International Journal of Molecular Sciences

8 pages, 492 KiB

Open AccessEditorial

Special Issue “New Challenges and Perspectives in Polycystic Ovary Syndrome”

by Jim Parker and Pierre Hofstee

Int. J. Mol. Sci. 2025, 26(6), 2665; https://doi.org/10.3390/ijms26062665 (registering DOI) - 15 Mar 2025

Polycystic ovary syndrome (PCOS) is a complex multisystem metabolic and endocrine disorder that impacts health throughout the lifespan [...] Full article

(This article belongs to the Special Issue New Challenges and Perspectives in Polycystic Ovary Syndrome)

25 pages, 37930 KiB

Open AccessArticle

β-hydroxy-β-methylbutyrate Attenuates Age-Dependent Loss of Flight Ability and Extends Lifespan in Drosophila

by Ravi Nagori and Jim O. Vigoreaux

Int. J. Mol. Sci. 2025, 26(6), 2664; https://doi.org/10.3390/ijms26062664 (registering DOI) - 15 Mar 2025

Abstract

β

-hydroxy-

β

-methylbutyrate (HMB) has been shown to enhance muscle function and strength in older humans and rodents after periods of consumption extending for several weeks. We investigated the feasibility of utilizing Drosophila as a model organism to study the biological effects [...] Read more.

β

-hydroxy-

β

-methylbutyrate (HMB) has been shown to enhance muscle function and strength in older humans and rodents after periods of consumption extending for several weeks. We investigated the feasibility of utilizing Drosophila as a model organism to study the biological effects of HMB on aging muscle when consumed throughout adult life. Using flight ability as an index of flight muscle function, we found that HMB attenuates the age-dependent decline in flight ability. Male and female flies fed a diet supplemented with 10 mg/mL HMB had significantly higher flight scores from median age until the onset of flight senescence than control flies fed a standard diet. HMB supplementation also resulted in improved flight scores in males before median age and delayed the onset of flight senescence in females. Notably, the consumption of HMB throughout adult life increased the rate of survival and extended lifespan. The effect on lifespan did not result from changes in food consumption or body weight. Old flies on the HMB-supplemented diet retained a higher proportion of flight muscle mitochondria whose morphology resembled that of young flies than the control diet group. Together, these results suggest that HMB attenuates the age-dependent decline in flight ability and prolongs lifespan by enhancing muscle health. Full article

(This article belongs to the Special Issue Drosophila: A Model System for Human Disease Research)

10 pages, 1851 KiB

Open AccessArticle

Gα_i2 Induces Cell Migration in PC3 Prostate Cancer Cells in the Absence of Rac1 Activation

by Rarnice Johnson, Silvia Caggia and Shafiq A. Khan

Int. J. Mol. Sci. 2025, 26(6), 2663; https://doi.org/10.3390/ijms26062663 (registering DOI) - 15 Mar 2025

Abstract

Metastatic prostate cancer occurs when the tumor spreads from the prostate gland to other parts of the body. Previous studies have shown that Gα_i2, a subunit of the heterotrimeric G protein complex, plays a critical role in inducing cell migration and [...] Read more.

Metastatic prostate cancer occurs when the tumor spreads from the prostate gland to other parts of the body. Previous studies have shown that Gα_i2, a subunit of the heterotrimeric G protein complex, plays a critical role in inducing cell migration and invasion in prostate cancer cells in response to diverse stimuli. Rac1 is a small rho-GTPase, which is activated by the phosphoinositide 3-kinase (PI3K)/AKT pathway and plays an essential role during cell migration. Previous studies have shown that the knockdown of Gα_i2 attenuates cell migration without causing any reduction in basal Rac1 activity in both PC3 and DU145 cells, and has only marginal effects on the epidermal growth facotor (EGF)-induced increase in Rac1 activity. Therefore, Gα_i2 may be involved in the regulation of cell motility and invasion independently or downstream of Rac1 activation. In this study, we investigated the possible mechanism of Gα_i2 at the level of the Rac1-dependent activation of Wiskott-Aldrich Syndrome Protein)-family verprolin homologous protein2 (Wave2) and actin related protein 2/3 (Arp 2/3) proteins, downstream effectors of activated Rac1. PC3 cells with a stable overexpression of constitutively active Rac1 were transfected with control siRNA or Gα_i2 siRNA to knockdown endogenous Gα_i2 expression. Western blot analysis showed that the Rac1-dependent activation of Wave2 was impaired in the absence of Gα_i2. The overexpression of constitutively active Gα_i2 (Gα_i2-Q205L) in PC3 cells significantly increased cell migration compared to cells transfected with control plasmids. In the parallel experiments, a specific Gα_i2 inhibitor blocked G_iα2-Q205L-induced cell migration in PC3 cells. Furthermore, the Rac1 inhibitor did not block increased cell migration in PC3 cells overexpressing constitutively active Gα_i2. We conclude that activated Gα_i2 plays a crucial role in cell migration in prostate cancer cells independent of Rac1 activation. Full article

(This article belongs to the Special Issue Molecular Research in Prostate Cancer)

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20 pages, 2945 KiB

Open AccessArticle

Genomic Prediction for Germplasm Improvement Through Inter-Heterotic-Group Line Crossing in Maize

by Dehe Cheng, Jinlong Li, Shuwei Guo, Yuandong Wang, Shizhong Xu, Shaojiang Chen and Wenxin Liu

Int. J. Mol. Sci. 2025, 26(6), 2662; https://doi.org/10.3390/ijms26062662 (registering DOI) - 15 Mar 2025

Abstract

Germplasm improvement is essential for maize breeding. Currently, intra-heterotic-group crossing is the major method for germplasm improvement, while inter-heterotic-group crossing is also used in breeding but not in a systematic way. In this study, five inbred lines from four heterotic groups were used [...] Read more.

Germplasm improvement is essential for maize breeding. Currently, intra-heterotic-group crossing is the major method for germplasm improvement, while inter-heterotic-group crossing is also used in breeding but not in a systematic way. In this study, five inbred lines from four heterotic groups were used to develop a connected segregating population through inter-heterotic-group line crossing (CSPIC), which comprised 5 subpopulations with 535 doubled haploid (DH) lines and 15 related test-cross populations including 1568 hybrids. Significant genetic variation was observed in most subpopulations, with several DH populations exhibiting superior phenotypes regarding traits such as plant height (PH), ear height (EH), days to anthesis (DTA), and days to silking (DTS). Notably, 10.8% of hybrids in the population POP5/C229 surpassed the high-yielding hybrid ND678 (CK). To reduce field planting costs and quickly screen for the best inter-heterotic-group DH lines and test-cross hybrids, we assessed the accuracy of genomic selection (GS) for within- and between-population predictions in the DH populations and the test-cross populations. Within the DH or the hybrid population, the prediction accuracy varied across populations and traits, with an average hybrid yield prediction accuracy of 0.41, reaching 0.54 in POP5/Z58. In the cross DH population predictions, the prediction accuracy of the half-sib population exceeded that of the non-sib cross population prediction, with the highest accuracy observed when the non-shared parents were from the same heterotic group, and the average phenotypic prediction accuracies of POP3 predicting POP2 and POP2 predicting POP3 were 0.54 and 0.45, respectively. In the cross hybrid population predictions, the accuracy was highest when both the training and the test sets came from the same DH populations, with an average accuracy of 0.43. The proportion of shared polymorphisms with respect to SNPs between the training and the test sets (PSP) exhibited a significant and strong correlation with the prediction accuracy of cross population prediction. This study demonstrates the feasibility of creating new heterotic groups through inter-heterotic-group crossing in germplasm improvement, and some cross population prediction patterns exhibited excellent prediction accuracy. Full article

(This article belongs to the Special Issue Understanding the Genetics of Complex Traits in Plants: Association Analysis and Genomic Selection Methods)

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18 pages, 5704 KiB

Open AccessArticle

Synergistic Effect of Ribitol and Shikonin Promotes Apoptosis in Breast Cancer Cells

by Ravi Doddapaneni, Jason D. Tucker, Pei J. Lu and Qi L. Lu

Int. J. Mol. Sci. 2025, 26(6), 2661; https://doi.org/10.3390/ijms26062661 (registering DOI) - 15 Mar 2025

Abstract

The mortality rate of breast cancer remains high, despite remarkable advances in chemotherapy. Therefore, it is imperative to identify new treatment options. In the present study, we investigated whether the metabolite ribitol enhances the cytotoxic effect of shikonin against breast cancer in vitro. [...] Read more.

The mortality rate of breast cancer remains high, despite remarkable advances in chemotherapy. Therefore, it is imperative to identify new treatment options. In the present study, we investigated whether the metabolite ribitol enhances the cytotoxic effect of shikonin against breast cancer in vitro. Here, we screened a panel of small molecules targeting energy metabolism against breast cancer. The results of the study revealed that ribitol enhances shikonin’s growth-inhibitory effects, with significant synergy. A significant (p < 0.01) increase in the percentage (56%) of apoptotic cells was detected in the combined treatment group, compared to shikonin single-treatment group (38%), respectively. The combined ribitol and shikonin treatment led to significant arrest of cell proliferation (40%) (p < 0.01) compared to untreated cells, as well as the induction of apoptosis. This was associated with upregulation of p53 (p < 0.05) and downregulation of c-Myc (p < 0.01), Bcl-xL (p < 0.001), and Mcl-1 (p < 0.05). Metabolomic analysis supports the premise that inhibition of the Warburg effect is involved in shikonin-induced cell death, which is likely further enhanced by dysregulation of glycolysis and the tricarboxylic acid (TCA) cycle, afflicted by ribitol treatment. In conclusion, the present study demonstrates that the metabolite ribitol selectively enhances the cytotoxic effect mediated by shikonin against breast cancer in vitro. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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17 pages, 3942 KiB

Open AccessArticle

Noradrenaline Synergistically Enhances Porphyromonas gingivalis LPS and OMV-Induced Interleukin-1β Production in BV-2 Microglia Through Differential Mechanisms

by Sakura Muramoto, Sachi Shimizu, Sumika Shirakawa, Honoka Ikeda, Sayaka Miyamoto, Misato Jo, Uzuki Takemori, Chiharu Morimoto, Zhou Wu, Hidetoshi Tozaki-Saitoh, Kosuke Oda, Erika Inoue, Saori Nonaka and Hiroshi Nakanishi

Int. J. Mol. Sci. 2025, 26(6), 2660; https://doi.org/10.3390/ijms26062660 (registering DOI) - 15 Mar 2025

Abstract

Infection with Porphyromonas gingivalis (Pg), which is a major periodontal pathogen, causes a large number of systemic diseases based on chronic inflammation such as diabetes and Alzheimer’s disease (AD). However, it is not yet fully understood how Pg can augment local [...] Read more.

Infection with Porphyromonas gingivalis (Pg), which is a major periodontal pathogen, causes a large number of systemic diseases based on chronic inflammation such as diabetes and Alzheimer’s disease (AD). However, it is not yet fully understood how Pg can augment local systemic immune and inflammatory responses during progression of AD. There is a strong association between depression and elevated levels of inflammation. Noradrenaline (NA) is a key neurotransmitter that modulates microglial activation during stress conditions. In this study, we have thus investigated the regulatory mechanisms of NA on the production of interleukin-1β (IL-1β) by microglia following stimulation with Pg virulence factors, lipopolysaccharide (LPS), and outer membrane vesicles (OMVs). NA (30–1000 nM) significantly enhanced the mRNA level, promoter activity, and protein level of IL-1β up to 20-fold in BV-2 microglia following treatment with Pg LPS (10 μg/mL) and OMVs (150 μg of protein/mL) in a dose-dependent manner. Pharmacological studies have suggested that NA synergistically augments the responses induced by Pg LPS and OMVs through different mechanisms. AP-1 is activated by the β₂ adrenergic receptor (Aβ₂R)-mediated pathway. NF-κB, which is activated by the Pg LPS/toll-like receptor 2-mediated pathway, is required for the synergistic effect of NA on the Pg LPS-induced IL-1β production by BV-2 microglia. Co-immunoprecipitation combined with Western blotting and the structural models generated by AlphaFold2 suggested that cross-coupling of NF-κB p65 and AP-1 c-Fos transcription factors enhances the binding of NF-κB p65 to the IκB site, resulting in the synergistic augmentation of the IL-1β promoter activity. In contrast, OMVs were phagocytosed by BV-2 microglia and then activated the TLR9/p52/RelB-mediated pathway. The Aβ₂R/Epac-mediated pathway, which promotes phagosome maturation, may be responsible for the synergistic effect of NA on the OMV-induced production of IL-1β in BV-2 microglia. Our study provides the first evidence that NA synergistically enhances the production of IL-1β in response to Pg LPS and OMVs through distinct mechanisms. Full article

(This article belongs to the Special Issue Physiological Functions and Pathological Effects of Microglia)

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23 pages, 5360 KiB

Open AccessArticle

The Protective Effects of Burdock Fructooligosaccharide on Preterm Labor Through Its Anti-Inflammatory Action

by Qunfei Ma, Ruoheng Du, Peihua Long, Kaiyi Sun, Youxia Wang, Ye Yang, Xinyu Shen and Lu Gao

Int. J. Mol. Sci. 2025, 26(6), 2659; https://doi.org/10.3390/ijms26062659 (registering DOI) - 15 Mar 2025

Abstract

Most pharmacotherapeutic chemicals/interventions used to manage preterm labor (PTL) often cause neonatal morbidity and maternal adverse reactions. Fructooligosaccharides, extracted from traditional Chinese medicine, can alleviate inflammation, demonstrate antiviral capabilities, and protect against antioxidant stress, implying a potential effective PTL treatment. In this study, [...] Read more.

Most pharmacotherapeutic chemicals/interventions used to manage preterm labor (PTL) often cause neonatal morbidity and maternal adverse reactions. Fructooligosaccharides, extracted from traditional Chinese medicine, can alleviate inflammation, demonstrate antiviral capabilities, and protect against antioxidant stress, implying a potential effective PTL treatment. In this study, we explored the protective effects of the purified burdock fructooligosaccharide (BFO), a Gfn-type fructose polymer, on inflammation-induced PTL. It was found that two doses of 30 mg/kg mouse BFO administration to pregnant mice at a 6 h interval can effectively ameliorate lipopolysaccharide (LPS)-induced PTL. Drug dynamic distribution analysis revealed that BFO was rather highly enriched in myometrial tissues, could inhibit oxytocin-induced uterine smooth muscle contraction, and could bind toll-like receptor 4 (TLR4) on the membrane of uterine smooth muscle cells, downregulating the expression of downstream genes, attenuating the upregulation of inflammatory cytokines in serum and the myometrium, as well as reversing the increased macrophage and neutrophil infiltration into the myometrium induced by LPS. It can also interfere with the levels of estrogen and progesterone, alleviating the occurrence of premature birth. These findings collectively suggest that BFO might serve as a promising therapeutic agent for inflammation-related preterm labor to safeguard the health of both the mother and fetus. Full article

(This article belongs to the Special Issue Molecular Research on Pathogenesis and Treatment of Pregnancy Complications)

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16 pages, 2310 KiB

Open AccessReview

Decoding Liver Fibrosis: How Omics Technologies and Innovative Modeling Can Guide Precision Medicine

by Gabriele Codotto, Benedetta Blarasin, Claudio Tiribelli, Cristina Bellarosa and Danilo Licastro

Int. J. Mol. Sci. 2025, 26(6), 2658; https://doi.org/10.3390/ijms26062658 (registering DOI) - 15 Mar 2025

Abstract

The burden of chronic liver disease (CLD) is dramatically increasing. It is estimated that 20–30% of the population worldwide is affected by CLD. Hepatic fibrosis is a symptom common to all CLDs. Although it affects liver functional activities, it is a reversible stage [...] Read more.

The burden of chronic liver disease (CLD) is dramatically increasing. It is estimated that 20–30% of the population worldwide is affected by CLD. Hepatic fibrosis is a symptom common to all CLDs. Although it affects liver functional activities, it is a reversible stage if diagnosed at an early stage, but no resolutive therapy to contrast liver fibrosis is currently available. Therefore, efforts are needed to study the molecular insights of the disease. Emerging cutting-edge fields in cellular and molecular biology are introducing innovative strategies. Spatial and single-cell resolution approaches are paving the way for a more detailed understanding of the mechanisms underlying liver fibrosis. Cellular models have been generated to recapitulate the in-a-dish pathophysiology of liver fibrosis, yielding remarkable results that not only uncover the underlying molecular mechanisms but also serve as patient-specific avatars for precision medicine. Induced pluripotent stem cells (iPSC) and organoids are incredible tools to reshape the modeling of liver diseases, describe their architecture, and study the residents of hepatic tissue and their heterogeneous population. The present work aims to give an overview of innovative omics technologies revolutionizing liver fibrosis research and the current tools to model this disease. Full article

(This article belongs to the Special Issue Liver Fibrosis: Molecular Pathogenesis, Diagnosis and Treatment)

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29 pages, 1282 KiB

Open AccessReview

N-Acetylcysteine in the Treatment of Acute Lung Injury: Perspectives and Limitations

by Daniela Mokra, Igor Porvaznik and Juraj Mokry

Int. J. Mol. Sci. 2025, 26(6), 2657; https://doi.org/10.3390/ijms26062657 (registering DOI) - 15 Mar 2025

Abstract

N-acetylcysteine (NAC) can take part in the treatment of chronic respiratory diseases because of the potent mucolytic, antioxidant, and anti-inflammatory effects of NAC. However, less is known about its use in the treatment of acute lung injury. Nowadays, an increasing number of studies [...] Read more.

N-acetylcysteine (NAC) can take part in the treatment of chronic respiratory diseases because of the potent mucolytic, antioxidant, and anti-inflammatory effects of NAC. However, less is known about its use in the treatment of acute lung injury. Nowadays, an increasing number of studies indicates that early administration of NAC may reduce markers of oxidative stress and alleviate inflammation in animal models of acute lung injury (ALI) and in patients suffering from distinct forms of acute respiratory distress syndrome (ARDS) or pulmonary infections including community-acquired pneumonia or Coronavirus Disease (COVID)-19. Besides low costs, easy accessibility, low toxicity, and rare side effects, NAC can also be combined with other drugs. This article provides a review of knowledge on the mechanisms of inflammation and oxidative stress in various forms of ALI/ARDS and critically discusses experience with the use of NAC in these disorders. For preparing the review, articles published in the English language from the PubMed database were used. Full article

(This article belongs to the Special Issue New Perspective in the Molecular Pathways Involved in Acute and Chronic Lung Injury)

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13 pages, 1993 KiB

Open AccessArticle

A Probiotic Mixture of Lactobacillus rhamnosus LR 32, Bifidobacterium lactis BL 04, and Bifidobacterium longum BB 536 Counteracts the Increase in Permeability Induced by the Mucosal Mediators of Irritable Bowel Syndrome by Acting on Zonula Occludens 1

by Maria Raffaella Barbaro, Francesca Bianco, Cesare Cremon, Giovanni Marasco, Vincenzo Stanghellini and Giovanni Barbara

Int. J. Mol. Sci. 2025, 26(6), 2656; https://doi.org/10.3390/ijms26062656 (registering DOI) - 15 Mar 2025

Abstract

Irritable Bowel Syndrome (IBS) is a disorder of gut- brain interaction characterized by recurrent abdominal pain associated with altered bowel habits. The therapeutic options for IBS patients include the use of probiotics. The aim of this study was to assess the effect of [...] Read more.

Irritable Bowel Syndrome (IBS) is a disorder of gut- brain interaction characterized by recurrent abdominal pain associated with altered bowel habits. The therapeutic options for IBS patients include the use of probiotics. The aim of this study was to assess the effect of a multi-strain probiotic made up by Lactobacillus rhamnosus LR 32, Bifidobacterium lactis BL 04, and Bifidobacterium longum BB 536 (Serobioma, Bromatech s.r.l., Milano, Italy) on an in vitro model of the intestinal epithelial barrier in the presence of mucosal mediators that are released by IBS patients. IBS (n = 28; IBS with predominant diarrhea, IBS-D = 10; IBS with predominant constipation, IBS-C = 9; and IBS with mixed bowel habits, IBS-M = 9) patients, diagnosed according to the Rome IV criteria, and asymptomatic controls (ACs, n = 7) were enrolled. Mucosal mediators that were spontaneously released by colonic biopsies were collected (supernatants). Two doses of Serobioma were tested with/without IBS/AC mediators. RNA was extracted from Caco-2 cells to evaluate the tight junction (TJ) expression. Serobioma (10⁶ CFU/mL) significantly reinforced the Caco-2 monolayer compared to growth medium alone (p < 0.05). IBS supernatants significantly increased Caco-2 paracellular permeability compared to the AC supernatants. The co-incubation of Caco-2 cells with IBS supernatants and Serobioma (10⁶ CFU/mL) avoided the paracellular permeability alterations that were induced by IBS supernatants alone (p < 0.001), and, in particular, IBS-D and IBS-M ones. The co-incubation of Serobioma (10⁶ CFU/mL) and IBS-D supernatants significantly increased ZO-1 expression compared to Caco-2 cells incubated with supernatants alone (p < 0.05), as confirmed via qPCR analyses. Serobioma (10⁶ CFU/mL) counteracts the paracellular permeability changes that are induced by IBS supernatants, in particular IBS-D and IBS-M supernatants, likely modulating ZO-1 expression. Full article

(This article belongs to the Special Issue Molecular Research in Prebiotics, Probiotics and Postbiotics: 2nd Edition)

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15 pages, 2290 KiB

Open AccessArticle

Tissue-Specific Effects of the DNA Helicase FANCJ/BRIP1/BACH1 on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders

by Diego Antonio Jimenez, Alexandra Walker, Karen Usdin and Xiaonan Zhao

Int. J. Mol. Sci. 2025, 26(6), 2655; https://doi.org/10.3390/ijms26062655 (registering DOI) - 15 Mar 2025

Abstract

Fragile X-related disorders (FXDs) are caused by the expansion of a CGG repeat tract in the 5’-UTR of the FMR1 gene. The expansion mechanism is likely shared with the 45+ other human diseases resulting from repeat expansion, a process that has been shown [...] Read more.

Fragile X-related disorders (FXDs) are caused by the expansion of a CGG repeat tract in the 5’-UTR of the FMR1 gene. The expansion mechanism is likely shared with the 45+ other human diseases resulting from repeat expansion, a process that has been shown to require key mismatch repair (MMR) factors. FANCJ, a DNA helicase involved in unwinding unusual DNA secondary structures, has been implicated in a number of DNA repair processes including MMR. To test the role of FANCJ in repeat expansion, we crossed FancJ-null mice to an FXD mouse model. We found that loss of FANCJ resulted in a trend towards more extensive expansion that was significant for the small intestine and male germline. This finding has interesting implications for the expansion mechanism and raises the possibility that other DNA helicases may be important modifiers of expansion risk in certain cell types. Full article

(This article belongs to the Special Issue Current Molecular Science of Fragile X Syndrome and Associated Disorders)

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16 pages, 1729 KiB

Open AccessArticle

Activation of Smooth Muscle K_ir2.1 Channels and Na⁺/K⁺-ATPase Mediates Dilation of Porcine Coronary Arterioles at Physiological Levels of Potassium

by Travis W. Hein, Habib M. Razavi, Xin Xu, Sonal Somvanshi, Mariappan Muthuchamy and Lih Kuo

Int. J. Mol. Sci. 2025, 26(6), 2654; https://doi.org/10.3390/ijms26062654 (registering DOI) - 15 Mar 2025

Abstract

Metabolic stress on the heart can cause dilation of coronary arterioles for blood flow recruitment. Although potassium ions (K⁺) released from the myocardium are a major mediator for this response, the underlying signaling pathways for vasodilation are incompletely understood. Herein, the [...] Read more.

Metabolic stress on the heart can cause dilation of coronary arterioles for blood flow recruitment. Although potassium ions (K⁺) released from the myocardium are a major mediator for this response, the underlying signaling pathways for vasodilation are incompletely understood. Herein, the roles of smooth muscle inward-rectifier K⁺ channel subtype 2.1 (K_ir2.1) and Na⁺/K⁺-ATPase were examined. Porcine coronary arterioles were isolated, cannulated, and pressurized for vasomotor study. Vessels developed basal tone and dilated concentration-dependently to extraluminal K⁺ from 7 to 20 mM. Higher K⁺ concentrations (25–40 mM) caused graded vasoconstriction. Vasodilation to K⁺ (10 mM) was not altered by endothelial removal, and blockade of ATP-sensitive K⁺ channels, voltage-sensitive K⁺ channels, or calcium-activated K⁺ channels did not affect K⁺-induced vasodilation. However, sustained but not abrupt transient vasodilation to K⁺ was reduced by the nonspecific K_ir channel inhibitor Ba²⁺ or K_ir2.1 channel blocker chloroethylclonidine. The Na⁺/K⁺-ATPase inhibitor ouabain attenuated K⁺-elicited vasodilation, and ouabain with Ba²⁺ abolished the response. Transfection of arterioles with K_ir2.1 antisense oligonucleotides abolished sustained but not transient dilation. It is concluded that extraluminal K⁺ elevation within the physiological range induces initial transient dilation of porcine coronary arterioles by activating smooth muscle Na⁺/K⁺-ATPase and sustained dilation via smooth muscle K_ir2.1 channels. Full article

(This article belongs to the Special Issue Cardiovascular and Cerebrovascular Diseases: From Pathology to Therapeutic Perspectives)

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21 pages, 916 KiB

Open AccessReview

The Burden of Non-Infectious Organ-Specific Immunopathology in Pediatric Common Variable Immunodeficiency

by Aleksandra Szczawińska-Popłonyk, Julia Bekalarska, Kacper Jęch, Nadia Knobloch, Oliwia Łukasik, Aleksandra Ossowska, Jędrzej Ruducha and Zuzanna Wysocka

Int. J. Mol. Sci. 2025, 26(6), 2653; https://doi.org/10.3390/ijms26062653 (registering DOI) - 15 Mar 2025

Abstract

The pediatric common variable immunodeficiency (CVID) is the most frequent symptomatic antibody production defect characterized by infectious and non-infectious autoimmune, inflammatory, and lymphoproliferative complications. The background for CVID-related organ-specific immunopathology is associated with immune dysregulation and immunophenotypic biomarkers with expansion of CD21low B [...] Read more.

The pediatric common variable immunodeficiency (CVID) is the most frequent symptomatic antibody production defect characterized by infectious and non-infectious autoimmune, inflammatory, and lymphoproliferative complications. The background for CVID-related organ-specific immunopathology is associated with immune dysregulation and immunophenotypic biomarkers with expansion of CD21low B cells, and dysfunctional memory B cell, follicular T cell, and regulatory T cell compartments. The ever-increasing progress in immunogenetics shows the heterogeneity of genetic background for CVID related to the complexity of clinical phenotypes. Multiple systemic modulatory pathways are determined by variants in such genes as TACI or TNFRSF13B gene encoding for BAFF-R, CTLA-4, LRBA, NFKB1 and NFKB2, and PIK3CD or PIK3R1. The organ-specific immunopathology encompasses a spectrum of disorders associated with immune dysregulation, such as granulomatous interstitial lung disease, hepatocellular nodular regenerative hyperplasia, enteropathy, neuropathy, endocrinopathies, and dermatoses. This review is aimed to define and delineate the organ-specific immunopathology in pediatric CVID. It is also conducted to gather data facilitating a better understanding of complex and heterogeneous immunophenotypes in the context of immune dysregulation mechanisms and genetic background determining manifestations of the disease and implicating personalized targeted therapies with biological agents. Full article

(This article belongs to the Special Issue Molecular Advances in Inborn Errors of Immunity)

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38 pages, 6041 KiB

Open AccessArticle

Deciphering of SOX9 Functions in Pancreatic Cancer Cells

by Kirill Kashkin, Liya Kondratyeva, Eugene Kopantzev, Ivan Abramov, Lyudmila Zhukova and Igor Chernov

Int. J. Mol. Sci. 2025, 26(6), 2652; https://doi.org/10.3390/ijms26062652 (registering DOI) - 15 Mar 2025

Abstract

SOX9 is widely regarded as a key master regulator of gene transcription, responsible for the development and differentiation programs within tissue and organogenesis, particularly in the pancreas. SOX9 overexpression has been observed in multiple tumor types, including pancreatic cancer, and is discussed as [...] Read more.

SOX9 is widely regarded as a key master regulator of gene transcription, responsible for the development and differentiation programs within tissue and organogenesis, particularly in the pancreas. SOX9 overexpression has been observed in multiple tumor types, including pancreatic cancer, and is discussed as a prognostic marker. In order to gain a more profound understanding of the role of SOX9 in pancreatic cancer, we have performed SOX9 knockdown in the COLO357 and PANC-1 cells using RNA interference, followed by full-transcriptome analysis of the siRNA-transfected cells. The molecular pathway enrichment analysis between SOX9-specific siRNA-transfected cells and control cells reveals the activation of processes associated with cellular signaling, cell differentiation, transcription, and methylation, alongside the suppression of genes involved in various stages of the cell cycle and apoptosis, upon the SOX9 knockdown. Alterations of the expression of transcription factors, epithelial–mesenchymal transition markers, oncogenes, tumor suppressor genes, and drug resistance-related genes upon SOX9 knockdown in comparison of primary and metastatic pancreatic cancer cells are discovered. The expression levels of genes comprising prognostic signatures for pancreatic cancer were also evaluated following SOX9 knockdown. Additional studies are needed to assess the properties and prognostic significance of SOX9 in pancreatic cancer using other biological models. Full article

(This article belongs to the Special Issue Deciphering Molecular Complexity of Pancreatic Cancer)

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25 pages, 1493 KiB

Open AccessArticle

Thieno[2,3-b]pyridines as a Novel Strategy Against Cervical Cancer: Mechanistic Insights and Therapeutic Potential

by Monika Čikeš Botić, Sandra Marijan, Mila Radan, Ivana Novak, Mateo Glumac, Lisa I. Pilkington, Zdravko Odak, David Barker, Jóhannes Reynisson and Vedrana Čikeš Čulić

Int. J. Mol. Sci. 2025, 26(6), 2651; https://doi.org/10.3390/ijms26062651 - 14 Mar 2025

Abstract

Cervical cancer is the fourth leading cause of cancer mortality in women worldwide, with limited therapeutic options for advanced or recurrent cases. In this study, the effects of a recent thieno[2,3-b]pyridine derivative, (E)-3-amino-5-(3-bromophenyl)acryloyl)-N-(3-chloro-2-methylphenyl)-6-methylthieno[2,3-b]pyridine-2-carboxamide (compound 1), on [...] Read more.

Cervical cancer is the fourth leading cause of cancer mortality in women worldwide, with limited therapeutic options for advanced or recurrent cases. In this study, the effects of a recent thieno[2,3-b]pyridine derivative, (E)-3-amino-5-(3-bromophenyl)acryloyl)-N-(3-chloro-2-methylphenyl)-6-methylthieno[2,3-b]pyridine-2-carboxamide (compound 1), on two cervical cancer cell lines, HeLa and SiHa, are investigated. Cytotoxicity was assessed by MTT assay, apoptosis rates were measured by flow cytometry, and metabolic profiling was performed by GC-MS. The study also examined the expression of eight glycosphingolipids (GSLs) in cancer stem cells (CSCs) and non-CSCs to assess glycophenotypic changes. Compound 1 showed significant cytotoxicity in both cell lines, with apoptosis identified as the primary mechanism of cell death. A significant reduction in the CSC population was observed, particularly in the SiHa cell line. Compound 1 treatment altered GSL expression and decreased GM2 levels in both CSCs and non-CSCs in the SiHa cell line and Gg3Cer levels in the HeLa cell line. Metabolic profiling identified 23 and 21 metabolites in the HeLa and SiHa cell lines, respectively, with significant differences in metabolite expression after treatment. These results underscore the potential of compound 1 as a promising therapeutic candidate for cervical cancer and warrant further investigation in preclinical and clinical settings. Full article

(This article belongs to the Special Issue Gynecological Cancer 2024)

14 pages, 966 KiB

Open AccessReview

Seborrheic Dermatitis: Exploring the Complex Interplay with Malassezia

by Francesca Piacentini, Emanuela Camera, Anna Di Nardo and Maria Lucia Dell’Anna

Int. J. Mol. Sci. 2025, 26(6), 2650; https://doi.org/10.3390/ijms26062650 - 14 Mar 2025

Abstract

Seborrheic dermatitis (SD) is a chronic inflammatory skin condition often involving the sebaceous-rich areas, characterized by erythematous scaly lesions. It is frequently observed in individuals with immune dysregulation, suggesting the interplay between the immune system and disease development. An altered immune environment leads [...] Read more.

Seborrheic dermatitis (SD) is a chronic inflammatory skin condition often involving the sebaceous-rich areas, characterized by erythematous scaly lesions. It is frequently observed in individuals with immune dysregulation, suggesting the interplay between the immune system and disease development. An altered immune environment leads to an exaggerated inflammatory response with the activation of innate immunity, involving the participation of mast cells, γδ T cells, and the NOD–LRR–pyrin-domain-containing protein 3 (NLRP3) inflammasome. This review aims to assess the complex relationship between Malassezia and the immune system in the pathogenesis of SD. We will explore how an impaired immune response predisposes the skin to Malassezia overgrowth and infection. We will examine the role of adaptive immunity, particularly T helper cells, in driving chronic inflammation in SD. All actors involved, whether part of innate or adaptive immunity, are responsible for the release of pro-inflammatory cytokines, which contribute to the progression of the disease. Therapeutic strategies aimed at the modulation of the immune response in SD have been tested in clinical trials evaluating the efficacy of immunomodulatory treatments in the management of SD. This review synthesizes insights from immunological studies and clinical trials to present an in-depth analysis of the immune mechanisms underpinning SD, thereby proposing targeted therapeutic strategies for its management. Full article

(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 5996 KiB

Open AccessArticle

Intratracheal Delivery of a Phospholamban Decoy Peptide Attenuates Cardiac Damage Following Myocardial Infarction

by Taewon Kook, Mi-Young Lee, Tae Hwan Kwak, Dongtak Jeong, Doo Sun Sim, Myung Ho Jeong, Youngkeun Ahn, Hyun Kook, Woo Jin Park and Seung Pil Jang

Int. J. Mol. Sci. 2025, 26(6), 2649; https://doi.org/10.3390/ijms26062649 - 14 Mar 2025

Abstract

Heart failure (HF) remains a major cause of mortality worldwide. While novel approaches, including gene and cell therapies, show promise, efficient delivery methods for such biologics to the heart are critically needed. One emerging strategy is lung-to-heart delivery using nanoparticle (NP)-encapsulated biologics. This [...] Read more.

Heart failure (HF) remains a major cause of mortality worldwide. While novel approaches, including gene and cell therapies, show promise, efficient delivery methods for such biologics to the heart are critically needed. One emerging strategy is lung-to-heart delivery using nanoparticle (NP)-encapsulated biologics. This study examines the efficiency of delivering a therapeutic peptide conjugated to a cell-penetrating peptide (CPP) to the heart via the lung-to-heart route through intratracheal (IT) injection in mice. The CPP, a tandem repeat of NP2 (dNP2) derived from the human novel LZAP-binding protein (NLBP), facilitates intracellular delivery of the therapeutic payload. The therapeutic peptide, SE, is a decoy peptide designed to inhibit protein phosphatase 1 (PP1)-mediated dephosphorylation of phospholamban (PLN). Our results demonstrated that IT injection of dNP2-SE facilitated efficient delivery to the heart, with peak accumulation at 3 h post-injection. The administration of dNP2-SE significantly ameliorated morphological and functional deterioration of the heart under myocardial infarction. At the molecular level, dNP2-SE effectively prevented PLN dephosphorylation in the heart. Immunoprecipitation experiments further revealed that dNP2-SE binds strongly to PP1 and disrupts its interaction with PLN. Collectively, our findings suggest that lung-to-heart delivery of a CPP-conjugated therapeutic peptide, dNP2-SE, represents a promising approach for the treatment of HF. Full article

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

16 pages, 3485 KiB

Open AccessArticle

Effects of Perfluorooctane Sulfonic Acid Exposure on Intestinal Microbial Community, Lipid Metabolism, and Liver Lesions in Mice

by Qianfeng Chen, Yulang Chi, Qingyu Zhu, Nana Ma, Lingli Min and Shouping Ji

Int. J. Mol. Sci. 2025, 26(6), 2648; https://doi.org/10.3390/ijms26062648 - 14 Mar 2025

Abstract

Perfluorooctane sulfonic acid (PFOS) is a persistent organic pollutant that has attracted much attention due to its wide environmental distribution and potential toxicity. Intestinal microbiota is an important regulator of host health, and its composition and metabolic function are easily interfered with by [...] Read more.

Perfluorooctane sulfonic acid (PFOS) is a persistent organic pollutant that has attracted much attention due to its wide environmental distribution and potential toxicity. Intestinal microbiota is an important regulator of host health, and its composition and metabolic function are easily interfered with by environmental pollutants. In this study, the effects of PFOS exposure on gut microbiota, lipid metabolism, and host health were investigated in mice. The results showed that PFOS exposure did not significantly change α diversity, but significantly affected the β diversity and community structure of intestinal microflora in mice. At the taxonomic level, the ratio of Firmicutes to Bacteroidetes decreased, and the changes in the abundance of specific bacteria were closely related to liver diseases and lipid metabolism disorders. PFOS exposure also interfered with the gut–liver axis mechanism, increased blood lipids and liver function related indicators in mice, and induced intestinal and liver histological lesions. This study revealed the toxic mechanism of PFOS mediated by intestinal microbiota, providing a new research perspective for health problems caused by environmental pollutants and theoretical support for the formulation of relevant public health policies. Full article

(This article belongs to the Collection New Advances in Molecular Toxicology)

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30 pages, 2382 KiB

Open AccessArticle

Optimising Cannabidiol Delivery: Improving Water Solubility and Permeability Through Phospholipid Complexation

by Thabata Muta, Riya Khetan, Yunmei Song and Sanjay Garg

Int. J. Mol. Sci. 2025, 26(6), 2647; https://doi.org/10.3390/ijms26062647 - 14 Mar 2025

Abstract

Cannabidiol (CBD) has demonstrated therapeutic potential in treating epilepsy, multiple sclerosis, Alzheimer’s, Parkinson’s, and Crohn’s diseases. Despite its promising effects and analgesic, anti-inflammatory, and anxiolytic properties, oral CBD’s full potential is hindered by poor water solubility (0.7–10 μg/mL), low permeability, and chemical instability. [...] Read more.

Cannabidiol (CBD) has demonstrated therapeutic potential in treating epilepsy, multiple sclerosis, Alzheimer’s, Parkinson’s, and Crohn’s diseases. Despite its promising effects and analgesic, anti-inflammatory, and anxiolytic properties, oral CBD’s full potential is hindered by poor water solubility (0.7–10 μg/mL), low permeability, and chemical instability. This study aimed to enhance CBD’s dissolution, stability, and gastrointestinal (GI) permeability by forming a CBD–phospholipid complex (CBD-PLC). We hypothesised that CBD-PLC would enhance CBD’s hydrophilicity, thus improving GI barrier permeability. This study involved screening an optimal phospholipid (PL) using a Design of Experiments (DoE) approach to prepare CBD-PLC with nanosized droplets (194.3 nm). Dissolution studies revealed significantly enhanced release rates for CBD-PLC—44.7% at 2 h and 67.1% at 3 h—compared to 0% for pure CBD and 7.2% for a physical mixture (PM). Cellular uptake studies showed that at 30 µM, CBD-PLC exhibited 32.7% higher apparent permeability coefficients (P_app), nearly doubling at 40 µM compared to pure CBD. Cytotoxicity tests confirmed safety over 24 h, while 12-month stability tests demonstrated consistent performance under varied conditions. The results indicate that CBD-PLC improves CBD’s solubility, permeability, and stability, offering a promising strategy to address the limitations of oral CBD delivery systems. Full article

(This article belongs to the Topic Natural Products and Drug Discovery)

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