International Journal of Molecular Sciences

16 pages, 1040 KiB

Open AccessReview

In Vivo Versus In Vitro Somatostatin Receptor Expression in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis of Correlation Studies

by Elisabetta Perrone, Giorgio Treglia, Romina Grazia Giancipoli, Lucia Leccisotti, Guido Rindi and Vittoria Rufini

Int. J. Mol. Sci. 2025, 26(14), 6551; https://doi.org/10.3390/ijms26146551 (registering DOI) - 8 Jul 2025

Abstract

Well-differentiated neuroendocrine neoplasms (NENs) are characterized by hyperexpression on the cell membrane of somatostatin receptors (SSTRs). The demonstration of SSTRs, mainly the subtype 2 (SSTR2), is the prerequisite for diagnostic and therapeutic strategies with radiolabeled somatostatin analogs (SSAs). SSTRs can be routinely demonstrated [...] Read more.

Well-differentiated neuroendocrine neoplasms (NENs) are characterized by hyperexpression on the cell membrane of somatostatin receptors (SSTRs). The demonstration of SSTRs, mainly the subtype 2 (SSTR2), is the prerequisite for diagnostic and therapeutic strategies with radiolabeled somatostatin analogs (SSAs). SSTRs can be routinely demonstrated in vivo by SSA-positron emission tomography/computed tomography (SSA-PET/CT) and in vitro by immunohistochemistry (IHC). This systematic review and meta-analysis aimed to gather evidence from the available literature on the correlation between the in vivo PET/CT and in vitro IHC SSTR expression in NEN patients. A systematic review and meta-analysis were conducted following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines. A comprehensive literature search was performed in PubMed/MEDLINE and Cochrane Library, selecting studies correlating SSTR expression in NENs via IHC and SSA-PET/CT. Data extraction, quality assessment, and statistical analysis were performed. Eleven studies met the inclusion criteria for systematic review (345 patients). Of these, eight studies (299 patients) provided sufficient quantitative data for meta-analysis. The pooled concordance between SSA-PET/CT and IHC was 76% (95% CI: 67.7–84.2), indicating a good correlation between in vivo and in vitro SSTR2 expression. Heterogeneity among studies was moderate (I² = 65%), reflecting different patient cohorts and methodologies regarding both SSA-PET/CT and IHC. No significant publication bias was detected. Our results confirmed good agreement between in vivo tumor uptake with SSA-PET/CT and in vitro SSTR2 expression with IHC, highlighting the potential of using IHC for clinical decision-making in NEN patients when SSA-PET/CT is not available. Full article

(This article belongs to the Special Issue Neuroendocrine Tumors: From Molecular Pathology to Novel Therapeutic Approaches, Including Theranostics)

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14 pages, 625 KiB

Open AccessArticle

Lower Initial Insulin-like Growth Factor-Binding Protein-3 Concentrations May Reflect Immune Suppression and Predict Increased Risk of Sepsis-Related Mortality

by Filippo Mearelli, Alessio Nunnari, Federica Chitti, Annalisa Rombini, Alessandra Macor, Donatella Denora, Luca Messana, Marianna Scardino, Ilaria Martini, Giulia Bolzan, Francesca Spagnol, Chiara Casarsa, Nicola Fiotti, Verena Zerbato, Stefano Di Bella, Carlo Tascini, Filippo Giorgio Di Girolamo, Mariella Sturma, Venera Costantino and Gianni Biolo

Int. J. Mol. Sci. 2025, 26(14), 6549; https://doi.org/10.3390/ijms26146549 (registering DOI) - 8 Jul 2025

Abstract

Insulin-like growth factor-binding protein-3 (IGFBP-3) plays a vital role in cellular growth, development, and survival. Incorporating IGFBP-3 into baseline prognostic evaluations may enhance the prediction of mortality in patients with sepsis. In this study, serum levels of IGFBP-3, C-reactive protein, procalcitonin, lactate, interleukin-6, [...] Read more.

Insulin-like growth factor-binding protein-3 (IGFBP-3) plays a vital role in cellular growth, development, and survival. Incorporating IGFBP-3 into baseline prognostic evaluations may enhance the prediction of mortality in patients with sepsis. In this study, serum levels of IGFBP-3, C-reactive protein, procalcitonin, lactate, interleukin-6, and mid-regional pro-adrenomedullin were measured upon admission to the internal medicine unit (IMU) in 139 patients with microbiologically confirmed sepsis. The objectives were as follows: (1) to classify septic patient phenotypes based on optimal thresholds of independent prognostic biomarkers and (2) to evaluate whether these biomarkers improve the predictive accuracy of a clinical model (Model 1), which includes the clinical predictors of 1-year mortality. Age, sequential organ failure assessment (SOFA) score, multiple sources of infection, and IGFBP-3 levels independently predicted 1-year mortality. Patients with IGFBP-3 levels below 10.64 had significantly lower median body temperature (p = 0.008), reduced lymphocyte count (p = 0.001), and higher 1-year mortality (p < 0.001). Model 1 included age, SOFA score, and the presence of multiple sources of sepsis as predictor variables. Model 2 incorporated the same variables as Model 1, with the addition of IGFBP-3 levels. When comparing their prognostic performance, Model 2 demonstrated superior predictive accuracy for mortality at 60, 90, and 365 days following admission to the IMU. Low IGFBP-3 levels at IMU admission are strongly associated with worse outcomes in septic patients, supporting its potential use as a prognostic biomarker. Full article

(This article belongs to the Section Molecular Immunology)

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15 pages, 3736 KiB

Open AccessArticle

Molecular Characterization of a Restriction Endonuclease PsaI from Pseudomonas anguilliseptica KM9 and Sequence Analysis of the PsaI R-M System

by Beata Furmanek-Blaszk, Iwona Mruk and Marian Sektas

Int. J. Mol. Sci. 2025, 26(14), 6548; https://doi.org/10.3390/ijms26146548 (registering DOI) - 8 Jul 2025

Abstract

A restriction enzyme PsaI, an isoschizomer of the type II restriction endonuclease HindIII, has been purified to homogeneity from Gram-negative bacilli Pseudomonas anguilliseptica KM9 found in a wastewater treatment plant in Poland. Experimental data revealed that R.PsaI is highly active in the presence [...] Read more.

A restriction enzyme PsaI, an isoschizomer of the type II restriction endonuclease HindIII, has been purified to homogeneity from Gram-negative bacilli Pseudomonas anguilliseptica KM9 found in a wastewater treatment plant in Poland. Experimental data revealed that R.PsaI is highly active in the presence of Co²⁺, Mg²⁺, and Zn²⁺ and reached a maximal level of activity between 2.5 and 10 mM while its activity was significantly decreased in the presence of Ca²⁺, Fe²⁺, Mn²⁺, and Ni²⁺. Moreover, we found that the purified R.PsaI did not require NaCl for enzyme activity. Restriction cleavage analysis followed by sequencing confirmed 5′-AAGCTT-3′ as the recognition site. The genes for restriction–modification system PsaI were identified and characterized. Downstream of the psaIM gene, we noticed an ORF that shares extensive similarity with recombinase family protein specifically involved in genome rearrangements. Sequence analysis revealed that the PsaI R-M gene complex showed striking nucleotide sequence similarity (>98%) with the genes of the PanI R-M system from a P. anguilliseptica MatS1 strain identified in a soil sample from Sri Lanka. Full article

(This article belongs to the Special Issue Genetic Engineering in Microbial Biotechnology)

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23 pages, 1383 KiB

Open AccessReview

The Critical Role of the Bile Acid Receptor TGR5 in Energy Homeostasis: Insights into Physiology and Therapeutic Potential

by Lucas Zangerolamo, Marina Carvalho and Helena C. L. Barbosa

Int. J. Mol. Sci. 2025, 26(14), 6547; https://doi.org/10.3390/ijms26146547 (registering DOI) - 8 Jul 2025

Abstract

Over the past decades, bile acids have been recognized as important signaling molecules with significant roles in metabolic health and disease. Many of their beneficial effects are mediated through the activation of the Takeda G protein-coupled receptor 5 (TGR5), a G protein-coupled receptor [...] Read more.

Over the past decades, bile acids have been recognized as important signaling molecules with significant roles in metabolic health and disease. Many of their beneficial effects are mediated through the activation of the Takeda G protein-coupled receptor 5 (TGR5), a G protein-coupled receptor ubiquitously expressed in both humans and animals. Upon activation, TGR5 stimulates adenylate cyclase, leading to increased cyclic adenosine monophosphate (cAMP) levels and subsequent activation of protein kinase A (PKA). PKA then phosphorylates and activates several downstream signaling pathways, including exchange protein directly activated by cAMP (EPAC), extracellular signal-regulated kinase 1/2 (ERK1/2), and protein kinase B (AKT). Through these pathways, TGR5 acts as a key molecular link between bile acid signaling and the regulation of energy metabolism. TGR5 activation has been associated with body weight loss in obese models, primarily by reducing food intake, enhancing thermogenesis in adipose tissue and muscle to increase energy expenditure, and improving insulin secretion. This review highlights recent advances in our understanding of TGR5 biology and critically examines its therapeutic potential, limitations, and controversies in the context of energy metabolism, offering new perspectives and opportunities for treating metabolic disorders. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors in Cell Signaling Transductions—2nd Edition)

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15 pages, 936 KiB

Open AccessReview

Lipodystrophy in HIV: Evolving Challenges and Unresolved Questions

by Marta Giralt, Pere Domingo, Tania Quesada-López, Rubén Cereijo and Francesc Villarroya

Int. J. Mol. Sci. 2025, 26(14), 6546; https://doi.org/10.3390/ijms26146546 - 8 Jul 2025

Abstract

The advent of effective antiretroviral therapy in the mid-1990s, which successfully prevented the progression to AIDS in people living with HIV (PLWH), was associated with the appearance of the so-called HIV-associated lipodystrophy. This condition involved subcutaneous fat atrophy; abdominal fat hypertrophy; and, in [...] Read more.

The advent of effective antiretroviral therapy in the mid-1990s, which successfully prevented the progression to AIDS in people living with HIV (PLWH), was associated with the appearance of the so-called HIV-associated lipodystrophy. This condition involved subcutaneous fat atrophy; abdominal fat hypertrophy; and, in some cases, lipomatosis. It was also associated with systemic metabolic disturbances, primarily insulin resistance and dyslipidemia. Following the replacement of certain antiretroviral drugs, particularly the thymidine-analog reverse transcriptase inhibitors stavudine and zidovudine, with less toxic alternatives, the incidences of lipoatrophy and lipomatosis significantly declined. However, lipodystrophy resulting from first-generation antiretroviral therapy does not always resolve after switching to newer agents. Although the widespread use of modern antiretroviral drugs—especially integrase strand transfer inhibitors and non-lipoatrophic reverse transcriptase inhibitors such as tenofovir alafenamide—has reduced the incidences of severe forms of lipodystrophy, these regimens are not entirely free of adipose tissue-related effects. Notably, they are associated with weight gain that resembles common obesity and can have adverse cardiometabolic consequences. Recent evidence also suggests the hypertrophy of specific fat depots, such as epicardial and perivascular adipose tissue, in PLWH on last-generation treatments, potentially contributing to increased cardiovascular risk. This evolving landscape underscores the persistent vulnerability of PLWH to adipose tissue alterations. While these morphological changes may not be as pronounced as those seen in classic HIV-associated lipodystrophy, they can still pose significant health risks. The continued optimization of treatment regimens and the vigilant monitoring of adipose tissue alterations and metabolic status remain essential strategies to improve the health of PLWH. Full article

(This article belongs to the Special Issue Molecular Insights into Lipodystrophy)

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15 pages, 575 KiB

Open AccessReview

Neuroactive Steroids as Novel Promising Drugs in Therapy of Postpartum Depression—Focus on Zuranolone

by Jolanta B. Zawilska and Ewa Zwierzyńska

Int. J. Mol. Sci. 2025, 26(13), 6545; https://doi.org/10.3390/ijms26136545 - 7 Jul 2025

Abstract

Postpartum depression (PPD) remains a significant health concern worldwide. Both non-pharmacological and pharmacological treatments are available for patients with PPD; however, the standard approach involving selective serotonin reuptake inhibitors (SSRIs) and other antidepressants fails to provide a rapid response. This narrative review presents [...] Read more.

Postpartum depression (PPD) remains a significant health concern worldwide. Both non-pharmacological and pharmacological treatments are available for patients with PPD; however, the standard approach involving selective serotonin reuptake inhibitors (SSRIs) and other antidepressants fails to provide a rapid response. This narrative review presents basic clinical and epidemiological data on PPD, summarizes currently used pharmacotherapies of PPD, highlights their limitations, and discusses new therapies based on a revised understanding of the disease’s pathogenesis. Numerous studies indicate that dysregulation of GABAergic neurotransmission, which may result from fluctuating levels of neuroactive steroids during pregnancy and the postpartum period, plays an important role in the complex pathology of PPD. Considering this, neuroactive steroids, which act as positive allosteric modulators of central GABA_A receptors (GABA_ARs), may offer new promising avenues for treating PPD. The first rapid-acting neurosteroid approved by the FDA to treat PPD in women is brexanolone, although its use is constrained by pharmacokinetic properties. The first oral neuroactive steroid-based antidepressant approved by the FDA for PPD is zuranolone. This review discusses the molecular mechanism of zuranolone action and the results of preclinical and clinical studies regarding the effectiveness and safety of the drug in treating PPD. Full article

(This article belongs to the Special Issue Stress-Related Disorders and Depression: From Molecular Basis to Therapy (2nd Edition))

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14 pages, 624 KiB

Open AccessReview

Microgravity Therapy as Treatment for Decelerated Aging and Successful Longevity

by Nadine Mozalbat, Lital Sharvit and Gil Atzmon

Int. J. Mol. Sci. 2025, 26(13), 6544; https://doi.org/10.3390/ijms26136544 - 7 Jul 2025

Abstract

Aging is a complex biological process marked by a progressive decline in cellular function, leading to age-related diseases such as neurodegenerative disorders, cancer, and cardiovascular diseases. Despite significant advancements in aging research, finding effective interventions to decelerate aging remains a challenge. This review [...] Read more.

Aging is a complex biological process marked by a progressive decline in cellular function, leading to age-related diseases such as neurodegenerative disorders, cancer, and cardiovascular diseases. Despite significant advancements in aging research, finding effective interventions to decelerate aging remains a challenge. This review explores microgravity as a novel therapeutic approach to combat aging and promote healthy longevity. The hallmarks of aging, including genomic instability, telomere shortening, and cellular senescence, form the basis for understanding the molecular mechanisms behind aging. Interestingly, microgravity has been shown to accelerate aging-like processes in model organisms and human tissues, making it an ideal environment for studying aging mechanisms in an accelerated manner. Spaceflight studies, such as NASA’s Twins Study and experiments aboard the International Space Station (ISS), reveal striking parallels between the physiological changes induced by microgravity and those observed in aging populations, including muscle atrophy, bone density loss, cardiovascular deconditioning, and immune system decline in a microgravity environment. However, upon microgravity recovery, cellular behavior, gene expression, and tissue regeneration were seen, providing vital insights into aging mechanisms and prospective therapeutic approaches. This review examines the potential of microgravity-based technologies to pioneer novel strategies for decelerating aging and enhancing healthspan under natural gravity, paving the way for breakthroughs in longevity therapies. Full article

(This article belongs to the Section Molecular Endocrinology and Metabolism)

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13 pages, 1204 KiB

Open AccessArticle

Acute Immune Cell Dynamics During Myocardial Infarction and Their Association with Mortality

by Harris Avgousti, Reina Nagasaka, Adovich S. Rivera, Anna Pawlowski, Edward B. Thorp and Matthew J. Feinstein

Int. J. Mol. Sci. 2025, 26(13), 6543; https://doi.org/10.3390/ijms26136543 - 7 Jul 2025

Abstract

Acute neutrophil responses following myocardial infarction (MI) play a central role in remodeling, contributing to both repair and potential maladaptive responses. Although prior studies have investigated circulating immune cell indices at a single time point during hospitalization for MI, limited data exist on [...] Read more.

Acute neutrophil responses following myocardial infarction (MI) play a central role in remodeling, contributing to both repair and potential maladaptive responses. Although prior studies have investigated circulating immune cell indices at a single time point during hospitalization for MI, limited data exist on acute intra-individual changes in circulating immune profiles during evolving MI. We analyzed clinical measurements, such as the count and proportion of immune cell components in a serial complete blood count, with differential tests conducted for patients hospitalized with ST-elevation MI (STEMI) in various hospitals in the Northwestern Medicine system from 1 January 2002 to 1 August 2024. Patients with STEMI diagnosis, troponin peaks ≥ 5 ng/mL, and cell count and proportion data prior to the troponin peak and within 24 h after the troponin peak were included. Primary analyses investigated the associations between the troponin peak and peri-STEMI changes in immune cell subsets. Multivariable-adjusted Cox models were used to investigate associations between these peri-STEMI immune cell changes and mortality at 1 year and 3 years. Among the 694 STEMI patients meeting the inclusion criteria, a higher troponin peak was associated with a modest peri-MI increase in neutrophil proportion. Higher adjusted peri-STEMI increases in neutrophil count and proportion were strongly associated with mortality at one and three years [hazard ratio (HR) = 1.31 (95% confidence interval (CI) 1.15–1.49) and HR = 1.27 (95% CI 1.14–1.45) per 1000 cells/μL absolute neutrophil increase, respectively]. Individuals with higher STEMI-related neutrophil increases had higher mortality at one year and three years, independent of the extent of troponin elevation. Full article

(This article belongs to the Special Issue Cardioimmunology: Inflammation and Immunity in Cardiovascular Disease)

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11 pages, 1069 KiB

Open AccessArticle

Evaluation of Torquetenovirus (TTV) Particle Integrity Utilizing PMAxx™

by Giuseppe Sberna, Claudia Minosse, Cosmina Mija, Eliana Specchiarello, Pietro Giorgio Spezia, Sara Belladonna, Giulia Berno, Lavinia Fabeni, Giulia Matusali, Silvia Meschi, Daniele Focosi and Fabrizio Maggi

Int. J. Mol. Sci. 2025, 26(13), 6542; https://doi.org/10.3390/ijms26136542 - 7 Jul 2025

Abstract

Torquetenovirus (TTV) is a ubiquitous, non-pathogenic DNA virus that has been suggested as a biomarker of immune competence, with the viral load correlating with the level of immunosuppression. However, by detecting non-intact viral particles, standard PCR-based quantification may overestimate the TTV viremia. To [...] Read more.

Torquetenovirus (TTV) is a ubiquitous, non-pathogenic DNA virus that has been suggested as a biomarker of immune competence, with the viral load correlating with the level of immunosuppression. However, by detecting non-intact viral particles, standard PCR-based quantification may overestimate the TTV viremia. To improve the clinical relevance of TTV quantification, in this study, we investigated the use of PMAxx™, a virion viability dye that selectively blocks the amplification of compromised virions. Serum samples from 10 Hepatitis C Virus-positive (HCV+) individuals, 81 liver transplant recipients (LTRs), and 40 people with HIV (PWH) were treated with PMAxx™ and analyzed for TTV DNA loads by digital droplet PCR (ddPCR). Furthermore, anti-SARS-CoV-2 IgG levels and neutralizing antibody (nAbs) titers were measured post-COVID-19 vaccination. Using ddPCR, the PMAxx™ treatment significantly reduced the TTV DNA levels in all the groups (mean reduction: 0.66 Log copies/mL), indicating the abundant presence of non-intact, circulating viral genomes. However, correlations between TTV DNA and SARS-CoV-2 IgG or nAbs were weak or absent in both PMAxx™-treated and untreated samples. These findings suggest that while PMAxx™ enhanced the specificity of TTV quantification, it did not improve the predictive value of TTV viremia at assessing vaccine-induced humoral responses. Full article

(This article belongs to the Section Molecular Microbiology)

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19 pages, 47429 KiB

Open AccessArticle

Overexpression of (P)RR in SHR and Renin-Induced HepG2 Cells Leads to Spontaneous Hypertension Combined with Metabolic Dysfunction-Associated Fatty Liver Disease

by Chen Gao, Xinyi Guo, Lingzhi Zhang, Xueman Lin and Hua Sun

Int. J. Mol. Sci. 2025, 26(13), 6541; https://doi.org/10.3390/ijms26136541 - 7 Jul 2025

Abstract

Hypertension and metabolic dysfunction-associated fatty liver disease (MAFLD) are both common chronic diseases globally. Nearly half of patients with hypertension are complicated by MAFLD. The mechanisms of the bidirectional promotion between the two remain unclear. The (pro) renin receptor ((P)RR) is one of [...] Read more.

Hypertension and metabolic dysfunction-associated fatty liver disease (MAFLD) are both common chronic diseases globally. Nearly half of patients with hypertension are complicated by MAFLD. The mechanisms of the bidirectional promotion between the two remain unclear. The (pro) renin receptor ((P)RR) is one of the classic members of the renin–angiotensin system (RAS) and serves as the receptor for prorenin. Although the role of (P)RR in the induction and progression of hypertension has been extensively studied, its role and underlying mechanisms in MAFLD remain underreported. In this study, we aim to investigate the role of (P)RR in the pathogenesis of hypertension combined with MAFLD. In this study, SHRs were used for the model for hypertension combined with MAFLD. Liver lipid content analysis, liver H&E staining, the detection of (P)RR, ERK and downstream proteins related to fatty acid synthesis and transport, and RNA sequencing and data analysis were performed. In the in vitro experiments, we activated (P)RR using renin and established the lipid deposition model of HepG2 cells induced by renin for the first time. (P)RR was specifically blocked using handle region peptide (HRP), and Nile red fluorescence staining, (P)RR/ERK/PPARγ protein expression analysis, and immunofluorescence were performed to further verify the role of (P)RR in the pathogenesis of hypertension combined with MAFLD. Our results demonstrate that (P)RR plays a role in the development and progression of hypertension combined with MAFLD. The hepatic TG and FFA levels in the SHRs were increased, and the protein expression of the (P)RR/ERK/PPARγ pathway and downstream proteins related to fatty acid synthesis and transport were upregulated. HRP reversed the activation of these proteins and reduced intracellular lipid accumulation. In conclusion, our study first reveals that (P)RR is a potential therapeutic target for hypertension combined with MAFLD. And we found the (P)RR/ERK/PPARγ axis for the first time, which plays an important role in the progression of spontaneous hypertension combined with MAFLD. Full article

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

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20 pages, 969 KiB

Open AccessArticle

The Role of Single Nucleotide Polymorphisms at the Arg399Gln Locus of the XRCC1 Gene in Patients with Non-Small Cell Lung Cancer (NSCLC)

by Beata Smolarz, Bartosz Cieślik-Wolski, Józef Kozak, Honorata Łukasiewicz, Dariusz Samulak, Dariusz Trzmielak, Hanna Romanowicz and Marianna Makowska

Int. J. Mol. Sci. 2025, 26(13), 6540; https://doi.org/10.3390/ijms26136540 - 7 Jul 2025

Abstract

In recent years, an increasingly important role in the etiopathogenesis of lung cancer has been attributed to genetic predisposition. Current genetic research suggests that the increased risk of this cancer may be due to gene polymorphism within repair genes. In the case of [...] Read more.

In recent years, an increasingly important role in the etiopathogenesis of lung cancer has been attributed to genetic predisposition. Current genetic research suggests that the increased risk of this cancer may be due to gene polymorphism within repair genes. In the case of lung cancer, observations about genes involved in the DNA repair system by cutting bases of nitrogen—base excision repair (BER)—seem to be interesting. Most attention has been devoted to the XRCC1 gene, which coordinates the various stages of BER. The aim of this study was to assess the role of the single nucleotide polymorphism Arg399Gln in the XRCC1 gene as a factor influencing the risk of lung cancer. The study involved 118 patients with non-small cell lung cancer (NSCLC). The control group consisted of 60 people who did not have cancer. The study proved that the polymorphism of the XRCC1 gene is characterized by a statistically significant relationship with the onset of cancer. There were no statistically significant differences between the Arg399Gln polymorphism of the XRCC1 gene and risk factors for non-small cell lung cancer, such as age, sex, smoking and its duration, or place of residence, as well as between the histological type of the tumor or its severity. Detailed analysis of three genotypes—Arg/Arg, Arg/Gln, and Gln/Gln—showed that the incidence of particular genotypes in the group of patients was, respectively, 16.10%, 27.12%, and 58.78%. In the case of the Gln/Gln genotype, the most common associated histopathological type was squamous cell carcinoma, and in the case of adenocarcinoma, the most common genotype was Arg/Arg. It was estimated that each Arg allele reduced the chance of tumor occurrence to 0.48 times the reference value, i.e., the Gln/Gln genotype class for the Arg/Gln genotype and the Arg/Gln genotype for the Arg/Arg genotype. The relationship between the male sex and the occurrence of cancer remained insignificant, in contrast to the presence of nicotinism. Studies suggest that the Arg399Gln polymorphism of the XRCC1 gene has limited prognostic significance in non-small cell lung cancer. Full article

(This article belongs to the Section Molecular Oncology)

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17 pages, 5071 KiB

Open AccessArticle

Defactinib in Combination with Mitotane Can Be an Effective Treatment in Human Adrenocortical Carcinoma

by Henriett Butz, Lőrinc Pongor, Lilla Krokker, Borbála Szabó, Katalin Dezső, Titanilla Dankó, Anna Sebestyén, Dániel Sztankovics, József Tóvári, Sára Eszter Surguta, István Likó, Katalin Mészáros, Andrea Deák, Fanni Fekete, Ramóna Vida, László Báthory-Fülöp, Erika Tóth, Péter Igaz and Attila Patócs

Int. J. Mol. Sci. 2025, 26(13), 6539; https://doi.org/10.3390/ijms26136539 - 7 Jul 2025

Abstract

Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter [...] Read more.

Adrenocortical carcinoma (ACC) is an aggressive cancer with a poor prognosis. Mitotane, the only FDA-approved treatment for ACC, targets adrenocortical cells and reduces cortisol levels. Although it remains the cornerstone of systemic therapy, its overall impact on long-term outcomes is still a matter of ongoing clinical debate. Drug repurposing is a cost-effective way to identify new therapies, and defactinib, currently in clinical trials as part of combination therapies for various solid tumours, may enhance ACC treatment. We aimed to assess its efficacy in combination with mitotane. We tested the combination of mitotane and defactinib in H295R, SW13, and mitotane-sensitive and -resistant HAC15 cells, using functional assays, transcriptomic profiling, 2D and 3D cultures, bioprinted tissues, and xenografts. We assessed drug interactions with NMR and toxicity in vivo, as mitotane and defactinib have never been previously administered together. Genomic data from 228 human ACC and 158 normal adrenal samples were also analysed. Transcriptomic analysis revealed dysregulation of focal adhesion along with mitotane-related pathways. Focal adhesion kinase (FAK) signalling was enhanced in ACC compared to normal adrenal glands, with PTK2 (encoding FAK) upregulated in 44% of tumour samples due to copy number alterations. High FAK signature scores correlated with worse survival outcomes. FAK inhibition by defactinib, both alone and in combination with mitotane, showed effective anti-tumour activity in vitro. No toxicity or drug—drug interactions were observed in vivo. Combination treatment significantly reduced tumour volume and the number of macrometastases compared to those in the mitotane and control groups, with defactinib-treated tumours showing increased necrosis in xenografts. Defactinib combined with conventionally used mitotane shows promise as a novel combination therapy for ACC and warrants further investigation. Full article

(This article belongs to the Special Issue Signalling Pathways in Metabolic Diseases and Cancers)

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21 pages, 795 KiB

Open AccessReview

The Role of Monocytes in the Natural History of Idiopathic Pulmonary Fibrosis: A Systematic Literature Review

by Diego Lema, Esteban Kosak Lopez, Justin Lam, Irakli Tskhakaia, Yurilu Gonzalez Moret and Shahrzad Abdollahi

Int. J. Mol. Sci. 2025, 26(13), 6538; https://doi.org/10.3390/ijms26136538 - 7 Jul 2025

Abstract

Emerging evidence suggests a significant association between monocytes and the pathophysiology and prognosis of idiopathic pulmonary fibrosis (IPF). This review aims to systematically evaluate current knowledge regarding blood monocyte counts and their relationship with the etiology, progression, and prognosis of IPF. We conducted [...] Read more.

Emerging evidence suggests a significant association between monocytes and the pathophysiology and prognosis of idiopathic pulmonary fibrosis (IPF). This review aims to systematically evaluate current knowledge regarding blood monocyte counts and their relationship with the etiology, progression, and prognosis of IPF. We conducted a systematic search in the PubMed database for articles published through 17 February 2025, using the MeSH terms “lung diseases, interstitial” and “monocytes,” which yielded 314 results. After filtering for full-text articles in English (n = 242), we included only studies focusing on blood monocyte counts with clinical implications in IPF. Articles relating to other cell types or non-IPF lung diseases were excluded. Our systematic search identified 12 relevant articles. Monocytes play an essential role in regulating inflammatory responses and resolution across multiple diseases, with established but incompletely understood contributions to lung fibrosis development in IPF. Correlations have been demonstrated between elevated blood monocyte counts and the following: (1) the presence and progression of interstitial lung abnormalities, (2) the progression from an indeterminate usual interstitial pneumonia (UIP) pattern on CT scans to definitive IPF, and (3) worse lung function parameters, an increased risk of acute exacerbations, and reduced overall survival in IPF patients. Monocytes serve as critical orchestrators throughout IPF’s natural history—from early interstitial changes to disease progression and acute exacerbations. Targeting monocyte recruitment pathways and reprogramming their differentiation represents a promising therapeutic approach, while circulating monocyte counts offer potential as accessible biomarkers for disease progression and treatment response. Future research should characterize stage-specific monocyte phenotypes to enable precision-targeted interventions. Full article

(This article belongs to the Special Issue New Advances in Autoimmune Diseases)

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17 pages, 847 KiB

Open AccessReview

Mechanistic Links Between Gut Dysbiosis, Insulin Resistance, and Autism Spectrum Disorder

by Patricia Guevara-Ramírez, Rafael Tamayo-Trujillo, Viviana A. Ruiz-Pozo, Santiago Cadena-Ullauri, Elius Paz-Cruz and Ana Karina Zambrano

Int. J. Mol. Sci. 2025, 26(13), 6537; https://doi.org/10.3390/ijms26136537 - 7 Jul 2025

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with gastrointestinal symptoms, gut dysbiosis, and metabolic dysfunctions such as insulin resistance (IR). Recent evidence suggests that the gut microbiota may influence both metabolic and neurological processes through the gut–brain–metabolic axis. This review [...] Read more.

Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with gastrointestinal symptoms, gut dysbiosis, and metabolic dysfunctions such as insulin resistance (IR). Recent evidence suggests that the gut microbiota may influence both metabolic and neurological processes through the gut–brain–metabolic axis. This review explores the molecular mechanisms linking dysbiosis, IR, and ASD, focusing on pathways such as TLR/NF-κB activation, PI3K/Akt/mTOR disruption, and the action of microbial metabolites, like short-chain fatty acids (SCFAs), lipopolysaccharide (LPS), and γ-aminobutyric acid (GABA). We discuss how dysbiosis may contribute to increased intestinal permeability, systemic inflammation, and neuroimmune activation, ultimately affecting brain development and behavior. Common microbial alterations in ASD and IR—including increased Clostridium, Desulfovibrio, and Alistipes, and reduced Bifidobacterium and butyrate-producing genera—suggest a shared pathophysiology. We also highlight potential therapeutic strategies, such as microbiota modulation, insulin-like growth factor 1 (IGF-1) treatment, and dietary interventions. Understanding these interconnected mechanisms may support the development of microbiota-targeted approaches for individuals with ASD metabolic comorbidities. Full article

(This article belongs to the Special Issue The Molecular and Cellular Aspects of Insulin Resistance)

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18 pages, 3458 KiB

Open AccessArticle

An mRNA Vaccine Targeting the C-Terminal Region of P1 Protein Induces an Immune Response and Protects Against Mycoplasma pneumoniae

by Fenglian Zhang, Chengwei Li, Yanan Wu, Hongyun Chuan, Shaohui Song, Yun Xie, Qi Zhu, Qianqian Chen, Fei Tong, Runfang Zhang, Guangbo Yuan, Xiaoyan Wu, Jian Zhou and Guoyang Liao

Int. J. Mol. Sci. 2025, 26(13), 6536; https://doi.org/10.3390/ijms26136536 - 7 Jul 2025

Abstract

Mycoplasma pneumoniae, a cell wall-deficient pathogen, primarily affects children and adolescents, causing Mycoplasma pneumoniae pneumonia (MPP). Following the relaxation of non-pharmaceutical interventions (NPIs) post COVID-19, there has been a global increase in MPP cases and macrolide-resistant strains. Vaccination against M. pneumoniae is [...] Read more.

Mycoplasma pneumoniae, a cell wall-deficient pathogen, primarily affects children and adolescents, causing Mycoplasma pneumoniae pneumonia (MPP). Following the relaxation of non-pharmaceutical interventions (NPIs) post COVID-19, there has been a global increase in MPP cases and macrolide-resistant strains. Vaccination against M. pneumoniae is being explored as a promising approach to reduce infections, limit antibiotic misuse, and prevent the emergence of drug-resistant variants. We developed an mRNA vaccine, mRNA-SP+P1, incorporating a eukaryotic signal peptide (tissue-type plasminogen activator signal peptide) fused to the C-terminal region of the P1 protein. Targeting amino acids 1288 to 1518 of the P1 protein, the vaccine was administered intramuscularly to BALB/c mice in a three-dose regimen. To evaluate immunogenicity, we quantified anti-P1 IgG antibody titers using enzyme-linked immunosorbent assays (ELISAs) and assessed cellular immune responses by analyzing effector memory T cell populations using flow cytometry. We also tested the functional activity of vaccine-induced sera for their ability to inhibit adhesion of the ATCC M129 strain to KMB17 cells. The vaccine’s protective efficacy was assessed against the ATCC M129 strain and its cross-protection against the ST3-resistant strain. Transcriptomic analysis was conducted to investigate gene expression changes in peripheral blood, aiming to uncover mechanisms of immune modulation. The mRNA-SP+P1 vaccine induces P1 protein-specific IgG antibodies and an effector memory T-cell response in BALB/c mice. Adhesion inhibition assays demonstrated that serum from vaccinated mice attenuatesthe adhesion ability of ATCC M129 to KMB17 cells. Furthermore, three doses of the vaccine confer significant and long-lasting, though partial, protection against the ATCC M129 strain and partial cross-protection against the ST3 drug-resistant strain. Transcriptome analysis revealed significant gene expression changes in peripheral blood, confirming the vaccine’s capacity to elicit an immune response from the molecular level. Our results indicate that the mRNA-SP+P1 vaccine appears to be an effective vaccine candidate against the prevalence of Mycoplasma pneumoniae. Full article

(This article belongs to the Section Molecular Immunology)

19 pages, 2774 KiB

Open AccessArticle

Genetic Variants in the Extracellular Matrix Gene TNXB Predicted to Alter Fibronectin III Domains in Arterial Aneurysmal and Dissection Diseases

by Charlene Norgan Radler, Tianci Wang, Jaden LeGate, Lily Crone, Parminder Deo, Jacob Wortley, Peyton Moore, Griffin Bryant, Katherine Smitherman and Mohanakrishnan Sathyamoorthy

Int. J. Mol. Sci. 2025, 26(13), 6535; https://doi.org/10.3390/ijms26136535 - 7 Jul 2025

Abstract

Arterial aneurysms are vascular conditions associated with life-threatening consequences in patients, such as dissection and rupture. Understanding their genetic basis is an evolving field, driven by the robust reporting of genetic variants associated with aneurysms in patients. In this study, we present clinical [...] Read more.

Arterial aneurysms are vascular conditions associated with life-threatening consequences in patients, such as dissection and rupture. Understanding their genetic basis is an evolving field, driven by the robust reporting of genetic variants associated with aneurysms in patients. In this study, we present clinical and genetic data from nine unrelated subjects with arterial aneurysms who were identified to harbor rare variants in the TNXB gene, mainly affecting fibronectin type III (FNIII) domains. The cohort included three female and six male subjects with a mean age of 53.5 years (SD = 14.4). The most frequently affected vascular territory was the thoracic ascending aorta (n = 7). A range of pathogenic impacts was predicted via multiple in silico tools that analyze evolutionary conservation and biochemical properties. Computational protein structure modeling with AlphaFold 3 predicted domain-specific alterations across multiple FNIII regions for four unique missense variants and one in-frame deletion, and premature protein truncation resulting from two frameshift variants. To our knowledge, this study is one of the first and largest to associate TNXB variants with arterial aneurysmal disease. Our findings demonstrate the potential of computational genomics and structural modeling to advance the understanding of extracellular matrix gene alterations in aneurysm pathogenesis. Full article

(This article belongs to the Special Issue Genes and Human Diseases 2.0)

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42 pages, 1314 KiB

Open AccessReview

Current Approaches to Aflatoxin B1 Control in Food and Feed Safety: Detection, Inhibition, and Mitigation

by Katarzyna Kępka-Borkowska, Katarzyna Chałaśkiewicz, Magdalena Ogłuszka, Mateusz Borkowski, Adam Lepczyński, Chandra Shekhar Pareek, Rafał Radosław Starzyński, Elżbieta Lichwiarska, Sharmin Sultana, Garima Kalra, Nihal Purohit, Barbara Gralak, Ewa Poławska and Mariusz Pierzchała

Int. J. Mol. Sci. 2025, 26(13), 6534; https://doi.org/10.3390/ijms26136534 - 7 Jul 2025

Abstract

Aflatoxins, toxic secondary metabolites produced primarily by Aspergillus flavus and Aspergillus parasiticus, pose a significant global health concern due to their frequent presence in crops, food, and feed—especially under climate change conditions. This review addresses the growing threat of aflatoxins by analyzing [...] Read more.

Aflatoxins, toxic secondary metabolites produced primarily by Aspergillus flavus and Aspergillus parasiticus, pose a significant global health concern due to their frequent presence in crops, food, and feed—especially under climate change conditions. This review addresses the growing threat of aflatoxins by analyzing recent advances in detection and mitigation. A comprehensive literature review was conducted, focusing on bioremediation, physical and chemical detoxification, and fungal growth inhibition strategies. The occurrence of aflatoxins in water systems was also examined, along with current detection techniques, removal processes, and regulatory frameworks. Emerging technologies such as molecular diagnostics, immunoassays, biosensors, and chromatographic methods are discussed for their potential to improve monitoring and control. Key findings highlight the increasing efficacy of integrative approaches combining biological and technological solutions and the potential of AI-based tools and portable devices for on-site detection. Intelligent packaging and transgenic crops are also explored for their role in minimizing contamination at the source. Overall, this review emphasizes the importance of continued interdisciplinary research and the development of sustainable, adaptive strategies to mitigate aflatoxin risks, thereby supporting food safety and public health in the face of environmental challenges. Full article

(This article belongs to the Section Molecular Microbiology)

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19 pages, 8019 KiB

Open AccessArticle

Identification of a PAK6-Mediated MDM2/p21 Axis That Modulates Survival and Cell Cycle Control of Drug-Resistant Stem/Progenitor Cells in Chronic Myeloid Leukemia

by Andrew Wu, Min Chen, Athena Phoa, Zesong Yang, Donna L. Forrest and Xiaoyan Jiang

Int. J. Mol. Sci. 2025, 26(13), 6533; https://doi.org/10.3390/ijms26136533 - 7 Jul 2025

Abstract

Chronic myeloid leukemia (CML) is a leading example of a malignancy where a molecular targeted therapy revolutionized treatment but has rarely led to cures. Overcoming tyrosine kinase inhibitor (TKI) drug resistance remains a challenge in the treatment of CML. We have recently identified [...] Read more.

Chronic myeloid leukemia (CML) is a leading example of a malignancy where a molecular targeted therapy revolutionized treatment but has rarely led to cures. Overcoming tyrosine kinase inhibitor (TKI) drug resistance remains a challenge in the treatment of CML. We have recently identified miR-185 as a predictive biomarker where reduced expression in CD34⁺ treatment-naïve CML cells was associated with TKI resistance. We have also identified PAK6 as a target gene of miR-185 that was upregulated in CD34⁺ TKI-nonresponder cells. However, its role in regulating TKI resistance remains largely unknown. In this study, we specifically targeted PAK6 in imatinib (IM)-resistant cells and CD34⁺ stem/progenitor cells from IM-nonresponders using a lentiviral-mediated PAK6 knockdown strategy. Interestingly, the genetic and pharmacological suppression of PAK6 significantly reduced proliferation and increased apoptosis in TKI-resistant cells. Cell survivability was further diminished when IM was combined with PAK6 knockdown. Importantly, PAK6 inhibition in TKI-resistant cells induced cell cycle arrest in the G2-M phase and cellular senescence, accompanied by increased levels of DNA damage-associated senescence markers. Mechanically, we identified a PAK6-mediated MDM2-p21 axis that regulates cell cycle arrest and senescence. Thus, PAK6 plays a critical role in determining alternative cell fates in leukemic cells, and targeting PAK6 may offer a therapeutic strategy to selectively eradicate TKI-resistant cells. Full article

(This article belongs to the Special Issue New Developments in Chronic Myeloid Leukemia)

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14 pages, 3320 KiB

Open AccessArticle

Regulation of Human Lung Adenocarcinoma Cell Proliferation by LncRNA AFAP-AS1 Through the miR-508/ZWINT Axis

by Sultan F. Kadasah and Abdulaziz M. S. Alqahtani

Int. J. Mol. Sci. 2025, 26(13), 6532; https://doi.org/10.3390/ijms26136532 - 7 Jul 2025

Abstract

Lung adenocarcinoma is a prevalent, aggressive cancer with a poor prognosis due to early metastasis and resistance to treatment. LncRNA AFAP1-AS1 has been shown to be associated with the development of multiple carcinomas. This study investigates the functional role of AFAP1-AS1 in lung [...] Read more.

Lung adenocarcinoma is a prevalent, aggressive cancer with a poor prognosis due to early metastasis and resistance to treatment. LncRNA AFAP1-AS1 has been shown to be associated with the development of multiple carcinomas. This study investigates the functional role of AFAP1-AS1 in lung adenocarcinoma cell proliferation via miR-508-3p and ZWINT. Human lung adenocarcinoma A549 cells were transfected with siRNA constructs against AFAP1-AS1 (si-AFAP1-AS1) to silence its expression. Cell proliferation was evaluated via CCK-8 and colony-forming assays. Apoptosis was assessed using AO/EB staining, and invasion was determined via Transwell assay. The interaction between AFAP1-AS1, miR-508-3p, and ZWINT was confirmed via dual luciferase reporter assay and qRT-PCR analysis. Data were analysed using appropriate statistical tests. AFAP1-AS1 was significantly upregulated in lung adenocarcinoma cells compared to normal BEAS-2B cells. Silencing of AFAP1-AS1 resulted in a marked reduction in A549 cell proliferation and colony development, as observed in CCK-8 and colony formation assays. The AO/EB assay showed a significant increase in apoptosis (30 ± 4.4%) in si-AFAP1-AS1 transfected cells compared to control si-NC (3 ± 1.2%). In addition, knockdown of AFAP1-AS1 led to an upsurge of pro-apoptotic Bax and decline of anti-apoptotic Bcl-2 expression. The dual luciferase assay established the interaction between AFAP1-AS1 and miR-508-3p. Furthermore, ZWINT, identified as a target of miR-508-3p, was significantly upregulated in lung adenocarcinoma tissues. Overexpression of ZWINT rescued the inhibitory effects of AFAP1-AS1 silencing on cell proliferation, colony formation, and apoptosis, while also reversing the reduction in cell invasion. AFAP1-AS1 accelerates the development of lung adenocarcinoma by cell proliferation, apoptosis, and invasion via the miR-508-3p/ZWINT axis. Thus, targeting AFAP1-AS1 or its downstream regulatory axis could offer novel therapeutic approaches in lung adenocarcinoma treatment. Full article

(This article belongs to the Special Issue Novel Molecular Pathways in Oncology, 3rd Edition)

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