International Journal of Molecular Sciences

39 pages, 1080 KB

Open AccessReview

BMAL1 Dysregulation as a Contributing Mechanism Linking Obesity to Oocyte and Endometrial Dysfunction in IVF

by Charalampos Voros, Fotios Chatzinikolaou, George Papadimas, Ioannis Papapanagiotou, Nektaria Zagorianakou, Ali Can Gunes, Athanasios Karpouzos, Kyriakos Bananis, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Stylianos Makrydimas, Ioannis Pikrides, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis

Int. J. Mol. Sci. 2026, 27(18), 8001; https://doi.org/10.3390/ijms27188001 - 8 Sep 2026

Abstract

Obesity affects nearly one in three women of reproductive age worldwide and consistently reduces success rates in in vitro fertilization, yet the molecular basis for this reduction remains fragmented across separate lines of evidence. Circadian clock genes, particularly BMAL1, orchestrate metabolic and reproductive [...] Read more.

Obesity affects nearly one in three women of reproductive age worldwide and consistently reduces success rates in in vitro fertilization, yet the molecular basis for this reduction remains fragmented across separate lines of evidence. Circadian clock genes, particularly BMAL1, orchestrate metabolic and reproductive physiology through transcription–translation feedback loops present in adipose tissue, ovarian granulosa cells, and endometrial stroma. Adiposity-driven metabolic shifts, including altered PPAR-γ signaling and reduced glutamine–methionine uptake, degrade BMAL1 expression and flatten its rhythmic oscillation in peripheral tissues. Within granulosa cells, loss of BMAL1 rhythmicity impairs mitochondrial biogenesis and disrupts UPRmt-mediated proteostasis, driving reactive oxygen species accumulation and compromising oocyte competence. Parallel disruption of clock-controlled transcription factors in endometrial epithelium and stroma is proposed to alter decidualization programs and displace the window of implantation, which would produce a receptivity defect independent of oocyte quality if confirmed directly in human tissue. Clinical data are consistent with a dual mechanism: obese women undergoing donor-oocyte cycles—where oocyte quality is controlled for—show reduced implantation rates in several but not all cohorts—a pattern compatible with an endometrial contribution distinct from oocyte-level damage, rather than proof of it. Synthesizing evidence from adipocyte biology, ovarian physiology, and endometrial receptivity research drawn largely from rodent models, cultured cell systems, and observational human cohorts, this review proposes BMAL1 dysregulation as a candidate unifying mechanism connecting obesity to impaired IVF outcomes at the gametic and uterine level, while acknowledging that direct causal evidence in humans is still lacking. Chronotherapeutic strategies, including melatonin supplementation and the timing of weight-loss interventions relative to ovarian stimulation, are discussed as hypotheses for future testing rather than current clinical recommendations. BMAL1 dysregulation is presented here as one candidate contributor among several interacting mechanisms, and any translational strategy would need to be part of a broader, coordinated approach to obesity-related IVF failure rather than a stand-alone intervention. Full article

(This article belongs to the Special Issue Molecular Metabolism in Human Health and Disease)

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23 pages, 3486 KB

Open AccessArticle

Biopesticidal Potential of the Cannabis sativa L. Metabolites: A Denoised, Docking-Informed QSAR Model

by Dinara Karamanova, Nikita Erin, Alexander Bodrov, Varvara Tkachenko, Victor Safronov and Maxim Fedorov

Int. J. Mol. Sci. 2026, 27(18), 8000; https://doi.org/10.3390/ijms27188000 - 8 Sep 2026

Abstract

Plant metabolites are a promising source of new biopesticides, but their chemical diversity exceeds the capacity of experimental screening. Cannabis sativa is a particularly attractive crop for discovering such compounds, although its metabolome has not been systematically evaluated for biopesticidal potential. Here, we [...] Read more.

Plant metabolites are a promising source of new biopesticides, but their chemical diversity exceeds the capacity of experimental screening. Cannabis sativa is a particularly attractive crop for discovering such compounds, although its metabolome has not been systematically evaluated for biopesticidal potential. Here, we computationally analyzed 5211 compounds annotated as C. sativa metabolites in the Cannabis Compound Database (CCD) using an integrated framework combining graph-based molecular prediction and protein–ligand interaction analysis. Initial prioritization employed a directed message passing neural network (DMPNN) trained on molecular graphs augmented with RDKit descriptors. The DMPNN predictions were integrated with a CatBoost-derived docking-consistency score based on residue-level Vina interaction terms, reducing the false-positive rate by about 60% compared with the structural model alone. Informative ligand-residue interactions were identified using a random matrix theory (RMT) framework. The DMPNN identified 1010 compounds as DMPNN-positive (score

\geq 0.70

), indicating structural characteristics more consistent with the DS2 pesticide reference set than with the DS3 AChE-inactive reference set. Then, these compounds were filtered using annotations from the CCD to retain 44 secondary metabolites. Finally, the 44 compounds were ranked by the final ensemble score. Compared with reference pesticides, C. sativa metabolites showed higher predicted median oral LD₅₀ values and fewer organ-specific toxicity alerts at the dataset level, although not for all endpoints. Overall, the combined structural and docking-informed workflow identified a small, chemically diverse set of high-ranking C. sativa compounds that can now be prioritized for experimental validation. Full article

(This article belongs to the Section Bioactives and Nutraceuticals)

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22 pages, 2662 KB

Open AccessReview

Anticancer Potential of Cherry Extracts and Major Flavonols: Focus on Quercetin and Kaempferol Molecular Mechanisms in Breast Cancer

by Evangelia K. Konstantinou, Kallirroi Dimiza, Maria Dimitriou, Anastasios Darras and Athanasios A. Panagiotopoulos

Int. J. Mol. Sci. 2026, 27(18), 7999; https://doi.org/10.3390/ijms27187999 - 8 Sep 2026

Abstract

Breast cancer remains one of the leading causes of global mortality, which has growing driving interest in dietary natural products for potential chemopreventive and complementary approaches. Cherries (Prunus species) are rich in bioactive phytochemicals, notably anthocyanins, hydroxycinnamic acids, and the flavonols quercetin [...] Read more.

Breast cancer remains one of the leading causes of global mortality, which has growing driving interest in dietary natural products for potential chemopreventive and complementary approaches. Cherries (Prunus species) are rich in bioactive phytochemicals, notably anthocyanins, hydroxycinnamic acids, and the flavonols quercetin and kaempferol. This review aims to examine and discuss current research on the molecular targets and mechanisms of action of whole cherry extracts and their primary flavonols quercetin and kaempferol across various breast cancer subtypes. Preclinical studies indicate that these compounds exert multi-targeted effects by inducing apoptosis, inhibiting cell proliferation, and suppressing metastatic pathways. Additionally, these flavonols show potential in reversing multidrug resistance. A whole-food approach highlights the candidate synergistic properties of these phytochemical complexes, but low oral bioavailability and rapid metabolism severely limit their clinical translation. Therefore, utilizing innovative drug delivery systems remains crucial to improving their stability, absorption, and overall therapeutic efficacy. Full article

(This article belongs to the Special Issue Bioactive Compounds from Food in Health and Diseases)

24 pages, 4902 KB

Open AccessArticle

Dibenzo[b,f]azocin-6(5H)-ones and Benzo[b]pyrido[2,3-f]azocin-5(6H)-ones: Useful Scaffolds for Development of Protein–Protein Interaction Inhibitors

by Michał Nowacki, Filipe Menezes, Başak Dağdeviren, Federico Ballabio, Valeria Napolitano, Chethan K. Krishna, Vishal C. Kalel, Ralf Erdmann, Michael Sattler, Grzegorz M. Popowicz and Maciej Dawidowski

Int. J. Mol. Sci. 2026, 27(18), 7998; https://doi.org/10.3390/ijms27187998 - 8 Sep 2026

Abstract

Modulation of protein–protein interactions (PPIs) by small molecules is a vital strategy in drug discovery. Nevertheless, due to the inherent nature of PPI interfaces, practical implementation of this approach remains a high-hanging fruit in medicinal chemistry. In this report, we develop a new [...] Read more.

Modulation of protein–protein interactions (PPIs) by small molecules is a vital strategy in drug discovery. Nevertheless, due to the inherent nature of PPI interfaces, practical implementation of this approach remains a high-hanging fruit in medicinal chemistry. In this report, we develop a new line of PEX14–PEX5 PPI inhibitors by homologation of a previously developed dibenzo[b,e]azepin-6(6H)-one scaffold. The challenging chemistry of 8-membered ring formation led to the development of novel PEX14 inhibitors featuring a 6+8+6 tricyclic system. The obtained analogs were tested for their capability of disrupting the PEX5-TbPEX14 PPI, as well as for in vitro activity against the T. brucei protist. Overall, the developed scaffold not only represents an interesting alternative for prospective trypanocidal TbPEX14 ligands but may also be useful in the design of inhibitors of other PPIs mediated by a similar topology of hydrophobic binding pockets. Full article

(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers, 4rd Edition)

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24 pages, 1245 KB

Open AccessReview

Can Micro- and Nanoplastics Modify Food-Allergy-Relevant Pathways?—A Comprehensive Narrative Review

by Natalia Rutkowska, Dawid Wisniewski, Patrycja Rogala, Michal Ostrowski and Sylwia Smolinska-Wilczynska

Int. J. Mol. Sci. 2026, 27(18), 7997; https://doi.org/10.3390/ijms27187997 - 8 Sep 2026

Abstract

Micro- and nanoplastics (MNPs) are widely detected in food, drinking water, food-contact materials, and human biological samples. This narrative review evaluates whether experimental evidence supports a role for MNPs as modifiers of food-allergen digestion, intestinal-barrier function, microbiota composition, and immune tolerance. In vitro [...] Read more.

Micro- and nanoplastics (MNPs) are widely detected in food, drinking water, food-contact materials, and human biological samples. This narrative review evaluates whether experimental evidence supports a role for MNPs as modifiers of food-allergen digestion, intestinal-barrier function, microbiota composition, and immune tolerance. In vitro studies indicate that protein-corona formation can alter allergen conformation, epitope accessibility, and proteolysis, although effects vary by polymer, particle size, dose, and digestive model. Rodent studies provide evidence that MNP exposure can disrupt epithelial integrity, induce oxidative and inflammatory signaling, and modify microbiota-dependent immune regulation. More direct food-allergy models have reported exacerbation of ovalbumin- and cow’s-milk-allergic responses, including Th2 polarization and changes in dendritic cell and regulatory T-cell compartments. Infants may represent a susceptible and highly exposed population because of immature digestive and barrier function and the use of plastic feeding equipment; however, the available pediatric evidence is limited to exposure studies and simulated digestion. The effect of MNP exposure on the incidence of food allergies, reaction thresholds, or clinical severity in humans has not yet been studied. Accordingly, current findings support biological plausibility and identify research priorities, but they do not establish causality in humans. Full article

(This article belongs to the Special Issue Understanding Allergy and Asthma at the Molecular Level)

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42 pages, 1565 KB

Open AccessReview

Targeting Cancer Hallmarks with Cirsium japonicum: Molecular Mechanisms and Therapeutic Potential

by Kyung-Hee Kim, Tae-Kyung Yeo, So-Jung Park, Hwa-Seung Yoo and Byong Chul Yoo

Int. J. Mol. Sci. 2026, 27(18), 7996; https://doi.org/10.3390/ijms27187996 - 8 Sep 2026

Abstract

Cirsium japonicum is a medicinal plant traditionally used in East Asian medicine and contains multiple bioactive constituents with potential anticancer properties. This review critically evaluates the anticancer effects of C. japonicum and its associated constituents within the Hallmarks of Cancer framework. Evidence was [...] Read more.

Cirsium japonicum is a medicinal plant traditionally used in East Asian medicine and contains multiple bioactive constituents with potential anticancer properties. This review critically evaluates the anticancer effects of C. japonicum and its associated constituents within the Hallmarks of Cancer framework. Evidence was classified as direct plant-specific evidence, constituent-based evidence, or contextual mechanistic evidence to distinguish findings obtained using botanical preparations from those generated using purified compounds derived from other sources. Direct studies of C. japonicum extracts, flavonoid fractions, phenylpropanoid glycosides, and C. japonicum var. maackii-mediated gold nanoparticles demonstrate antitumor, cytotoxic, antiangiogenic, immunomodulatory, and ferroptosis-associated activities, although target-level validation remains limited. Among its associated constituents, pectolinarigenin has the most developed mechanistic evidence, involving RRM2–CDK1, TOP2A, STAT3, and PI3K/AKT/mTOR signaling. Apigenin, luteolin, acacetin, linarin, cirsimaritin, and pectolinarin additionally influence regulated cell death, proliferative signaling, angiogenesis, metastasis, immune regulation, metabolic vulnerability, senescence, and therapy response. However, much of this evidence relies on pathway-associated changes rather than direct target engagement or genetic validation. Furthermore, the pharmacokinetics, systemic exposure, botanical standardization, tumor selectivity, and clinical relevance of these compounds remain insufficiently characterized. Future studies should prioritize standardized preparations, quantitative exposure analysis, functional target validation, clinically relevant models, and carefully designed combination strategies. Collectively, C. japonicum provides a promising multi-hallmark framework for anticancer investigation, but substantial translational evidence is still required before its therapeutic potential can be established. Full article

(This article belongs to the Special Issue Medicinal Plants, Animal-Derived Products, and Natural Compounds: Roles in Health and Disease)

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16 pages, 3844 KB

Open AccessArticle

Comparative Effects of Pairwise Combinations of Carboplatin, Everolimus, and Astaxanthin on Cell Viability, Migration, and Inflammatory Biomarkers in SKOV3 Ovarian Cancer Cells

by Mete Hakan Karalok, Burcu Biltekin, Ebru Karci and Hafize Uzun

Int. J. Mol. Sci. 2026, 27(18), 7995; https://doi.org/10.3390/ijms27187995 - 8 Sep 2026

Abstract

Ovarian cancer remains a major cause of gynecological cancer-related mortality, highlighting the need for novel therapeutic strategies capable of enhancing antitumor activity while targeting multiple mechanisms involved in tumor progression. Everolimus, an inhibitor of the mammalian target of rapamycin pathway, and carboplatin are [...] Read more.

Ovarian cancer remains a major cause of gynecological cancer-related mortality, highlighting the need for novel therapeutic strategies capable of enhancing antitumor activity while targeting multiple mechanisms involved in tumor progression. Everolimus, an inhibitor of the mammalian target of rapamycin pathway, and carboplatin are established antineoplastic agents with distinct mechanisms of action, whereas astaxanthin is a bioactive carotenoid with antioxidant, anti-inflammatory, and potential anticancer properties. This study compared the individual and pairwise combination effects of carboplatin, everolimus, and astaxanthin on cell viability, migratory capacity, and inflammatory and tumor-associated biomarkers in SKOV3 ovarian cancer cells. Human SKOV3 ovarian cancer cells were cultured under standard conditions and exposed to different concentrations of carboplatin, everolimus, and astaxanthin, either individually or as pairwise two-drug combinations, for 24–72 h. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. Cell migration was evaluated using a scratch wound-healing assay. Based on the experimental treatment protocol, 100 nM everolimus, 100 μM carboplatin, and 100 μM astaxanthin, alone and in combination, were further evaluated for their effects on β-defensin 1, β-defensin 2, α-defensin 1, tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) levels. Biomarker concentrations were determined by ELISA. Experiments were independently performed in triplicate. Everolimus, carboplatin, and astaxanthin produced concentration- and time-dependent alterations in SKOV3 cell viability, with more pronounced cytotoxic effects generally observed following prolonged exposure. The pairwise combination treatments also substantially affected cell viability, particularly at later experimental time points. Assessment of migratory capacity demonstrated significant differences in wound closure among treatment groups at 24, 48, and 72 h (p = 0.0224, p = 0.0155, and p = 0.0028, respectively), indicating a time-dependent inhibitory effect on SKOV3 cell migration. Treatment with carboplatin, everolimus, and astaxanthin, individually or in pairwise combinations, also significantly modulated β-defensin 1, β-defensin 2, α-defensin 1, TNF-α, and IL-1β levels compared with control cells, with the magnitude and direction of these changes varying according to treatment regimen and exposure duration. Everolimus, carboplatin, and astaxanthin exerted significant time- and treatment-dependent effects on the viability and migratory behavior of SKOV3 ovarian cancer cells and markedly modulated defensin and pro-inflammatory cytokine responses. The findings demonstrate distinct treatment- and time-dependent responses to the individual agents and their pairwise combinations in SKOV3 ovarian cancer cells. These observations represent preliminary comparative in vitro effects rather than evidence of pharmacological synergy or therapeutic benefit. Further mechanistic studies using additional ovarian cancer cell lines, formal drug interaction analyses, and in vivo models are required to establish the biological and potential therapeutic relevance of these treatment combinations. Full article

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13 pages, 985 KB

Open AccessArticle

Generation and Characterization of the Human Anti-HTNV Antibody KJJ4

by Ziyan Chen, Yanbo Wang, Yongli Hou, Liang Fang, Linfeng Cheng, Yusi Zhang, Chunmei Zhang, Yun Zhang, Ying Ma, Kang Tang and Lihua Chen

Int. J. Mol. Sci. 2026, 27(18), 7994; https://doi.org/10.3390/ijms27187994 - 8 Sep 2026

Abstract

Hantaan virus (HTNV) is the predominant causative agent of hemorrhagic fever with renal syndrome (HFRS) in China, yet no specific antiviral therapy is currently available. Neutralizing antibodies (NAbs) represent a promising strategy, but most existing anti-HTNV NAbs are heterologous and carry immunogenicity risks. [...] Read more.

Hantaan virus (HTNV) is the predominant causative agent of hemorrhagic fever with renal syndrome (HFRS) in China, yet no specific antiviral therapy is currently available. Neutralizing antibodies (NAbs) represent a promising strategy, but most existing anti-HTNV NAbs are heterologous and carry immunogenicity risks. Here, two fully human antibodies from a previously established human anti-HTNV phage display library were generated and characterized. KJJ3, a VL-VL tandem antibody derived from clone 3–12, showed weak binding to inactivated HTNV and minimal neutralizing activity (IC₅₀ = 27.12 μg/mL). However, KJJ4, an engineered IgG4 antibody derived from clone 4–19 and carrying the S108P hinge mutation to prevent Fab-arm exchange, bound inactivated HTNV antigen and recombinant glycoprotein Gn (residues 19–371) in a dose-dependent manner, with only weak binding to Gc. Surface plasmon resonance yielded an association rate constant of 4.70 × 10³ M⁻¹s⁻¹, a dissociation rate constant of 3.06 × 10⁻³ s⁻¹, and an equilibrium dissociation constant of 650 nM for monomeric Gn_19–371. In a Vero E6 focus-reduction microneutralization assay, KJJ4 neutralized HTNV in vitro with an IC₅₀ of 2.879 μg/mL. These data establish KJJ4 as a fully human anti-HTNV antibody with experimentally defined in vitro binding and neutralizing activity, warranting further evaluation in animal models of HTNV infection. Full article

(This article belongs to the Special Issue Advances in Therapeutic Antibody Engineering)

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22 pages, 1175 KB

Open AccessArticle

Allostatic and Circadian Drives in Patients with Bipolar Disorder in Depressive Episodes or with Post-Traumatic Stress Disorder Versus Healthy Controls: Neuroendocrine Comparison Through Cortisol and 6-Sulfatoxymelatonin Overnight Urine Excretion

by Valerio Dell’Oste, Matteo Gambini, Virginia Pedrinelli, Berenice Rimoldi, Lionella Palego, Gino Giannaccini, Laura Betti and Claudia Carmassi

Int. J. Mol. Sci. 2026, 27(18), 7993; https://doi.org/10.3390/ijms27187993 - 8 Sep 2026

Abstract

Neuroendocrine and circadian dysfunctions are thought to underlie bipolar disorder (BD) and could be implemented as markers of complex symptom conditions, including the presence of Post-Traumatic Stress Disorder (PTSD) comorbidity. The primary objective of this study was to investigate neuroendocrine profiles in different [...] Read more.

Neuroendocrine and circadian dysfunctions are thought to underlie bipolar disorder (BD) and could be implemented as markers of complex symptom conditions, including the presence of Post-Traumatic Stress Disorder (PTSD) comorbidity. The primary objective of this study was to investigate neuroendocrine profiles in different BD phenotypes through the measure of nocturnal urinary levels of Cortisol (stress-response factor) and 6-sulfatoxymelatonin (aMT6s; light/dark signal) in euthymic BD patients diagnosed with PTSD (PTSD group) or with major depressive episodes without trauma symptoms (DEP group). Both groups were compared against healthy controls (CTL). Nighttime urinary levels of aMT6s and Cortisol were analyzed by competitive ELISA, with ensuing values normalized for specific gravity. The Cortisol-to-aMT6s ratio (Cort/aMT6s) was calculated as an exploratory proxy for the homeostatic balance between HPA-mediated catabolic/coping activities and Melatonin-related reparative functions. Clinical severity and psychosocial activities were assessed by using mood HAM-D, YMRS, trauma IES-R and functioning WSAS scales. Results revealed distinct biological patterns: PTSD subjects showed increased nocturnal Cortisol compared to DEP and CTL groups, whereas DEP patients exhibited lower aMT6s levels and an elevated Cort/aMT6s ratio. Cortisol and aMT6s correlated positively in PTSD, while the ratio correlated positively with Cortisol solely in controls. Clinically, Cortisol correlated positively with IES-R and functional impairment (WSAS), whereas aMT6s correlated negatively with HAM-D and YMRS scores. Present findings suggest a possible neuroendocrine divergence in BD patients with depression versus PTSD: nocturnal Melatonin deficiency may be associated with depression, while HPA-axis hyperactivity and altered crosstalk between the two systems may characterize PTSD comorbidity, with the Cort/aMT6s ratio as a potential index of impaired daily functioning. These results could be promising for the use of biomarkers linked to allostatic and circadian responses within the BD spectrum. Full article

(This article belongs to the Special Issue Molecular Biomarkers in Mood Disorders)

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13 pages, 1148 KB

Open AccessArticle

TLR4: A Potential Therapeutic Target in the Experimental Pathogenesis of Hemolytic-Uremic Syndrome

by Elisa Varrone, Veronica Pepe, Gianluca Storci, Massimiliano Bonafè, Barbara Brunetti and Maurizio Brigotti

Int. J. Mol. Sci. 2026, 27(18), 7992; https://doi.org/10.3390/ijms27187992 - 8 Sep 2026

Abstract

Childhood infections by Shiga toxin (Stx)-producing Escherichia coli (STEC) cause bloody diarrhea and the life-threatening hemolytic-uremic syndrome (HUS). Stx2, produced by STEC in the gut, is released into the bloodstream and interacts with circulating cells (monocytes, neutrophils, and platelets) through two different receptors: [...] Read more.

Childhood infections by Shiga toxin (Stx)-producing Escherichia coli (STEC) cause bloody diarrhea and the life-threatening hemolytic-uremic syndrome (HUS). Stx2, produced by STEC in the gut, is released into the bloodstream and interacts with circulating cells (monocytes, neutrophils, and platelets) through two different receptors: Gb3Cer (globotriaosylceramide) and Toll-like receptor 4 (TLR4). Consequently, blood cells form leukocyte/platelet aggregates and release pathogenic Stx2-containing extracellular vesicles (EVs) that, by damaging the kidney, induce the transition from bloody diarrhea to HUS. Human blood was incubated with Stx2 to induce the formation of neutrophil/platelet and platelet-only aggregates (observed in May–Grünwald Giemsa-stained blood smears) and pathogenic blood cell–derived EVs (isolated by size-exclusion chromatography or differential centrifugation) toxic to Vero cells (assessed by a viability assay). In the presence of a monoclonal antibody against TLR4 (anti-TLR4), the formation of neutrophil/platelet and platelet-only aggregates was greatly reduced compared to treatment with Stx2 alone. Moreover, anti-TLR4 significantly decreased the total mass of pathogenic blood cell–derived EVs produced by Stx2 (detected by nanoparticle tracking analysis), which proved less toxic to Vero cells than those produced by Stx2 alone. The impairment of the Stx2-TLR4 axis obtained during the experimental pathogenesis of HUS provides proof-of-concept evidence supporting TLR4 as a potential therapeutic target. Full article

(This article belongs to the Special Issue Pathogenic Escherichia coli: Cellular Biology, Mechanisms of Pathogenesis, Therapeutic Approaches and Strategies for Disease Intervention)

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14 pages, 1097 KB

Open AccessReview

Intrapancreatic Fat and Risk of Pancreatic Ductal Adenocarcinoma—Pathophysiology, Clinical Implications, and Future Directions

by Svenja Meyhöfer, Paula Lünswilken, Dimitris Grammatopoulos, Harpal Randeva, Jens U. Marquardt and Hendrik Lehnert

Int. J. Mol. Sci. 2026, 27(18), 7991; https://doi.org/10.3390/ijms27187991 - 8 Sep 2026

Abstract

Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies worldwide, with limited improvements in long-term survival despite significant progress in systemic therapy. This review focuses predominantly on pancreatic ductal adenocarcinoma (PDAC), the most common and best-studied pancreatic malignancy, while referencing other pancreatic [...] Read more.

Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies worldwide, with limited improvements in long-term survival despite significant progress in systemic therapy. This review focuses predominantly on pancreatic ductal adenocarcinoma (PDAC), the most common and best-studied pancreatic malignancy, while referencing other pancreatic neoplasms only where directly relevant to intrapancreatic fat biology. Obesity has emerged as a major modifiable risk factor for PDAC. In addition, increasing attention has focused on ectopic fat depots, particularly intrapancreatic fat, as potential mediators linking metabolic disease to pancreatic carcinogenesis. This narrative review summarizes the classification and epidemiology of PDAC, the relationship between obesity and pancreatic cancer risk, the biology of intrapancreatic fat, as well as putative mechanisms by which intrapancreatic fat may promote pancreatic carcinogenesis. In addition, we will review current diagnostic approaches, therapeutic and preventive considerations, and key unanswered questions for future research on the relevance of intrapancreatic fat deposits. Collectively, available evidence supports intrapancreatic fat as a biologically plausible and potential mediator of pancreatic cancer risk, warranting further prospective investigation. Full article

(This article belongs to the Special Issue Obesity and Cancer Risk: Molecular Mechanisms and Perspectives)

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19 pages, 2538 KB

Open AccessArticle

MORG1 Haploinsufficiency Is Associated with Stage- and Sex-Dependent Renoprotection and Signalling Alterations in Diabetic Kidney Disease

by Jonas Till Ihle, Luisa Duong, Nadja Ziller, Eric Jankowski, Karin Elflein, Alexander Berndt, Nikolaus Gaßler, Gunter Wolf and Ivonne Loeffler

Int. J. Mol. Sci. 2026, 27(18), 7990; https://doi.org/10.3390/ijms27187990 - 8 Sep 2026

Abstract

Type 2 diabetes mellitus (T2DM) is a major age-associated metabolic disease, and aging substantially contributes to the increasing burden and progression of chronic complications, including diabetic kidney disease (DKD). However, the molecular mechanisms underlying changes in renal susceptibility during disease progression remain incompletely [...] Read more.

Type 2 diabetes mellitus (T2DM) is a major age-associated metabolic disease, and aging substantially contributes to the increasing burden and progression of chronic complications, including diabetic kidney disease (DKD). However, the molecular mechanisms underlying changes in renal susceptibility during disease progression remain incompletely understood. We hypothesized that the scaffold protein mitogen-activated protein kinase organizer 1 (MORG1/WDR83) contributes to stage-dependent differences in DKD and that these effects may vary according to biological sex. Heterozygous Morg1 deletion was introduced into the diabetic C57BLKS/J db/db mouse model, and male and female mice were analysed at early and later disease stages alongside non-diabetic controls. Renal fibrosis, albuminuria, HIF-1α expression, mTORC1 and ERK1/2 activity, and renal cortical gene expression were assessed. Morg1 haploinsufficiency was associated with reduced renal fibrosis and albuminuria during early diabetes, whereas these protective effects were less evident in later-stage diabetic animals. HIF-1α expression decreased during progression in most groups but was relatively preserved in later-stage female Morg1 heterozygotes, whereas mTORC1 and ERK1/2 signalling was altered in a genotype- and stage-dependent manner. These findings identify MORG1 as a context-dependent modifier of DKD whose renoprotective effects change across disease progression, linking MORG1-associated signalling to the evolving renal phenotype of an age-associated metabolic disease. Full article

(This article belongs to the Special Issue Molecular Understanding Involved in Age-Related Diseases)

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19 pages, 1738 KB

Open AccessArticle

Endolysin LysSte134_1 Reduces Staphylococcus Bacterial Load in Infected Wounds In Vivo

by Natalia N. Golosova, Yana A. Khlusevich, Bogdana I. Kravchuk, Yuliya N. Kozlova, Timir M. Yakovlev, Svetlana A. Grishkova and Andrey L. Matveev

Int. J. Mol. Sci. 2026, 27(18), 7989; https://doi.org/10.3390/ijms27187989 - 8 Sep 2026

Abstract

Staphylococcus aureus is an ESKAPE pathogen, defined by its ability to evade antibacterial treatment, and together with S. epidermidis is a leading Gram-positive cause of wound infection. The emergence of methicillin- and vancomycin-resistant strains further limits conventional antibiotic treatment. The staphylococcal endolysin LysSte134_1 [...] Read more.

Staphylococcus aureus is an ESKAPE pathogen, defined by its ability to evade antibacterial treatment, and together with S. epidermidis is a leading Gram-positive cause of wound infection. The emergence of methicillin- and vancomycin-resistant strains further limits conventional antibiotic treatment. The staphylococcal endolysin LysSte134_1 was produced recombinantly, its proper folding confirmed by zymography, and its lytic activity demonstrated against planktonic cultures of both S. aureus and S. epidermidis. The combination of LysSte134_1 with 10% 1,3-propanediol and Zn²⁺ increased CFU reduction in both species relative to LysSte134_1 with Zn²⁺ alone. In a murine wound model, topical application of LysSte134_1 significantly reduced the bacterial burden in wound tissue, achieving a 2–3-log reduction in MRSA and below the detection limit for S. epidermidis. Treatment was accompanied by normalization of peripheral leukocyte counts and a shift in the serum cytokine profile from a sustained pro-inflammatory state with elevated IL-6, IL-17 and IL-10 toward levels comparable to non-infected controls. These results suggest the potential utility of LysSte134_1 as a component of topical antibacterial formulations and support further investigation in models of staphylococcal wound infection. Full article

(This article belongs to the Special Issue Antibacterial Drug Discovery and Molecular Mechanisms of Antimicrobial Resistance)

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1 pages, 143 KB

Open AccessCorrection

Correction: Feroz et al. Non-Muscle Myosin II A: Friend or Foe in Cancer? Int. J. Mol. Sci. 2024, 25, 9435

by Wasim Feroz, Briley SoYoung Park, Meghna Siripurapu, Nicole Ntim, Mary Kate Kilroy, Arwah Mohammad Ali Sheikh, Rosalin Mishra and Joan T. Garrett

Int. J. Mol. Sci. 2026, 27(18), 7988; https://doi.org/10.3390/ijms27187988 - 8 Sep 2026

Abstract

In the original publication [...] Full article

(This article belongs to the Section Molecular Oncology)

12 pages, 6004 KB

Open AccessArticle

Tonabersat Blocks Gap Junctions and Alleviates Thermal Pain Behavior in Mice

by Munia Abul Hawa, Rachel Feldman-Goriachnik and Menachem Hanani

Int. J. Mol. Sci. 2026, 27(18), 7987; https://doi.org/10.3390/ijms27187987 - 8 Sep 2026

Abstract

Gap junctions (GJs) are channels that enable exchange of ions and small molecules between cells, and have been implicated in the development and maintenance of neuropathic pain. Injury-induced glial activation in sensory ganglia is associated with increased coupling by GJs, which in turn [...] Read more.

Gap junctions (GJs) are channels that enable exchange of ions and small molecules between cells, and have been implicated in the development and maintenance of neuropathic pain. Injury-induced glial activation in sensory ganglia is associated with increased coupling by GJs, which in turn enhances neuronal excitability, contributing to pain signaling. Tonabersat (TON) was suggested to act as a GJ blocker with analgesic actions, but these claims have been disputed. Here we examined whether TON blocks GJs and whether it influences pain behavior in a mouse pain model. Gap junctional coupling was assayed by the dye coupling method in mouse liver and trigeminal ganglia. Pain behavior was tested in a mouse model of chemotherapy-induced pain, using von Frey filaments (tactile sensitivity), the acetone method (cold sensitivity) and hot plate (heat sensitivity). Intracellular dye injection showed that TON and the GJ blocker carbenoxolone (both 50 µM) inhibited gap junctional coupling by 70% and 82%, respectively. In the trigeminal ganglia, TON and carbenoxolone inhibited gap junctional coupling by 74 and 77%, respectively. TON selectively reduced heat and cold hypersensitivity, but not mechanical threshold. Carbenoxolone reduced all hypersensitivity types. No sex differences were observed. We conclude that both TON and carbenoxolone reduced coupling, indicating their potential to influence GJ-mediated coupling. In behavioral tests TON showed a selective effect for thermal hypersensitivity, but the underlying mechanism is unclear. Carbenoxolone produced a somewhat greater reduction in coupling compared with TON. These findings suggest that GJs play a role in pain pathways and highlight the need to explore whether other pain-relieving drugs act by blocking GJs. Full article

(This article belongs to the Special Issue Neuroinflammation: Molecular Targets and Therapeutic Advances)

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17 pages, 1598 KB

Open AccessArticle

Pulsed Electromagnetic Fields Enhance Resveratrol-Induced Apoptosis Through Modulation of Apoptotic Signaling in U87-MG Glioblastoma Cells

by Sinan Kandir, Atike Dogan, Kayhan Ates, Sukru Ozen, Serdar Karakurt and Cigdem Gokcek-Sarac

Int. J. Mol. Sci. 2026, 27(18), 7986; https://doi.org/10.3390/ijms27187986 - 8 Sep 2026

Abstract

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor characterized by dysregulated cellular signaling and resistance to apoptosis. Pulsed electromagnetic field (PEMF) exposure has been reported to modulate cancer-related cellular processes, while resveratrol (RES), a natural polyphenol, exhibits notable antiproliferative and pro-apoptotic actions. [...] Read more.

Glioblastoma multiforme (GBM) is an aggressive primary brain tumor characterized by dysregulated cellular signaling and resistance to apoptosis. Pulsed electromagnetic field (PEMF) exposure has been reported to modulate cancer-related cellular processes, while resveratrol (RES), a natural polyphenol, exhibits notable antiproliferative and pro-apoptotic actions. Here, we investigated whether 75 Hz PEMF potentiates RES-mediated apoptosis in human glioblastoma U87-MG cells by examining key molecules involved in apoptotic signaling and the transcriptional responses of PI3K/AKT/mTOR pathway-related genes. U87-MG glioblastoma cells and non-tumour human astroglial SVG-P12 cells were cultured and divided into the following six groups: (I) untreated cells; (II) RES-treated cells; (III) temozolomide (TMZ)-treated cells; (IV) PEMF-exposed cells; (V) cells treated with RES followed by PEMF exposure; and (VI) cells treated with TMZ followed by PEMF exposure. Cell viability was assessed in both cell lines by alamar blue assay, and selectivity indices were derived from the resulting IC50 values. Apoptotic responses and gene expression profiles were assessed in U87-MG cells by flow cytometry and qRT-PCR, while selected apoptosis-related proteins were evaluated by Western blotting. RES treatment induced stronger cytotoxic effects than TMZ in U87-MG cells, and this response was markedly enhanced following PEMF exposure, the IC₅₀ falling from 33.64 to 10.53 µg/mL. In SVG-P12 astroglia the IC₅₀ of RES rose from 17.95 to 98.31 µg/mL under the same exposure, so that the selectivity index of RES increased from 0.53 to 9.34, whereas that of TMZ remained essentially unchanged (1.54 versus 1.50). Combined RES and PEMF treatment significantly increased both early and late apoptosis. Molecular analyses revealed upregulation of pro-apoptotic markers accompanied by an increased Bax/BcL-2 ratio, consistent with protein-level changes. Transcripts of PI3K/AKT/mTOR pathway-related components were also elevated relative to untreated cells, but to a markedly lesser extent than the apoptotic markers. PEMF exposure significantly enhances the pro-apoptotic effects of RES in glioblastoma cells while relatively preserving SVG-P12 cell viability, supporting further investigation of this combination as a potential adjuvant approach. Full article

(This article belongs to the Section Molecular Oncology)

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19 pages, 3445 KB

Open AccessArticle

Genome-Wide Identification of SNF7 Gene Family in Maize and Potential Roles in Response to Abiotic and Biotic Stress

by Dan Wang, Wei Hu, Cuiping Xin, Xinyan Sun, Wenbo Yang, Meichen Zhu, Huimin Li, Yanping Fan and Yanyong Cao

Int. J. Mol. Sci. 2026, 27(18), 7985; https://doi.org/10.3390/ijms27187985 - 8 Sep 2026

Abstract

Sucrose non-fermenting protein 7 (SNF7) is a core operator of the endosomal sorting complex required for transport III (ESCRT-III) component mediating protein sorting and degradation. To date, the SNF7 gene family remains poorly characterized in plants, particularly in maize (Zea mays L.). [...] Read more.

Sucrose non-fermenting protein 7 (SNF7) is a core operator of the endosomal sorting complex required for transport III (ESCRT-III) component mediating protein sorting and degradation. To date, the SNF7 gene family remains poorly characterized in plants, particularly in maize (Zea mays L.). Here, we integrated bioinformatic and transcriptomic analyses to systematically characterize the ZmSNF7 gene family and its regulatory potential in stress responses. In total, 20 ZmSNF7 genes were identified genome-wide and classified into three phylogenetic clades, with conserved motifs and similar tertiary structures within the same clade. Abundant hormone- and stress-responsive cis-elements were detected in their promoters. Protein interaction prediction indicated ZmSNF7 proteins interact with intra-family members and other ESCRT components. Gene Ontology (GO) enrichment analysis suggested ZmSNF7s are primarily involved in endomembrane system organization and vesicular trafficking. Transcriptomic data revealed divergent ZmSNF7 expression patterns under drought, Rice black-streaked dwarf virus (RBSDV) infection, Colletotrichum graminicola (C. graminicola) inoculation and Asian corn borer (ACB) infestation. Collectively, this study comprehensively characterized the ZmSNF7 gene family and broadened our functional understanding of ZmSNF7 in mediating plant responses to biotic and abiotic stresses. Full article

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

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17 pages, 2661 KB

Open AccessArticle

ADCK1 Regulates Mitochondrial Bioenergetics in Hepatocellular Carcinoma In Vitro

by Noel Jacquet and Yunfeng Zhao

Int. J. Mol. Sci. 2026, 27(18), 7984; https://doi.org/10.3390/ijms27187984 - 8 Sep 2026

Abstract

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming and mitochondrial dysfunction, yet the molecular regulators underlying these alterations remain incompletely understood. AarF domain-containing kinase 1 (ADCK1) is an evolutionarily conserved protein associated with mitochondrial function, but its role in HCC bioenergetics has [...] Read more.

Hepatocellular carcinoma (HCC) is characterized by profound metabolic reprogramming and mitochondrial dysfunction, yet the molecular regulators underlying these alterations remain incompletely understood. AarF domain-containing kinase 1 (ADCK1) is an evolutionarily conserved protein associated with mitochondrial function, but its role in HCC bioenergetics has not been defined. In this study, we investigated the effects of ADCK1 on mitochondrial metabolism using CRISPR/Cas9-mediated ADCK1 knockout in HepG2 and SNU-449 HCC cells. Mitochondrial respiration, glycolytic activity, ATP production, lactate generation, mitochondrial membrane potential, and superoxide production were assessed following ADCK1 KO. ADCK1 KO resulted in marked reductions in basal and maximal mitochondrial respiration, ATP-linked respiration, glycolytic activity, intracellular ATP, and lactate production in both HCC cell models. ADCK1 KO also reduced mitochondrial membrane potential in a clone-dependent manner. Despite these profound bioenergetic defects, mitochondrial superoxide production was not consistently altered across the knockout clones. These findings indicate that ADCK1 supports both oxidative phosphorylation and glycolytic metabolism and is required for maintenance of bioenergetic homeostasis in HCC cells. Collectively, our results identify ADCK1 as a previously unrecognized regulator of HCC mitochondrial metabolism. Full article

(This article belongs to the Special Issue Mitochondria: Molecular Targeting in Cancer, Neurodegenerative Diseases, and Aging)

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18 pages, 1115 KB

Open AccessArticle

Synthesis, Cytotoxicity and Antimicrobial Action of 11 Analogs of Nifuroxazide

by Daniil N. Yarullin, Olga I. Logacheva, Aleksandra K. Isagulieva, Olga N. Sineva, Vera S. Sadykova, Maksim N. Zavalishin and George A. Gamov

Int. J. Mol. Sci. 2026, 27(18), 7983; https://doi.org/10.3390/ijms27187983 - 8 Sep 2026

Abstract

The global spread of multidrug-resistant bacteria, alongside the rising burden of oncological diseases, poses an increasing threat to human health and public healthcare systems worldwide. Substantial efforts are underway to discover new drugs and to reposition or repurpose existing ones. Recently, nifuroxazide introduced [...] Read more.

The global spread of multidrug-resistant bacteria, alongside the rising burden of oncological diseases, poses an increasing threat to human health and public healthcare systems worldwide. Substantial efforts are underway to discover new drugs and to reposition or repurpose existing ones. Recently, nifuroxazide introduced into clinical practice in the late 1960s has attracted considerable attention due to its antitumor potential. However, its poor absorption in the intestinal tract limits its applicability as a systemic antitumor agent, a limitation that can be addressed through chemical modification. In this study, we evaluated 11 nifuroxazide analogs featuring systematic modifications to both the five-membered ring (replacement of furan with thiophene) and the six-membered aromatic ring (variation in the position and nature of substituents). MTT cytotoxicity assays performed on HCT116 and HEK293 cell lines revealed that 5-nitrofurfurylidene hydrazide of 2-pyridinecarboxylic acid and 5-nitrothien-2-yl hydrazide of 2-pyridinecarboxylic acid exhibit selective toxicity toward tumor cells while showing significantly lower toxicity to non-tumor cells, indicating potential for further investigation in more complex biological models. Antimicrobial activity testing identified 5-nitrofurfurylidene hydrazide of 3-hydroxybenzoic acid and 5-nitrofurfurylidene hydrazide of 3-pyridinecarboxylic acid as particularly potent. Full article

(This article belongs to the Special Issue Schiff Bases and Their Metal Complexes: Structure, Synthesis, and Biological Application)

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