International Journal of Molecular Sciences

16 pages, 2515 KiB

Open AccessArticle

Chr23-miR-200s and Dmrt1 Control Sexually Dimorphic Trade-Off Between Reproduction and Growth in Zebrafish

by Si Ge, Ying Liu, Haoran Huang, Jiawang Yu, Xiaohui Li, Qiaohong Lin, Peipei Huang and Jie Mei

Int. J. Mol. Sci. 2025, 26(4), 1785; https://doi.org/10.3390/ijms26041785 - 19 Feb 2025

Viewed by 419

Abstract

In animals, a trade-off exists between reproduction and growth, which are the most fundamental traits. Males and females exhibit profound differences in reproduction and growth in fish species. However, the precise molecular mechanism governing this phenomenon is still not clear. Here, we uncovered [...] Read more.

In animals, a trade-off exists between reproduction and growth, which are the most fundamental traits. Males and females exhibit profound differences in reproduction and growth in fish species. However, the precise molecular mechanism governing this phenomenon is still not clear. Here, we uncovered that chr23-miR-200s and dmrt1 knockout specifically caused an impairment in reproduction and an increase in body growth in female and male zebrafish, respectively. Chr23-miR-200s and Dmrt1 directly regulate the stat5b gene by targeting its 3′UTR and promoter. The loss of stat5b completely abolished the elevated growth performance in chr23-miR-200s-KO or dmrt1^−/− zebrafish. Moreover, the dmrt1 transgenic zebrafish had significantly lower body length and body weight than the control males, accompanied by a significant reduction in stat5b expression in the liver of transgenic fish. In summary, our study proposes a regulatory model elucidating the roles of chr23-miR-200s and Dmrt1 in controlling the sexually dimorphic trade-off between reproduction and growth. Full article

(This article belongs to the Section Molecular Biology)

► Show Figures

Figure 1

20 pages, 10073 KiB

Open AccessArticle

Role of Glycans in Equine Endometrial Cell Uptake of Extracellular Vesicles Derived from Amniotic Mesenchymal Stromal Cells

by Giulia Gaspari, Anna Lange-Consiglio, Fausto Cremonesi and Salvatore Desantis

Int. J. Mol. Sci. 2025, 26(4), 1784; https://doi.org/10.3390/ijms26041784 - 19 Feb 2025

Viewed by 385

Abstract

Extracellular vesicles (EVs) are important mediators of cell–cell communication thanks to their ability to transfer their bioactive cargo, thus regulating a variety of physiological contexts. EVs derived from amniotic mesenchymal/stromal cells (eAMC-EVs) are internalized by equine endometrial cells (eECs) with positive effects on [...] Read more.

Extracellular vesicles (EVs) are important mediators of cell–cell communication thanks to their ability to transfer their bioactive cargo, thus regulating a variety of physiological contexts. EVs derived from amniotic mesenchymal/stromal cells (eAMC-EVs) are internalized by equine endometrial cells (eECs) with positive effects on regenerative medicine treatments. As the cellular uptake of EVs is influenced by the glycan profile of both EVs and target cells, this study is focused on the role of surface glycans in the uptake of eAMC-EVs by recipient eECs. Equine ECs were obtained by enzymatic digestion of uteri from healthy mares. Equine AMC-EVs were isolated from amniotic cell cultures according to a standardized protocol. The glycan pattern was studied using a panel of lectins in combination with fucosidase and neuraminidase treatment. Both eECs and eAMC-EVs expressed N-linked high mannose glycans, as well as fucosylated and sialylated glycans. All these glycans were involved in the uptake of eAMC-EVs by eECs. The internalization of eAMC-EVs was strongly reduced after cleavage of α1,2-linked fucose and α2,3/α2,6-linked sialic acids. These results demonstrate that surface glycans are involved in the internalization of eAMC-EVs by eECs and that fucosylated and sialylated glycans are highly relevant in the transfer of bioactive molecules with effects on regenerative medicine treatments. Full article

(This article belongs to the Special Issue Extracellular Vesicles: From Molecular Mechanisms to Therapeutic Applications)

► Show Figures

Figure 1

17 pages, 1214 KiB

Open AccessReview

Metformin’s Effects on Cognitive Function from a Biovariance Perspective: A Narrative Review

by Dimitrie Chele, Carmen-Adella Sirbu, Marian Mitrica, Mihai Toma, Octavian Vasiliu, Anca-Maria Sirbu, Francois Jerome Authier, Dan Mischianu and Alice Elena Munteanu

Int. J. Mol. Sci. 2025, 26(4), 1783; https://doi.org/10.3390/ijms26041783 - 19 Feb 2025

Viewed by 445

Abstract

This study examines the effects of metformin on brain functions focusing on the variability of the results reported in the literature. While some studies suggest that metformin may have neuroprotective effects in diabetic patients, others report an insignificant impact of metformin on cognitive [...] Read more.

This study examines the effects of metformin on brain functions focusing on the variability of the results reported in the literature. While some studies suggest that metformin may have neuroprotective effects in diabetic patients, others report an insignificant impact of metformin on cognitive function, or even a negative effect. We propose that this inconsistency may be due to intrinsic cellular-level variability among individuals, which we term “biovariance”. Biovariance persists even in demographically homogeneous samples due to complex and stochastic biological processes. Additionally, the complex metabolic actions of metformin, including its influence on neuroenergetics and neuronal survival, may produce different effects depending on individual metabolic characteristics. Full article

(This article belongs to the Special Issue Neuroprotective Strategies 2024)

► Show Figures

Figure 1

14 pages, 904 KiB

Open AccessArticle

A Genetic Test to Identify People at High Risk of Heart Failure

by Xintian Ge, Bek Brittain, Luke Dawson, Girish Dwivedi, David M. Kaye and Grant Morahan

Int. J. Mol. Sci. 2025, 26(4), 1782; https://doi.org/10.3390/ijms26041782 - 19 Feb 2025

Viewed by 538

Abstract

Earlier intervention may delay or prevent heart failure (HF), a widespread health problem. However, it is not currently possible to identify those who are most at risk, especially before the appearance of any clinical signs. This study presents the development and subsequent validation [...] Read more.

Earlier intervention may delay or prevent heart failure (HF), a widespread health problem. However, it is not currently possible to identify those who are most at risk, especially before the appearance of any clinical signs. This study presents the development and subsequent validation of a novel genetic test for predicting the risk of HF, utilizing data from three independent cohorts of Australian and US subjects. We developed a first-phase test using the Baker Biobank case–control cohort, identifying 41 genetic variants indicative of HF risk through genome-wide interaction and association analyses. Subsequently, a second-phase test was designed. This identified 29 additional single-nucleotide polymorphisms. The combination of these two tests resulted in an aggregate test with a high predictive accuracy, achieving an Area Under the Curve of 0.93 and a balanced accuracy of 0.89. High genetic risk subjects in the Baker Biobank cohort had an odds ratio of 533.2. The test’s robustness was validated by applying it to data from the Busselton Health Study and the Atherosclerosis Risk in Communities cohorts, yielding, respectively, Areas Under the Curve of 0.83 and 0.72, a balanced accuracy of 0.76 and 0.67, and Odds Ratios of 12.3 and 4.6. These results highlight the critical role of genetic factors in the development of heart failure and demonstrate this test’s potential as a significant tool for clinical HF risk prediction. Full article

(This article belongs to the Special Issue Genetic Prediction of Risk of Common Diseases)

► Show Figures

Graphical abstract

14 pages, 1321 KiB

Open AccessArticle

Exploring Heterogeneity of Fecal Microbiome in Long COVID Patients at 3 to 6 Months After Infection

by Jelle M. Blankestijn, Nadia Baalbaki, Rosanne J. H. C. G. Beijers, Merel E. B. Cornelissen, W. Joost Wiersinga, Mahmoud I. Abdel-Aziz and Anke H. Maitland-van der Zee

Int. J. Mol. Sci. 2025, 26(4), 1781; https://doi.org/10.3390/ijms26041781 - 19 Feb 2025

Viewed by 574

Abstract

An estimated 10% of COVID-19 survivors have been reported to suffer from complaints after at least three months. The intestinal microbiome has been shown to impact long COVID through the gut–lung axis and impact the severity. We aimed to investigate the relationship between [...] Read more.

An estimated 10% of COVID-19 survivors have been reported to suffer from complaints after at least three months. The intestinal microbiome has been shown to impact long COVID through the gut–lung axis and impact the severity. We aimed to investigate the relationship between the gut microbiome and clinical characteristics, exploring microbiome heterogeneity through clustering. Seventy-nine patients with long COVID evaluated at 3 to 6 months after infection were sampled for fecal metagenome analysis. Patients were divided into two distinct hierarchical clusters, based solely on the microbiome composition. Compared to cluster 1 (n = 67), patients in cluster 2 (n = 12) showed a significantly reduced lung function (FEV₁, FVC, and DLCO) and during acute COVID-19 showed a longer duration of hospital admissions (48 compared to 7 days) and higher rates of ICU admissions (92% compared to 22%). Additionally, the microbiome composition showed a reduced alpha diversity and lower proportion of butyrate-producing bacteria in cluster 2 together with higher abundances of Ruminococcus gnavus, Escherichia coli, Veillonella spp. and Streptococcus spp. and reduced abundances of Faecalibacterium prausnitzii and Eubacteria spp. Further research could explore the effect of pre- and pro-biotic supplementation and its impact on lung function and societal participation in long COVID. Full article

(This article belongs to the Section Molecular Microbiology)

► Show Figures

Figure 1

35 pages, 1692 KiB

Open AccessReview

Impact of Nutrient Stress on Plant Disease Resistance

by Héctor Martín-Cardoso and Blanca San Segundo

Int. J. Mol. Sci. 2025, 26(4), 1780; https://doi.org/10.3390/ijms26041780 - 19 Feb 2025

Viewed by 480

Abstract

Plants are constantly exposed to abiotic and biotic stresses that seriously affect crop yield and quality. A coordinated regulation of plant responses to combined abiotic/biotic stresses requires crosstalk between signaling pathways initiated by each stressor. Interconnected signaling pathways further finetune plant stress responses [...] Read more.

Plants are constantly exposed to abiotic and biotic stresses that seriously affect crop yield and quality. A coordinated regulation of plant responses to combined abiotic/biotic stresses requires crosstalk between signaling pathways initiated by each stressor. Interconnected signaling pathways further finetune plant stress responses and allow the plant to respond to such stresses effectively. The plant nutritional status might influence disease resistance by strengthening or weakening plant immune responses, as well as through modulation of the pathogenicity program in the pathogen. Here, we discuss advances in our understanding of interactions between nutrient stress, deficiency or excess, and immune signaling pathways in the context of current agricultural practices. The introduction of chemical fertilizers and pesticides was a major component of the Green Revolution initiated in the 1960s that greatly boosted crop production. However, the massive application of agrochemicals also has adverse consequences on the environment and animal/human health. Therefore, an in-depth understanding of the connections between stress caused by overfertilization (or low bioavailability of nutrients) and immune responses is a timely and novel field of research with important implications for disease control in crop species. Optimizing nutrient management practices tailored to specific environmental conditions will be crucial in maximizing crop production using environmentally friendly systems. Full article

(This article belongs to the Special Issue New Insights into Plant Pathology and Abiotic Stress)

► Show Figures

Figure 1

23 pages, 5414 KiB

Open AccessArticle

Transcriptome and Functional Comparison of Primary and Immortalized Endothelial Cells of the Human Choroid Plexus at the Blood–Cerebrospinal Fluid Barrier

by Lea Denzer, Walter Muranyi, Rosanna Herold, Carolin Stump-Guthier, Hiroshi Ishikawa, Carsten Sticht, Horst Schroten, Christian Schwerk and Stefan Weichert

Int. J. Mol. Sci. 2025, 26(4), 1779; https://doi.org/10.3390/ijms26041779 - 19 Feb 2025

Viewed by 341

Abstract

The human choroid plexus (CP) is the location of the blood–cerebrospinal fluid (CSF) barrier (BCSFB). Whereas the epithelial cells of the CP mainly contribute to the formation of the BCSFB, the vessels of the CP are built by fenestrated endothelial cells. Still, the [...] Read more.

The human choroid plexus (CP) is the location of the blood–cerebrospinal fluid (CSF) barrier (BCSFB). Whereas the epithelial cells of the CP mainly contribute to the formation of the BCSFB, the vessels of the CP are built by fenestrated endothelial cells. Still, the CP endothelium can contribute to barrier function. By ectopic expression of human telomerase reverse transcriptase (hTERT) in primary human CP endothelial cells (HCPEnCs), we recently generated and characterized immortalized HCPEnCs (iHCPEnCs). Here, we compared primary cells of the sixth passage (HCPEnCs p6) with a lower (p20) and a higher passage (p50) of iHCPEnCs by transcriptome analysis. A high concordance of HCPEnCs and both passages of iHCPEnCs was observed, as only small proportions of the transcripts examined were significantly altered. Differentially expressed genes (DEGs) were identified and assigned to potentially affected biological processes by gene set enrichment analysis (GSEA). Various components of the endothelial barrier-relevant Wnt signaling were detected in HCPEnCs and iHCPEnCs. Functional analysis of HCPEnCs and iHCPEnCs showed equal marginal activation of Wnt signaling, supporting the downregulation of β-catenin (CTNNB) signaling in CP endothelial cells, and a contribution to the barrier function by the CP endothelium was retained until passage 100 (p100) of iHCPEnCs. Overall, our data support the suitability of iHCPEnCs as an in vitro model of the CP endothelium over extended passages. Full article

(This article belongs to the Special Issue Advanced Research Progress of Blood-Brain Barrier)

► Show Figures

Figure 1

41 pages, 996 KiB

Open AccessReview

Current Therapeutic Landscape for Metabolic Dysfunction-Associated Steatohepatitis

by Arun George Devasia, Adaikalavan Ramasamy and Chen Huei Leo

Int. J. Mol. Sci. 2025, 26(4), 1778; https://doi.org/10.3390/ijms26041778 - 19 Feb 2025

Viewed by 480

Abstract

In recent years, “metabolic dysfunction-associated steatotic liver disease” (MASLD) has been proposed to better connect liver disease to metabolic dysfunction, which is the most common chronic liver disease worldwide. MASLD affects more than 30% of individuals globally, and it is diagnosed by the [...] Read more.

In recent years, “metabolic dysfunction-associated steatotic liver disease” (MASLD) has been proposed to better connect liver disease to metabolic dysfunction, which is the most common chronic liver disease worldwide. MASLD affects more than 30% of individuals globally, and it is diagnosed by the combination of hepatic steatosis and obesity, type 2 diabetes, or two metabolic risk factors. MASLD begins with the buildup of extra fat, often greater than 5%, within the liver, causing liver hepatocytes to become stressed. This can proceed to a more severe form, metabolic dysfunction-associated steatohepatitis (MASH), in 20–30% of people, where inflammation in the liver causes tissue fibrosis, which limits blood flow over time. As fibrosis worsens, MASH may lead to cirrhosis, liver failure, or even liver cancer. While the pathophysiology of MASLD is not fully known, the current “multiple-hits” concept proposes that dietary and lifestyle factors, metabolic factors, and genetic or epigenetic factors contribute to elevated oxidative stress and inflammation, causing liver fibrosis. This review article provides an overview of the pathogenesis of MASLD and evaluates existing therapies as well as pharmacological drugs that are currently being studied in clinical trials for MASLD or MASH. Full article

(This article belongs to the Special Issue Diabetes and Its Complications: From Molecular Mechanisms to Novel Therapeutic Approaches)

► Show Figures

Figure 1

17 pages, 3391 KiB

Open AccessArticle

Mechanism of Action and Interaction of Garlic Extract and Established Therapeutics in Prostate Cancer

by Marco Hoffmann, Jana Sauer, Marie Book, Thomas Frank Ermler, Petra Fischer, Sven Gerlach, Kareem Beltagi, Agnieszka Morgenroth, Radu Alexa, Jennifer Kranz and Matthias Saar

Int. J. Mol. Sci. 2025, 26(4), 1777; https://doi.org/10.3390/ijms26041777 - 19 Feb 2025

Viewed by 394

Abstract

A detailed characterization of the mechanism of action of garlic extract (GE) on prostate cancer (PCa) cells is essential to ensure its safe use as a complementary therapy, particularly when combined with established treatments. A case report highlighted the potential benefits of GE [...] Read more.

A detailed characterization of the mechanism of action of garlic extract (GE) on prostate cancer (PCa) cells is essential to ensure its safe use as a complementary therapy, particularly when combined with established treatments. A case report highlighted the potential benefits of GE in PCa management. A patient diagnosed with PCa, presenting an initial prostate-specific antigen (PSA) of 11.8 ng/mL, maintained PSA levels between 3.5 and 6 ng/mL for over 14 years with daily GE intake. To study GE’s anti-proliferative effects and interactions with established therapeutics, healthy prostate epithelial cells (PNT2) and PCa cells (LNCaP, PC3, VCaP) were treated with GE. Proliferation, Integrin β1 pattern, DNA-damage, as well as androgen receptor (AR) and Cytochrome P450 (CYP450) expression were investigated. GE reduced the proliferation of LNCaP and PC3 cells compared to healthy PNT2 cells but had contrary effects on VCaP cells. The combination of GE with standard therapies, including chemotherapy, androgen deprivation therapy (ADT), and Poly-(ADP-ribose)-Polymerase inhibitors (PARPi), reduced the efficacy of these treatments in tumor cells, potentially due to the GE-induced upregulation of the metabolic enzyme CYP2C9 in PCa cell lines. These findings indicate that while GE has anti-proliferative effects, the use of highly concentrated natural extracts must be carefully assessed by expert physicians on a case-by-case basis, especially when combined with established therapies. Full article

(This article belongs to the Special Issue Anticancer Drug Discovery Based on Natural Products)

► Show Figures

Figure 1

16 pages, 3675 KiB

Open AccessArticle

Targeting Heat Shock Transcription Factor 4 Enhances the Efficacy of Cabozantinib and Immune Checkpoint Inhibitors in Renal Cell Carcinoma

by Saeki Saito, Hirofumi Yoshino, Seiya Yokoyama, Mitsuhiko Tominaga, Gang Li, Junya Arima, Ichiro Kawahara, Ikumi Fukuda, Akihiko Mitsuke, Takashi Sakaguchi, Satoru Inoguchi, Ryosuke Matsushita, Yasutoshi Yamada, Shuichi Tatarano, Akihide Tanimoto and Hideki Enokida

Int. J. Mol. Sci. 2025, 26(4), 1776; https://doi.org/10.3390/ijms26041776 - 19 Feb 2025

Viewed by 371

Abstract

Recently, immune checkpoint inhibitors (ICIs) and cabozantinib, a tyrosine kinase inhibitor (TKI), have been used to treat renal cell carcinoma (RCC); the combination of these agents has become a standard treatment for RCC. TKIs generally target vascular endothelial growth factor. However, cabozantinib is [...] Read more.

Recently, immune checkpoint inhibitors (ICIs) and cabozantinib, a tyrosine kinase inhibitor (TKI), have been used to treat renal cell carcinoma (RCC); the combination of these agents has become a standard treatment for RCC. TKIs generally target vascular endothelial growth factor. However, cabozantinib is characterized by its targeting of MET. Therefore, cabozantinib can be used as a late-line therapy for TKI-resistant RCC. According to data from The Cancer Genome Atlas (TCGA), heat shock transcription factor 4 (HSF4) expression is higher in RCC tissues than in normal renal tissues. HSF4 binds to the MET promoter in colorectal carcinoma to enhance MET expression and promote tumor progression. However, the functional role of HSF4 in RCC is unclear. We performed loss-of-function assays of HSF4, and our results showed that HSF4 knockdown in RCC cells significantly decreased cell functions. Moreover, MET expression was decreased in HSF4-knockdown cells but elevated in sunitinib-resistant RCC cells. The combination of cabozantinib and HSF4 knockdown reduced cell proliferation in sunitinib-resistant cells more than each monotherapy alone. Furthermore, HSF4 knockdown combined with an ICI showed synergistic suppression of tumor growth in vivo. Overall, our strategy involving HSF4 knockdown may enhance the efficacy of existing therapies, such as cabozantinib and ICIs. Full article

(This article belongs to the Special Issue Novel Combination Therapies for the Solid Cancers Treatment)

► Show Figures

Figure 1

30 pages, 3746 KiB

Open AccessArticle

Short Synthesis of Structurally Diverse N-Acylhomoserine Lactone Analogs and Discovery of Novel Quorum Quenchers Against Gram-Negative Pathogens

by Marina Porras, Dácil Hernández and Alicia Boto

Int. J. Mol. Sci. 2025, 26(4), 1775; https://doi.org/10.3390/ijms26041775 - 19 Feb 2025

Viewed by 223

Abstract

Quorum quenchers are emerging as an alternative to conventional antimicrobials, since they hinder the development of virulence or resistance mechanisms but without killing the microorganisms, thus, reducing the risk of antimicrobial resistance. Many quorum quenchers are analogs of the natural quorum-sensing signaling molecules [...] Read more.

Quorum quenchers are emerging as an alternative to conventional antimicrobials, since they hinder the development of virulence or resistance mechanisms but without killing the microorganisms, thus, reducing the risk of antimicrobial resistance. Many quorum quenchers are analogs of the natural quorum-sensing signaling molecules or autoinducers. Thus, different analogs of natural N-acylhomoserine lactones (AHLs) have been reported for controlling virulence or reducing the production of biofilms in Gram-negative pathogens. Herein we report the preparation of AHL analogs with a variety of N-substituents in just two steps from readily available N-substituted hydroxyproline esters. The substrates underwent an oxidative radical scission of the pyrrolidine ring. The resulting N-substituted β-aminoaldehyde underwent reduction and in situ cyclization to give a variety of homoserine lactones, with N- and N,N-substituted amino derivatives and with high optical purity. The libraries were screened for the inhibition of violacein production in Chromobacterium violaceum, a Gram-negative pathogen. For the first time, N,N-disubstituted AHL analogs were studied. Several N-sulfonyl derivatives, one carbamoyl, and one N-alkyl-N-sulfonyl homoserine lactone displayed a promising inhibitory activity. Moreover, they did not display microbicide action against S. aureus, C. jejuni, S. enterica, P. aeruginosa, and C. albicans, confirming a pure QQ activity. The determination of structure–activity relationships and in silico ADME studies are also reported, which are valuable for the design of next generations QQ agents. Full article

(This article belongs to the Special Issue Molecular Advances in Biotechnological Approaches to Developing Effective Antimicrobial Agents)

► Show Figures

Figure 1

18 pages, 4108 KiB

Open AccessArticle

Mining the Candidate Transcription Factors Modulating Tanshinones’ and Phenolic Acids’ Biosynthesis Under Low Nitrogen Stress in Salvia miltiorrhiza

by Yating Cheng, Siqi Gui, Siyu Hao, Xiujuan Li, Chao Zhuang, Yifei Shi, Wei Zhou and Guoyin Kai

Int. J. Mol. Sci. 2025, 26(4), 1774; https://doi.org/10.3390/ijms26041774 - 19 Feb 2025

Viewed by 248

Abstract

Mining valuable genes is helpful to breed high-quality Salvia miltiorrhiza exhibiting efficient nitrogen fertilizer utilization efficiency. In the present study, transcriptome sequencing was introduced to select the candidate transcription factors (TFs) involved in tanshinones’ (TAs) and phenolic acids’ (PHAs) biosynthesis as well as [...] Read more.

Mining valuable genes is helpful to breed high-quality Salvia miltiorrhiza exhibiting efficient nitrogen fertilizer utilization efficiency. In the present study, transcriptome sequencing was introduced to select the candidate transcription factors (TFs) involved in tanshinones’ (TAs) and phenolic acids’ (PHAs) biosynthesis as well as low nitrogen (LN) stress. In totally, 97.71 Gb clean data was obtained from fifteen sequencing samples and 30,975 unigenes were assembled. Among of them, 27,843 unigenes were successfully annotated. Overall, 8663 differential expression genes (DEGs) were identified, among of which 5034 unigenes were up-regulated, and 3629 unigenes were down-regulated. By enrichment of DEGs together with gene co-expression network construction, 10 candidate TFs including HSFB2b, LBD12, ERF1A, ERF98, LBD25, HSF24, RAM1, HSFA4B, TCP8, and WRKY24 were finally retrieved, which are predicted to participate in modulating TA and PHA biosynthesis under LN stress. Quantitative real-time polymerase chain reaction (qRT-PCR) detection was introduced to further detect the expression profile of candidate TFs under LN stress. These findings offer a valuable resource for in-depth study of TAs ‘and PHAs’ biosynthesis under LN stress in S. miltiorrhiza. Full article

(This article belongs to the Section Molecular Plant Sciences)

► Show Figures

Figure 1

22 pages, 3749 KiB

Open AccessReview

Microbiota and Inflammatory Markers: A Review of Their Interplay, Clinical Implications, and Metabolic Disorders

by Emiliano Peña-Durán, Jesús Jonathan García-Galindo, Luis Daniel López-Murillo, Alfredo Huerta-Huerta, Luis Ricardo Balleza-Alejandri, Alberto Beltrán-Ramírez, Elsa Janneth Anaya-Ambriz and Daniel Osmar Suárez-Rico

Int. J. Mol. Sci. 2025, 26(4), 1773; https://doi.org/10.3390/ijms26041773 - 19 Feb 2025

Viewed by 1730

Abstract

The human microbiota, a complex ecosystem of microorganisms, plays a pivotal role in regulating host immunity and metabolism. This review investigates the interplay between microbiota and inflammatory markers, emphasizing their impact on metabolic and autoimmune disorders. Key inflammatory biomarkers, such as C-reactive protein [...] Read more.

The human microbiota, a complex ecosystem of microorganisms, plays a pivotal role in regulating host immunity and metabolism. This review investigates the interplay between microbiota and inflammatory markers, emphasizing their impact on metabolic and autoimmune disorders. Key inflammatory biomarkers, such as C-reactive protein (CRP), interleukin-6 (IL-6), lipopolysaccharides (LPS), zonulin (ZO-1), and netrin-1 (Ntn1), are discussed in the context of intestinal barrier integrity and chronic inflammation. Dysbiosis, characterized by alterations in microbial composition and function, directly modulates the levels and activity of these biomarkers, exacerbating inflammatory responses and compromising epithelial barriers. The disruption of microbiota is further correlated with increased intestinal permeability and chronic inflammation, serving as a precursor to conditions like type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease. Additionally, this review examines therapeutic strategies, including probiotics and prebiotics, designed to restore microbial balance, mitigate inflammation, and enhance metabolic homeostasis. Emerging evidence positions microbiota-targeted interventions as critical components in the advancement of precision medicine, offering promising avenues for diagnosing and treating inflammatory and metabolic disorders. Full article

(This article belongs to the Special Issue Molecular Progression of Gut Microbiota)

► Show Figures

Figure 1

21 pages, 2381 KiB

Open AccessReview

It Takes a Village of Chromatin Remodelers to Regulate rDNA Expression

by Mathieu G. Levesque and David J. Picketts

Int. J. Mol. Sci. 2025, 26(4), 1772; https://doi.org/10.3390/ijms26041772 - 19 Feb 2025

Viewed by 400

Abstract

Ribosome biogenesis is one of the most fundamental and energetically demanding cellular processes. In humans, the ribosomal DNA (rDNA) repeats span a large region of DNA and comprise 200 to 600 copies of a ~43 kb unit spread over five different chromosomes. Control [...] Read more.

Ribosome biogenesis is one of the most fundamental and energetically demanding cellular processes. In humans, the ribosomal DNA (rDNA) repeats span a large region of DNA and comprise 200 to 600 copies of a ~43 kb unit spread over five different chromosomes. Control over ribosome biogenesis is closely tied to the regulation of the chromatin environment of this large genomic region. The proportion of rDNA loci which are active or silent is altered depending on the proliferative or metabolic state of the cell. Repeat silencing is driven by epigenetic changes culminating in a repressive heterochromatin environment. One group of proteins facilitating these epigenetic changes in response to growth or metabolic demands are ATP-dependent chromatin remodeling protein complexes that use ATP hydrolysis to reposition nucleosomes. Indeed, some chromatin remodelers are known to have indispensable roles in regulating the chromatin environment of rDNA. In this review, we highlight these proteins and their complexes and describe their mechanistic roles at rDNA. We also introduce the developmental disorders arising from the dysfunction of these proteins and discuss how the consequent dysregulation of rDNA loci may be reflected in the phenotypes observed. Full article

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

► Show Figures

Figure 1

31 pages, 3851 KiB

Open AccessArticle

Bioactivity and Neuroprotective Effects of Extra Virgin Olive Oil in a Mouse Model of Cerebral Ischemia: An In Vitro and In Vivo Study

by Salvatore Scacco, Silvia Acquaviva, Fábio França Vieira e Silva, John H. Zhang, Lorenzo Lo Muzio, Gaetano Corso, Vito Carlo Alberto Caponio, Pierluigi Reveglia, Lucia Lecce, Maria Eleonora Bizzoca, Prativa Sherchan, Stefania Cantore and Andrea Ballini

Int. J. Mol. Sci. 2025, 26(4), 1771; https://doi.org/10.3390/ijms26041771 - 19 Feb 2025

Viewed by 484

Abstract

Cerebral ischemia is a pathological condition characterized by complete blood and oxygen supply deprivation to neuronal tissue. The ischemic brain compensates for the rapid decline in ATP levels by increasing the anaerobic glycolysis rate, which leads to lactate accumulation and subsequent acidosis. Astrocytes [...] Read more.

Cerebral ischemia is a pathological condition characterized by complete blood and oxygen supply deprivation to neuronal tissue. The ischemic brain compensates for the rapid decline in ATP levels by increasing the anaerobic glycolysis rate, which leads to lactate accumulation and subsequent acidosis. Astrocytes play a critical role in regulating cerebral energy metabolism. Mitochondria are significant targets in hypoxia-ischemia injury, and disruptions in mitochondrial homeostasis and cellular energetics worsen outcomes, especially in the elderly. Elevated levels of n-3 polyunsaturated fatty acids (PUFAs) protect the adult and neonatal brain from ischemic damage by suppressing inflammation, countering oxidative stress, supporting neurovascular unit reconstruction, and promoting oligodendrogenesis. This study examines extra virgin olive oil (EVOO) treatment on TNC WT and TNC M23 cells, focusing on oxygen consumption and reactive oxygen species (ROS) production. This study investigates the effects of different durations of middle cerebral artery occlusion (MCAo) and EVOO administration on cerebral infarct volume, neurological scores, mitochondrial function, and cell viability. Cerebral infarct volume increased with longer ischemia times, while EVOO treatment (0.5 mg/kg/day) significantly reduced infarction across all MCAo durations. The oxygen consumption assays demonstrate EVOO’s dose-dependent stimulation of mitochondrial respiration in astrocytes, particularly at lower concentrations. Furthermore, EVOO-treated cells reduce ROS production during hypoxia, improve cell viability under ischemic stress, and enhance ATP production in ischemic conditions, underscoring EVOO’s neuroprotective potential. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Pharmacological Approaches for Brain Injury)

► Show Figures

Figure 1

31 pages, 1870 KiB

Open AccessReview

Unveiling the Mechanisms of Pain in Endometriosis: Comprehensive Analysis of Inflammatory Sensitization and Therapeutic Potential

by Yixiao Chen and Tian Li

Int. J. Mol. Sci. 2025, 26(4), 1770; https://doi.org/10.3390/ijms26041770 - 19 Feb 2025

Viewed by 592

Abstract

Endometriosis is a complicated, estrogen-dependent gynecological condition with a high morbidity rate. Pain, as the most common clinical symptom of endometriosis, severely affects women’s physical and mental health and exacerbates socioeconomic burden. However, the specific mechanisms behind the occurrence of endometriosis-related pain remain [...] Read more.

Endometriosis is a complicated, estrogen-dependent gynecological condition with a high morbidity rate. Pain, as the most common clinical symptom of endometriosis, severely affects women’s physical and mental health and exacerbates socioeconomic burden. However, the specific mechanisms behind the occurrence of endometriosis-related pain remain unclear. It is currently believed that the occurrence of endometriosis pain is related to various factors, such as immune abnormalities, endocrine disorders, the brain–gut axis, angiogenesis, and mechanical stimulation. These factors induce systemic chronic inflammation, which stimulates the nerves and subsequently alters neural plasticity, leading to nociceptive sensitization and thereby causing chronic pain. In this paper, we compile and review the articles published on the study of nociceptive sensitization and endometriosis pain mechanisms. Starting from the factors influencing the chronic pain associated with endometriosis, we explain the relationship between these factors and chronic inflammation and further elaborate on the potential mechanisms by which chronic inflammation induces nociceptive sensitization. We aim to reveal the possible mechanisms of endometriosis pain, as well as nociceptive sensitization, and offer potential new targets for the treatment of endometriosis pain. Full article

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

► Show Figures

Figure 1

15 pages, 2851 KiB

Open AccessArticle

Human Placenta MSC-Derived DNA Fragments Exert Therapeutic Effects in a Skin Wound Model via the A2A Receptor

by Hankyu Lee, Hyun-Jung Lee, Hyeon-Jun Jang, Hyeri Park and Gi Jin Kim

Int. J. Mol. Sci. 2025, 26(4), 1769; https://doi.org/10.3390/ijms26041769 - 19 Feb 2025

Viewed by 402

Abstract

PDRN, polydeoxyribonucleotide, which is used as a tissue-regeneration material, is present in human cells under physiological conditions and stimulates regeneration and metabolic activity. PDRN can be used as a biomaterial for several types of regeneration, including wound healing, to promote cell growth and [...] Read more.

PDRN, polydeoxyribonucleotide, which is used as a tissue-regeneration material, is present in human cells under physiological conditions and stimulates regeneration and metabolic activity. PDRN can be used as a biomaterial for several types of regeneration, including wound healing, to promote cell growth and growth-factor production. The aims of this study were to determine the effect of PDRN derived from human placenta-derived mesenchymal stem cells (hPD-MSCs) on cellular regeneration through A2A receptor signaling and to investigate its therapeutic effects in a mouse model of wound healing. Human PDRN (UNIPlax) was extracted from hPD-MSCs fragmented via a sonication system and evaluated for its effect on the migration of HaCaT cells in an in vitro system and in a wound-healing mouse model in vivo. Compared with the sham treatment, UNIPlax treatment significantly increased the migration of injured HaCaT cells (p < 0.05). Additionally, the tube formation of human umbilical vein endothelial cells (HUVECs) was greater than that of the sham group (p < 0.05), and the effects of this treatment were mediated through the A2A receptor. Furthermore, UNIPlax treatment led to a decrease in wound size; in addition, the area of granulation and the rate of collagen formation at the wound site were significantly greater than those in the sham group in the wound-healing mouse model (p < 0.001). We also confirmed that UNIPlax promoted tissue regeneration and the expression of VEGF through the A2A receptor. Taken together, these findings indicate that UNIPlax has potential for regeneration of damaged tissues, including during wound healing. Full article

(This article belongs to the Special Issue Novel MSC Perspectives: From Cell Regulation to Tissue Regeneration 4.0)

► Show Figures

Figure 1

15 pages, 1057 KiB

Open AccessReview

Exploring the Therapeutic Potential of BRCA1 and BRCA2 as Targets in Canine Oncology: A Comprehensive Review of Their Role in Cancer Development and Treatment

by Jayson Cagadas Pasaol, Agnieszka Śmieszek and Aleksandra Pawlak

Int. J. Mol. Sci. 2025, 26(4), 1768; https://doi.org/10.3390/ijms26041768 - 19 Feb 2025

Viewed by 681

Abstract

Tumor diseases represent a significant global health challenge, impacting both humans and companion animals, notably dogs. The parallels observed in the pathophysiology of cancer between humans and dogs underscore the importance of advancing comparative oncology and translational research methodologies. Furthermore, dogs serve as [...] Read more.

Tumor diseases represent a significant global health challenge, impacting both humans and companion animals, notably dogs. The parallels observed in the pathophysiology of cancer between humans and dogs underscore the importance of advancing comparative oncology and translational research methodologies. Furthermore, dogs serve as valuable models for human cancer research due to shared environments, genetics, and treatment responses. In particular, breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2), which are critical in human cancer, also influence the development and progression of canine tumors. The role of BRCA1 and BRCA2 in canine cancers remains underexplored, but its potential significance as therapeutic targets is strongly considered. This systematic review aims to broaden the discussion of BRCA1 and BRCA2 beyond mammary tumors, exploring their implications in various canine cancers. By emphasizing the shared genetic underpinnings between species and advocating for a comparative approach, the review indicates the potential of BRCA genes as targets for innovative cancer therapies in dogs, contributing to advances in human and veterinary oncology. Full article

(This article belongs to the Special Issue Molecular Biology of Cancer—Implications for Diagnosis and Treatment: 3rd Edition)

► Show Figures

Figure 1

20 pages, 1755 KiB

Open AccessReview

Immune Modulatory Effects of Vitamin D on Herpesvirus Infections

by Daniel Galdo-Torres, Sabina Andreu, Oliver Caballero, Israel Hernández-Ruiz, Inés Ripa, Raquel Bello-Morales and José Antonio López-Guerrero

Int. J. Mol. Sci. 2025, 26(4), 1767; https://doi.org/10.3390/ijms26041767 - 19 Feb 2025

Viewed by 444

Abstract

In addition to its classical role in calcium and phosphate metabolism regulation, vitamin D also has an important impact on immunity modulation. Vitamin D regulates the immune response, shifting from a proinflammatory state to a more tolerogenic one by increasing the release of [...] Read more.

In addition to its classical role in calcium and phosphate metabolism regulation, vitamin D also has an important impact on immunity modulation. Vitamin D regulates the immune response, shifting from a proinflammatory state to a more tolerogenic one by increasing the release of anti-inflammatory cytokines while downregulating proinflammatory cytokines. Thus, low levels of vitamin D have been associated with an increased risk of developing autoimmune diseases like multiple sclerosis and type 1 diabetes. Furthermore, this prohormone also enhances the release of well-known antimicrobial peptides, like cathelicidin LL-37 and β-defensins; therefore, it has been proposed that vitamin D serum levels might be related to the risk of well-known pathogen infections, including herpesviruses. These are a group of widely spread viral pathogens that can cause severe encephalitis or tumors like Kaposi’s sarcoma and Burkitt lymphoma. However, there is no consensus on the minimum levels of vitamin D or the recommended daily dose, making it difficult to establish a possible association between these two factors. This narrative non-systematic review will analyze the mechanisms by which vitamin D regulates the immune system and recent studies about whether there is an association between vitamin D serum levels and herpesvirus infections. Full article

(This article belongs to the Special Issue Advancements in Host-Directed Antiviral Therapies)

► Show Figures

Figure 1

20 pages, 3638 KiB

Open AccessArticle

Application of an Integrated Single-Cell and Three-Dimensional Spheroid Culture Platform for Investigating Drug Resistance Heterogeneity and Epithelial–Mesenchymal Transition (EMT) in Lung Cancer Subclones

by Shin-Hu Chen, Jian-Hong Yu, Yu-Chun Lin, Yi-Ming Chang, Nien-Tzu Liu and Su-Feng Chen

Int. J. Mol. Sci. 2025, 26(4), 1766; https://doi.org/10.3390/ijms26041766 - 19 Feb 2025

Viewed by 355

Abstract

Lung cancer is a leading cause of cancer-related mortality worldwide, largely due to its heterogeneity and intrinsic drug resistance. Malignant pleural effusions (MPEs) provide diverse tumor cell populations ideal for studying these complexities. Although chemotherapy and targeted therapies can be initially effective, subpopulations [...] Read more.

Lung cancer is a leading cause of cancer-related mortality worldwide, largely due to its heterogeneity and intrinsic drug resistance. Malignant pleural effusions (MPEs) provide diverse tumor cell populations ideal for studying these complexities. Although chemotherapy and targeted therapies can be initially effective, subpopulations of cancer cells with phenotypic plasticity often survive treatment, eventually developing resistance. Here, we integrated single-cell isolation and three-dimensional (3D) spheroid culture to dissect subclonal heterogeneity and drug responses, aiming to inform precision medicine approaches. Using A549 lung cancer cells, we established a cisplatin-resistant line and isolated three resistant subclones (Holoclone, Meroclone, Paraclone) via single-cell sorting. In 3D spheroids, Docetaxel and Alimta displayed higher IC50 values than in 2D cultures, suggesting that 3D models better reflect clinical dosing. Additionally, MPE-derived Holoclone and Paraclone subclones exhibited distinct sensitivities to Giotrif and Capmatinib, revealing their heterogeneous drug responses. Molecular analyses confirmed elevated ABCB1, ABCG2, cancer stem cell (CSC) markers (OCT4, SOX2, CD44, CD133), and epithelial–mesenchymal transition (EMT) markers (E-cadherin downregulation, increased Vimentin, N-cadherin, Twist) in resistant subclones, correlating with enhanced migration and invasion. This integrated approach clarifies the interplay between heterogeneity, CSC/EMT phenotypes, and drug resistance, providing a valuable tool for predicting therapeutic responses and guiding personalized, combination-based lung cancer treatments. Full article

(This article belongs to the Special Issue Lung Cancers: An Update on Molecular Diagnostics and Therapy)

► Show Figures

Figure 1

15 pages, 1950 KiB

Open AccessArticle

ADRB2 Polymorphisms (rs1042713 and rs1042714) and Blood Pressure Response to the Cold Pressor Test in Combat Athletes and Non-Athletes

by Marek Sawczuk, Agata Gąsiorowska, Agnieszka Maciejewska-Skrendo, Monika Chudecka, Katarzyna Kotarska, Patrizia Proia, Jolanta Marszałek, Paulina Małkowska and Katarzyna Leźnicka

Int. J. Mol. Sci. 2025, 26(4), 1765; https://doi.org/10.3390/ijms26041765 - 19 Feb 2025

Viewed by 267

Abstract

Adrenergic receptors (AR) play a vital role in cardiovascular system regulation. The ADRB2 gene, encoding the β2-AR receptor, has genetic variability potentially impacting blood pressure (BP) regulation. Evidence for such associations has been inconsistent. This study investigates the relationship between two ADRB2 polymorphisms [...] Read more.

Adrenergic receptors (AR) play a vital role in cardiovascular system regulation. The ADRB2 gene, encoding the β2-AR receptor, has genetic variability potentially impacting blood pressure (BP) regulation. Evidence for such associations has been inconsistent. This study investigates the relationship between two ADRB2 polymorphisms (rs1042713, Gly16Arg, and rs1042714, Glu27Gln) and BP changes during the cold pressor test (CPT) in young, healthy men, including combat athletes. The study included two groups: combat athletes and non-athlete students. BP (systolic, SBP; diastolic, DBP) was measured at rest and at pain tolerance during CPT. Genetic analysis was conducted for rs1042713 and rs1042714 polymorphisms. Athletes had higher SBP and DBP than students, with both values increasing during pain tolerance compared to rest. Differences in BP responses during CPT were genotype-dependent. Students with the Gly16Gly16 genotype had significantly higher SBP than Arg16 allele carriers, while this variation was not observed in athletes. Athletes with the Glu27 allele exhibited higher SBP than 27Gln homozygotes, unlike students. Gly16 and Glu27 alleles are linked to elevated stress-induced BP responses in young Polish men. However, BP regulation involves multiple genetic and environmental factors not explored in this study. Full article

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

► Show Figures

Figure 1

27 pages, 11242 KiB

Open AccessArticle

Bioinformatics Analysis of the Anti-Inflammatory Mechanism and Potential Therapeutic Efficacy of Kezimuke granules in Treating Urinary Tract Infections by Inhibiting NLRP3 Inflammasome Activation

by Alhar Baishan, Alifeiye Aikebaier, Dilihuma Dilimulati, Nuerbiye Nueraihemaiti, Yipaerguli Paerhati, Sendaer Hailati, Nulibiya Maihemuti and Wenting Zhou

Int. J. Mol. Sci. 2025, 26(4), 1764; https://doi.org/10.3390/ijms26041764 - 19 Feb 2025

Viewed by 335

Abstract

Kezimuke granules (KZMK), derived from traditional Kazakh folk medicine, exhibit a variety of pharmacological properties. Long-term clinical studies have demonstrated their efficacy in clearing heat, detoxifying, promoting qi circulation, and alleviating gonorrhea. However, their specific pharmacological effects on urinary tract infections remain unclear. [...] Read more.

Kezimuke granules (KZMK), derived from traditional Kazakh folk medicine, exhibit a variety of pharmacological properties. Long-term clinical studies have demonstrated their efficacy in clearing heat, detoxifying, promoting qi circulation, and alleviating gonorrhea. However, their specific pharmacological effects on urinary tract infections remain unclear. This study employed UHPLC-MS/MS technology to identify the blood components of KZMK and integrated network pharmacology with bioinformatics analysis for molecular docking validation. The anti-inflammatory activity of KZMK was further evaluated using a rat model of LPS-induced cystitis. A total of 17 components in KZMK were identified as capable of entering the bloodstream. Predictive analysis revealed that its primary targets include Caspase-1, NLRP3, STAT1, TLR4, and TNF, with the NLRP3 inflammasome signaling pathway emerging as the key mechanism. In vivo studies showed that KZMK effectively reduced the white blood cell (WBC) count and bladder index in urine sediments of rats with cystitis. Additionally, KZMK alleviated bladder congestion, edema, and histopathological changes in the animals. Treatment with KZMK led to decreased levels of IL-18 and IL-1β cytokines. KZMK significantly inhibited the expression of NLRP3, GSDMD, and Caspase-1 in LPS-induced cystitis, further confirming its anti-inflammatory effects. These findings indicate that KZMK provides protection against LPS-induced cystitis, primarily by inhibiting the activation of the NLRP3 inflammasome. Collectively, the results suggest that KZMK holds promise as a potential therapeutic option for urinary tract infections. Full article

(This article belongs to the Special Issue Computational Molecular Biology of Metabolic Pathways and Signal Transduction Pathways)

► Show Figures

Figure 1

13 pages, 1229 KiB

Open AccessArticle

Selection of Reference Genes for Normalization of Gene Expression After Exposure of Human Endothelial and Epithelial Cells to Hypoxia

by Juliane Hannemann, Lena Schmidt-Hutten, Jannik Hannemann, Fiona Kleinsang and Rainer Böger

Int. J. Mol. Sci. 2025, 26(4), 1763; https://doi.org/10.3390/ijms26041763 - 19 Feb 2025

Viewed by 215

Abstract

The selection of a stably expressed reference gene is a critical step for the quantitation of gene expression by qRT-PCR. We tested the stability of expression of nine putative reference genes in normoxia and hypoxia in four different human cell types: coronary (HCAECs) [...] Read more.

The selection of a stably expressed reference gene is a critical step for the quantitation of gene expression by qRT-PCR. We tested the stability of expression of nine putative reference genes in normoxia and hypoxia in four different human cell types: coronary (HCAECs) and pulmonary endothelial cells (HPAECs), EA.hy926 endothelial cells, and A549 alveolar epithelial cells. Cells were cultured in normoxic and hypoxic conditions for up to 72 h. Total RNA was isolated and used for qRT-PCR. Stability of expression was assessed by calculating the coefficient of variation of the cycle threshold (Ct CV) by pairwise comparison of ΔCt values, and by the NormFinder algorithm. A final rank was calculated for each gene. Finally, we analyzed VEGFA expression by using GAPDH or the optimal candidate reference gene found in this study. Gene expression was variable between cell lines and experimental conditions. The most stable reference gene across all cell lines was TBP, followed by RPLP1 and RPL13A. VEGFA expression was significantly upregulated by 4-fold in hypoxia when using TBP as reference, whilst this result was insignificant when GAPDH was used. The selection of a stably expressed reference gene is a critical step for the generation of reliable and reproducible data in gene expression studies. The most appropriate reference gene may vary in different cell lines and experimental conditions; it should be chosen individually for each experimental set-up. Full article

(This article belongs to the Section Molecular Biology)

► Show Figures

Figure 1

14 pages, 3496 KiB

Open AccessArticle

Transcriptome Analysis and Resistance Identification of bar and BPH9 Co-Transformation Rice

by Sanhe Li, Changyan Li, Jianyu Wang, Lei Zhou, Bian Wu, Zaihui Zhou, Xiaolei Fan, Aiqing You and Kai Liu

Int. J. Mol. Sci. 2025, 26(4), 1762; https://doi.org/10.3390/ijms26041762 - 19 Feb 2025

Viewed by 247

Abstract

Insect pests and weeds are the two major biotic factors affecting crop yield in the modern agricultural system. In this study, a brown planthopper (BPH) resistance gene (BPH9) and glufosinate tolerance gene (bar) were stacked into a single T-DNA [...] Read more.

Insect pests and weeds are the two major biotic factors affecting crop yield in the modern agricultural system. In this study, a brown planthopper (BPH) resistance gene (BPH9) and glufosinate tolerance gene (bar) were stacked into a single T-DNA cassette and transformed into an indica rice (Oryza sativa L.) line H23. The present study employed a gene stacking process that combines more than one gene/trait into an individual transgenic plant to meet the increasing cropping demands under complex conditions. The transgenic rice H23 (H23R) co-expressing bar and BPH9 genes demonstrated both glufosinate tolerance and BPH resistance. We utilized transcriptome data to reveal the mechanism of BPH9-mediated brown planthopper resistance and to analyze the impact of exogenous transgenic fragments on upstream and downstream genes at insertion sites. The evaluation of insect resistance and glufosinate tolerance confirmed H23R as an excellent double-resistant transgenic rice. These findings indicate that H23R can satisfy insect management and weed control in the modern rice agricultural system. However, a deregulation study will help with prospective commercial planting. Full article

(This article belongs to the Special Issue Research on Plant Genomics and Breeding: 2nd Edition)

► Show Figures

Figure 1

15 pages, 5457 KiB

Open AccessArticle

miR-212-5p Regulates PM_2.5-Induced Apoptosis by Targeting LAMC2 and LAMA3

by Yunna Jia, Xiqing Zhang, Cuizhu Zhao, Zhenhua Ma, Ke Sun, Yize Sun, Xiaohui Du, Meng Liu, Xiaojun Liang, Xiuzhen Yu and Yunhang Gao

Int. J. Mol. Sci. 2025, 26(4), 1761; https://doi.org/10.3390/ijms26041761 - 19 Feb 2025

Viewed by 290

Abstract

Fine particulate matter (PM_2.5) is often linked to a range of respiratory diseases and cellular damage. Although studies have shown that the expression profiles of microRNAs (miRNAs) are altered during lung damage brought on by PM_2.5, the underlying functions [...] Read more.

Fine particulate matter (PM_2.5) is often linked to a range of respiratory diseases and cellular damage. Although studies have shown that the expression profiles of microRNAs (miRNAs) are altered during lung damage brought on by PM_2.5, the underlying functions of miRNAs remain poorly understood. In this research, we explored the role of PM_2.5-induced apoptosis in detail and focused on the miRNA (miR-212-5p) that regulates apoptosis. Through a dual-luciferase assay, a direct targeting connection between laminin subunits γ2 (LAMC2) and α3 (LAMA3) and miR-212-5p was successfully demonstrated. This study focused on revealing the negative regulatory relationship between miR-212-5p and LAMC2 and LAMA3, providing important clues for a deeper understanding of the relevant physiological and pathological mechanisms. The present study showed that LAMC2 and LAMA3 positively regulate the PI3K-AKT pathway and negatively regulate the NF-κB pathway, which directly leads to significant changes in apoptosis rates. This study reveals a previously unrecognized molecular mechanism by showing that miR-212-5p directly targets LAMC2 and LAMA3 and thus associates with PM_2.5-induced apoptosis via the PI3K/AKT/NF-κB pathway. These findings not only redefine the role of miR-212-5p in apoptosis but also open up new avenues for future research. Full article

(This article belongs to the Special Issue RNA-Based Therapies for Lung Diseases)

► Show Figures

Graphical abstract

67 pages, 865 KiB

Open AccessReview

Pharmacogenetics in Response to Biological Agents in Inflammatory Bowel Disease: A Systematic Review

by Octavio Ballesta-López, Mayte Gil-Candel, María Centelles-Oria, Juan Eduardo Megías-Vericat, Antonio Solana-Altabella, Hugo Ribes-Artero, Pilar Nos-Mateu, Javier García-Pellicer and José Luis Poveda-Andrés

Int. J. Mol. Sci. 2025, 26(4), 1760; https://doi.org/10.3390/ijms26041760 - 19 Feb 2025

Viewed by 425

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders influenced by microbial, environmental, genetic, and immune factors. The introduction of biological agents has transformed IBD therapy, improving symptoms, reducing complications, and enhancing patients’ quality of life. However, approximately 30% of patients exhibit primary non-response, [...] Read more.

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders influenced by microbial, environmental, genetic, and immune factors. The introduction of biological agents has transformed IBD therapy, improving symptoms, reducing complications, and enhancing patients’ quality of life. However, approximately 30% of patients exhibit primary non-response, and 50% experience a loss of response over time. Genetic and non-genetic factors contribute to variability in treatment outcomes. This systematic review aims to thoroughly analyze and assess existing studies exploring the relationships between genetic variations and individual responses to biologic drugs, in order to identify genetic markers that are predictive of treatment efficacy, risk of adverse effects, or drug toxicity, thereby informing clinical practice and guiding future research. PubMed and EMBASE papers were reviewed by three independent reviewers according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] guidelines. Of the 883 records screened, 99 met the inclusion criteria. The findings of this review represent an initial step toward personalized medicine in IBD, with the potential to improve clinical outcomes in biological therapy. Full article

(This article belongs to the Special Issue Inflammatory Bowel Disease: From Genetics to Treatment)

► Show Figures

Figure 1

18 pages, 2618 KiB

Open AccessReview

Bi-Directional Relationship Between Bile Acids (BAs) and Gut Microbiota (GM): UDCA/TUDCA, Probiotics, and Dietary Interventions in Elderly People

by Emanuele Francini, Gretta V. Badillo Pazmay, Stefania Fumarola, Antonio Domenico Procopio, Fabiola Olivieri and Francesca Marchegiani

Int. J. Mol. Sci. 2025, 26(4), 1759; https://doi.org/10.3390/ijms26041759 - 19 Feb 2025

Viewed by 474

Abstract

The gut microbiota (GM), the set of microorganisms that colonizes our intestinal tract, can undergo many changes, some of which are age related. Several studies have shown the importance of maintaining a healthy GM for a good quality of life. In the elderly, [...] Read more.

The gut microbiota (GM), the set of microorganisms that colonizes our intestinal tract, can undergo many changes, some of which are age related. Several studies have shown the importance of maintaining a healthy GM for a good quality of life. In the elderly, maintaining a good GM may become a real defense against infection by pathogens, such as C. difficile. In addition to the GM, bile acids (BAs) have been shown to provide an additional defense mechanism against the proliferation of pathogenic bacteria and to regulate bacterial colonization of the gut. BAs are molecules produced in the host liver and secreted with the bile into the digestive tract, and they are necessary for the digestion of dietary lipids. In the gut, host-produced BAs are metabolized by commensal bacteria to secondary BAs. In general GM and host organisms interact in many ways. This review examines the relationship between GM, BAs, aging, and possible new approaches such as dietary interventions, administration of ursodesoxycholic acid/tauroursodesoxycholic acid (UDCA/TUDCA), and probiotics to enrich the microbial consortia of the GM in the elderly and achieve a eubiotic state necessary for maintaining good health. The presence of Firmicutes and Actinobacteria together with adequate levels of secondary BAs would provide protection and improve the frailty state in the elderly. In fact, an increase in secondary BAs has been observed in centenarians who have reached old age without serious health issues, which may justify their active role in achieving longevity. Full article

(This article belongs to the Special Issue Molecular Insights into Metabolic Pathways and Age-Related Pathologies)

► Show Figures

Figure 1

15 pages, 1525 KiB

Open AccessArticle

Tracking the Evolution of Cutaneous Melanoma by Multiparameter Flow Sorting and Genomic Profiling

by Luca Roma, Thomas Lorber, Sabrina Rau, Michael T. Barrett, Caner Ercan, Federica Panebianco, Salvatore Piscuoglio, Katharina Glatz, Lukas Bubendorf and Christian Ruiz

Int. J. Mol. Sci. 2025, 26(4), 1758; https://doi.org/10.3390/ijms26041758 - 19 Feb 2025

Viewed by 338

Abstract

Intratumoral heterogeneity and clonal evolution are pivotal in the progression and metastasis of melanoma. However, when combined with variable tumor cellularity, intratumoral heterogeneity limits the sensitivity and accuracy of uncovering a cancer’s clonal evolution. In this study, we combined fluorescence-activated cell sorting (FACS) [...] Read more.

Intratumoral heterogeneity and clonal evolution are pivotal in the progression and metastasis of melanoma. However, when combined with variable tumor cellularity, intratumoral heterogeneity limits the sensitivity and accuracy of uncovering a cancer’s clonal evolution. In this study, we combined fluorescence-activated cell sorting (FACS) with whole-exome sequencing (WES) to investigate the clonal composition and evolutionary patterns in seven melanoma biopsies obtained from three patients, each having both primary site and metastatic samples. We employed a multiparameter ploidy sorting approach to isolate tumor populations based on DNA ploidy and melanoma biomarkers (SOX10 or S100), enabling us to investigate clonal evolution with high resolution. Our approach increased the mean tumor purity from 70% (range 19–88%) in unsorted material to 91% (range 87–96%) post-sorting. Our findings revealed significant inter- and intratumor heterogeneity, with one patient exhibiting two genomically distinct clonal tumor populations within a single primary site biopsy, each giving rise to different metastases. Our findings highlight the critical role of intratumoral heterogeneity and clonal evolution in melanoma, especially when analyzing tumor trajectories. The unique combination of multiparameter FACS and WES provides a powerful method for identifying clonal populations and reconstructing clonal evolution. This study provides valuable insights into the clonal architecture of melanoma and lays the groundwork for future research with larger patient groups. Full article

(This article belongs to the Special Issue Recent Research on Bioinformatics for Precision Medicine)

► Show Figures

Figure 1

21 pages, 6008 KiB

Open AccessArticle

The Potential Impact of Edible Fruit Extracts on Bacterial Nucleases in Preliminary Research—In Silico and In Vitro Insight

by Łukasz Szeleszczuk, Malwina Brożyna, Bartłomiej Dudek, Marcin Czarnecki, Adam Junka and Monika E. Czerwińska

Int. J. Mol. Sci. 2025, 26(4), 1757; https://doi.org/10.3390/ijms26041757 - 19 Feb 2025

Viewed by 272

Abstract

The extracts from fruits of Chaenomeles japonica (Thunb.) Lindl. ex Spach (CJE), Cornus mas L. (CME), and Hippophaё rhamnoides L. (HRE) are known inhibitors of a variety of eukaryotic hydrolases, engaged in the digestion of fats and polysaccharides. However, there are no data [...] Read more.

The extracts from fruits of Chaenomeles japonica (Thunb.) Lindl. ex Spach (CJE), Cornus mas L. (CME), and Hippophaё rhamnoides L. (HRE) are known inhibitors of a variety of eukaryotic hydrolases, engaged in the digestion of fats and polysaccharides. However, there are no data on their potential interaction with the bacterial hydrolases participating in the replication of microbial nucleic acids. This analysis predicted the interaction of the most abundant constituents of HRE, CJE, and CME with the bacterial nucleases. The analysis covered the molecular docking of isorhamnetin glycosides, procyanidins C1 and B2, epicatechin, loganic acid, and cornuside with bacterial enzymes (Escherichia coli endonuclease 1, colicin E9, and ribonuclease H; or Staphylococcus aureus thermonuclease and nuclease SbcCD). The suggested complexes have been subjected to molecular mechanics with generalized Born and surface area solvation (MM/GBSA) calculations. The second aim was the in vitro evaluation of the influence of the CJE, HRE, and CME on the metabolic activity of bacterial biofilm of selected microbial strains, as well as fibroblasts (L929) and adenocarcinoma intestinal cells (Caco-2) toxicity. Among all extracts, CME showed the most relevant effect on the survival of planktonic cells and biofilm of E. coli and Pseudomonas aeruginosa. As a result of in silico studies, most virtual hits were predicted to inhibit the proteins under investigation, except for procyanidin C1. Further research on the direct interaction of phytochemicals and selected enzymes in vitro is required and challenged. Full article

(This article belongs to the Special Issue Antimicrobial Agents and Resistance Mechanisms)

► Show Figures

Figure 1

17 pages, 2417 KiB

Open AccessArticle

Density Functional Theory Study of Methylene Blue Demethylation as a Key Step in Degradation Mediated by Reactive Oxygen Species

by Silvia González and Ximena Jaramillo-Fierro

Int. J. Mol. Sci. 2025, 26(4), 1756; https://doi.org/10.3390/ijms26041756 - 19 Feb 2025

Viewed by 261

Abstract

Methylene blue (MB), a widely used organic dye, poses significant environmental challenges due to its stability and persistence in aquatic ecosystems. This study employs density functional theory (DFT) to investigate the demethylation mechanisms of MB mediated by reactive oxygen species (ROS), a critical [...] Read more.

Methylene blue (MB), a widely used organic dye, poses significant environmental challenges due to its stability and persistence in aquatic ecosystems. This study employs density functional theory (DFT) to investigate the demethylation mechanisms of MB mediated by reactive oxygen species (ROS), a critical initial step in its photocatalytic degradation. Computational analyses reveal that demethylation is energetically favorable, particularly when mediated by hydroxyl radicals (^•OH) and hydroxyl ions (OH⁻) with reaction energies of −154 kcal/mol and −214 kcal/mol, respectively. These pathways lead to the formation of key intermediates, such as Azure B, methanol (CH₃OH), and formaldehyde (CH₂O), which align with experimentally detected degradation byproducts. The study further demonstrates that the dissociation of hydrogen peroxide species (H₂O₂, H₂O₂⁻, H₂O₂⁺) plays a fundamental role in generating the ROS required for MB degradation. Potential energy surface analyses confirm that these ROS-driven processes are thermodynamically and kinetically viable. The findings provide a theoretical framework that bridges existing knowledge gaps in MB degradation, reinforcing the role of ROS in advanced photocatalytic systems and contributing to the optimization of wastewater treatment strategies. This work underscores the importance of integrating computational and experimental approaches to develop more effective strategies for the remediation of recalcitrant pollutants in wastewater. Full article

(This article belongs to the Section Biochemistry)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Int. J. Mol. Sci., Volume 26, Issue 4 (February-2 2025) – 391 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI