infertility parameters such as the seminal profile and the reproductive outcomes. Comprehensive research in PubMed/Medline and Scopus databases was conducted and 28 studies were included in the present review. Fourteen studies provided data regarding the impact of DNA fragmentation and seminal parameters and showed a correlation of significantly lower sperm count, lower concentration, motility, and abnormal morphology with an increased DNA fragmentation index (DFI). Similarly, 15 studies provided data regarding the impact of DFI on reproductive outcomes. Two studies showed higher aneuploidy rates with higher DFI values, and seven studies showed significantly lower pregnancy rates and live birth rates with higher DFI values. Ultimately, the studies included in this review highlight, collectively, the importance of measuring sperm DFI in the assessment of male infertility. Further studies are needed to explore the effectiveness of interventions aiming to reduce DFI levels. Full article

(This article belongs to the Special Issue Exploring the Molecular Mechanisms of the Microbiome in Reproductive Health and Reproductive Immunity)

► Show Figures

Figure 1

28 pages, 3657 KiB

Open AccessReview

Development of mRNA Lipid Nanoparticles: Targeting and Therapeutic Aspects

by Yaping Liu, Yingying Huang, Guantao He, Chun Guo, Jinhua Dong and Linping Wu

Int. J. Mol. Sci. 2024, 25(18), 10166; https://doi.org/10.3390/ijms251810166 (registering DOI) - 22 Sep 2024

Abstract

Lipid nanoparticles (LNPs) have emerged as leading non-viral carriers for messenger RNA (mRNA) delivery in clinical applications. Overcoming challenges in safe and effective mRNA delivery to target tissues and cells, along with controlling release from the delivery vehicle, remains pivotal in mRNA-based therapies. [...] Read more.

Lipid nanoparticles (LNPs) have emerged as leading non-viral carriers for messenger RNA (mRNA) delivery in clinical applications. Overcoming challenges in safe and effective mRNA delivery to target tissues and cells, along with controlling release from the delivery vehicle, remains pivotal in mRNA-based therapies. This review elucidates the structure of LNPs, the mechanism for mRNA delivery, and the targeted delivery of LNPs to various cells and tissues, including leukocytes, T-cells, dendritic cells, Kupffer cells, hepatic endothelial cells, and hepatic and extrahepatic tissues. Here, we discuss the applications of mRNA–LNP vaccines for the prevention of infectious diseases and for the treatment of cancer and various genetic diseases. Although challenges remain in terms of delivery efficiency, specific tissue targeting, toxicity, and storage stability, mRNA–LNP technology holds extensive potential for the treatment of diseases. Full article

(This article belongs to the Special Issue Nanoparticles: From Synthesis to Applications 2.0)

► Show Figures

Figure 1

15 pages, 4239 KiB

Open AccessArticle

Solanesol Ameliorates Anxiety-like Behaviors via the Downregulation of Cingulate T Cell-Restricted Intracellular Antigen-1 in a Complete Freund’s Adjuvant-Induced Mouse Model

by Shufan Ding, Yifan Li, Zhichao Chen, Jingnan Hu, Jiayi Li, Junlan Li and Yongjie Wang

Int. J. Mol. Sci. 2024, 25(18), 10165; https://doi.org/10.3390/ijms251810165 (registering DOI) - 21 Sep 2024

Abstract

Anxiety disorder is a universal disease related to neuro-inflammation. Solanesol has shown positive effects because of its anti-inflammatory, anti-tumor, and anti-ulcer properties. This study focused on determining whether solanesol could ameliorate anxiety-like behaviors in a mouse model of neuro-inflammation and identify its working [...] Read more.

Anxiety disorder is a universal disease related to neuro-inflammation. Solanesol has shown positive effects because of its anti-inflammatory, anti-tumor, and anti-ulcer properties. This study focused on determining whether solanesol could ameliorate anxiety-like behaviors in a mouse model of neuro-inflammation and identify its working targets. Complete Freund’s adjuvant (CFA)-induced mice that were intra-peritoneally administered with solanesol (50 mg/kg) for 1 week showed a statistically significant reduction in anxiety-like behaviors, as measured by open field and elevated plus-maze tests. Western blot analysis revealed that CFA-induced upregulation of the levels of pro-inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor α (TNF-α), which played crucial roles in regulating anxiety, returned to normal in the anterior cingulate cortex (ACC) after solanesol treatment. The level of T cell-restricted intracellular antigen-1 (TIA1), a key component of stress granules, also decreased in the ACC. Moreover, immunofluorescence results indicated that solanesol suppressed CFA-induced microglial and astrocytic activation in the ACC. CFA was injected in the hind paws of TIA1^Nestin conditional knockout (cKO) mice to confirm whether TIA1 is a potential modulatory molecule that influences pro-inflammatory cytokines and anxiety-like behaviors. Anxiety-like behaviors could not be observed in cKO mice after CFA injection with IL-1β and TNF-α levels not remarkedly increasing. Our findings suggest that solanesol inhibits neuro-inflammation by decreasing the TIA1 level to reduce IL-1β and TNF-α expression, meanwhile inhibiting microglial and astrocytic activation in the ACC and ultimately ameliorating anxiety-like behaviors in mice. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

► Show Figures

Figure 1

11 pages, 750 KiB

Open AccessArticle

Mechanical Properties of a Solvated Biomolecule: RGD (1FUV) Peptide

by Puja Adhikari, Bahaa Jawad and Wai-Yim Ching

Int. J. Mol. Sci. 2024, 25(18), 10164; https://doi.org/10.3390/ijms251810164 (registering DOI) - 21 Sep 2024

Abstract

The mechanical properties of proteins/peptides play an essential role in their functionalities and implications, as well as their structure and dynamic properties. Understanding mechanical properties is pivotal to our knowledge of protein folding and the molecular basis of diverse cellular processes. Herein, we [...] Read more.

The mechanical properties of proteins/peptides play an essential role in their functionalities and implications, as well as their structure and dynamic properties. Understanding mechanical properties is pivotal to our knowledge of protein folding and the molecular basis of diverse cellular processes. Herein, we present a computational approach using ab initio quantum mechanical calculations to determine the mechanical properties—such as bulk modulus, shear modulus, Young’s modulus, and Poisson’s ratio—of a solvated Arg-Gly-Asp (RGD) peptide model. Since this peptide serves as the RGD-directed integrin recognition site and may participate in cellular adhesion, it is considered a promising small peptide for medicinal applications. This successful approach paves the way for investigating larger and more complex biomolecules. Full article

(This article belongs to the Section Molecular Biology)

20 pages, 3533 KiB

Open AccessArticle

Exploring the Kinetics and Thermodynamics of a Novel Histidine Ammonia-Lyase from Geobacillus kaustophilus

by Francisco Manuel Salas-Garrucho, Alba Carrillo-Moreno, Lellys M. Contreras, Felipe Rodríguez-Vico, Josefa María Clemente-Jiménez and Francisco Javier Las Heras-Vázquez

Int. J. Mol. Sci. 2024, 25(18), 10163; https://doi.org/10.3390/ijms251810163 (registering DOI) - 21 Sep 2024

Abstract

Histidine ammonia-lyase (HAL) plays a pivotal role in the non-oxidative deamination of L-histidine to produce trans-urocanic, a crucial process in amino acid metabolism. This study examines the cloning, purification, and biochemical characterization of a novel HAL from Geobacillus kaustophilus (GkHAL) [...] Read more.

Histidine ammonia-lyase (HAL) plays a pivotal role in the non-oxidative deamination of L-histidine to produce trans-urocanic, a crucial process in amino acid metabolism. This study examines the cloning, purification, and biochemical characterization of a novel HAL from Geobacillus kaustophilus (GkHAL) and eight active site mutants to assess their effects on substrate binding, catalysis, thermostability, and secondary structure. The GkHAL enzyme was successfully overexpressed and purified to homogeneity. Its primary sequence displayed 40.7% to 43.7% similarity with other known HALs and shared the same oligomeric structure in solution. Kinetic assays showed that GkHAL has optimal activity at 85 °C and pH 8.5, with high thermal stability even after preincubation at high temperatures. Mutations at Y52, H82, N194, and E411 resulted in a complete loss of catalytic activity, underscoring their essential role in enzyme function, while mutations at residues Q274, R280, and F325 did not abolish activity but did reduce catalytic efficiency. Notably, mutants R280K and F325Y displayed novel activity with L-histidinamide, expanding the substrate specificity of HAL enzymes. Circular dichroism (CD) analysis showed minor secondary structure changes in the mutants but no significant effect on global GkHAL folding. These findings suggest that GkHAL could be a promising candidate for potential biotechnological applications. Full article

(This article belongs to the Special Issue The Characterization and Application of Enzymes in Bioprocesses)

► Show Figures

Figure 1

Journal Description

International Journal of Molecular Sciences

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI