International Journal Of Molecular Sciences[JOURNAL]
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200 papers
From Chronic Inflammation to Malignancy: Molecular Mechanisms and Therapeutic Insights in Oral Carcinogenesis.
Huang YJ, Shi G, Lv F … +5 more , Deng R, Zhan Q, Zhang Z, Song J, Xu Z
Int J Mol Sci · 2026 Jun · PMID 42353345 · Full text
Oral squamous cell carcinoma (OSCC) frequently develops within chronically injured oral mucosa and may be preceded by clinically recognizable oral potentially malignant disorders (OPMDs), which provide an important windo...
Oral squamous cell carcinoma (OSCC) frequently develops within chronically injured oral mucosa and may be preceded by clinically recognizable oral potentially malignant disorders (OPMDs), which provide an important window for cancer interception. This review examines how etiological exposures, persistent inflammation, and lesion-specific epithelial-stromal-immune interactions cooperate during the transition from mucosal injury to dysplasia, carcinoma in situ, and invasive OSCC. Major carcinogenic exposures, including tobacco, alcohol, and areca nut, are considered together with context-dependent contributors such as microbial dysbiosis, viral infection, and immune-mediated epithelial injury. At the molecular level, inflammation-driven oral carcinogenesis involves cytokine and chemokine amplification, oxidative and nitrosative stress, NF-κB and STAT3 activation, the COX-2/PGE axis, genomic instability, field cancerization, epithelial-stromal crosstalk, angiogenesis, immune dysregulation, and epigenetic and non-coding RNA-mediated reprogramming. Emerging tools such as molecular risk assessment, liquid biopsy, optical imaging, spatially resolved profiling, and artificial intelligence-assisted models may improve identification of high-risk lesions, although most biomarkers require further prospective validation. Prevention should therefore integrate exposure control, biopsy-based diagnosis, local treatment when indicated, long-term surveillance, and trial-based precision strategies according to lesion risk, intervention window, and safety profile. This review supports a shift from lesion-centered management toward risk-adapted precision prevention in inflammation-driven oral carcinogenesis.
Differential Modulation of GLP-1R by Dietary Ginsenosides Points to a Putative Extracellular Allosteric Site.
Caspi A, Khazanov N, Helman A … +4 more , Lankry H, Levavi-Sivan B, Senderowitz H, Kerem Z
Int J Mol Sci · 2026 Jun · PMID 42353344 · Full text
The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) central to metabolic regulation, and its potential modulation by dietary phytochemicals is increasingly recognized as physiolog...
The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) central to metabolic regulation, and its potential modulation by dietary phytochemicals is increasingly recognized as physiologically relevant. Understanding how such compounds interact with GLP-1R is important for clarifying mechanisms that may contribute to gut-to-brain signaling. In this study, we examined three structurally related dietary ginsenosides, Rg1, Rg2, and Rg3, as potential modulators of GLP-1R using luciferase reporter assays and computational analyses. Despite sharing similar molecular weights, a common dammarane scaffold, and comparable sugar moieties, the three ginsenosides displayed distinct effects on GLP-1R activity: Rg2 and Rg3 potently reduced receptor activation in a dose-dependent manner when co-administered with Exendin-4, whereas Rg1 had minimal effect. Computational screening of the GLP-1R structure for binding sites identified a putative extracellular pocket on the protein that can accommodate these compounds, while molecular docking and binding free energy calculations provided predicted affinities qualitatively reflecting the phytochemicals' experimental activities. These findings point to a plausible extracellular mechanism through which dietary ginsenosides may influence GLP-1R responsiveness at the intestinal interface. Our results point to the possibility that non-absorbed phytochemicals can differentially modulate gut-expressed receptors, suggesting a novel pathway for dietary signaling relevant to ethnopharmacology and metabolic health.
Comparative Analysis of Serum and Tissue miRNA Expression Profiles and Regulatory Pathways in Early-Stage Ovarian Cancer Using Public Databases.
Cai S, Tan H, Niu X … +2 more , Eskar N, Liu Z
Int J Mol Sci · 2026 Jun · PMID 42353343 · Full text
To characterize the distinct expression profiles of microRNAs (miRNAs) in serum and tissue and to delineate the heterogeneity of their regulatory mechanisms in early-stage ovarian cancer (EOC), thereby identifying candid...
To characterize the distinct expression profiles of microRNAs (miRNAs) in serum and tissue and to delineate the heterogeneity of their regulatory mechanisms in early-stage ovarian cancer (EOC), thereby identifying candidate biomarkers for non-invasive early diagnosis. Differentially expressed miRNAs were identified by integrating publicly available datasets of EOC tissues and serum samples from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). Core miRNAs were subsequently screened through integrated differential expression analysis, weighted gene co-expression network analysis (WGCNA), and feature importance ranking derived from optimized machine learning models. Protein-protein interaction (PPI) networks and functional enrichment analyses (GO and KEGG) were performed on predicted target genes to systematically compare the functional discrepancies between serum- and tissue-derived miRNAs. No overlapping core miRNAs were observed between the two compartments. Serum miRNAs exhibited an overall up-regulated trend, whereas tissue miRNAs were predominantly down-regulated. Although the regulatory pathways demonstrated significant heterogeneity, they ultimately converged on the cell cycle and the PI3K-Akt signaling pathway, indicating high functional homology. Furthermore, serum miRNAs are not merely passive leakage products from tissues; current evidence suggests they may be selectively packaged into exosomes to participate in tumor regulation. Despite divergent expression profiles, serum and tissue miRNAs share homologous regulatory functions in EOC. These findings suggest that serum miRNAs accurately reflect the core molecular status of tumor tissues, providing a robust molecular foundation for liquid biopsy-based early detection strategies.
IMMUND: A Diagnostic and Therapeutic Pipeline to Uncover the Convergence in Functional Perturbation at Early Stages of Neurodegenerative Diseases and Multiple Sclerosis Based on Protein Markers.
Dey A, Sanyal D, Chattopadhyay K … +3 more , Maulik U, Uversky VN, Sen S
Int J Mol Sci · 2026 Jun · PMID 42353342 · Full text
Neuroinflammation is a key hallmark of both neurodegenerative and neurospecific autoimmune diseases, including multiple sclerosis (MS), where immune dysregulation contributes to cellular stress, autophagy, and disease pr...
Neuroinflammation is a key hallmark of both neurodegenerative and neurospecific autoimmune diseases, including multiple sclerosis (MS), where immune dysregulation contributes to cellular stress, autophagy, and disease progression in Alzheimer's disease (AD), Parkinson's disease (PD), and MS. Emerging evidence suggests a shared mechanism behind MS, AD, and PD, driven by chronic interaction between the peripheral immune system and the central nervous system (CNS). While MS was traditionally viewed as a primary autoimmune condition, recent research indicated that all three disorders involve a breakdown of the blood-brain barrier (BBB). This structural failure enables peripheral immune cells and cytokines to enter the brain, causing sustained neuroinflammation and accelerating disease progression. Here, we propose an end-to-end framework for identification of the diagnostic and therapeutic cell-specific protein markers commonly regulated in mild-moderate AD (MMAD), early-stage PD (ESPD), and MS within peripheral blood mononuclear cells (PBMCs). PBMC markers were first identified based on shared differential protein expression, followed by filtering for BBB permeability. Subsequently, sorted cell markers were mapped to disease-specific neural cell types. Our analysis suggests that PBMC-derived cells, including astrocyte- and monocyte-like populations, share overlapping transcriptional signatures and functional similarity with macrophages and neuroglial cells, indicating potential transcriptional similarity or functional convergence. Furthermore, intra- and inter-cellular pathway analysis suggested both shared and disease-specific signaling mechanisms, with kinase-integrin interactions emerging as key regulatory factors. Selected potential seed markers, primarily kinases and immunoglobulins, were further analyzed through evolutionary sequence-structure space to identify druggable structural features. Next, protein moonlighting possibilities were tested to enhance the temporal functional trajectory of the markers for precise therapeutic impact. Hence, the framework provides a robust strategy to identify immune-based disease-specificcandidate diagnostic andpotential therapeutic targets.
Comparison of PBS-Caffeine and Caffeine Buffers for Inhibiting Exocytosis During Horseshoe Crab Blood Collection and Improving the Yield of Limulus Amebocyte Lysate (LAL) for Endotoxin Detection.
Zhang J, Zhang S, Zhang M
Int J Mol Sci · 2026 Jun · PMID 42353341 · Full text
Limulus amebocyte lysate (LAL) detects bacterial endotoxin through a serine-protease coagulation cascade in which Factor C responds to lipopolysaccharide and Factor G to (1,3)-β-D-glucan. Sustainable LAL production depen...
Limulus amebocyte lysate (LAL) detects bacterial endotoxin through a serine-protease coagulation cascade in which Factor C responds to lipopolysaccharide and Factor G to (1,3)-β-D-glucan. Sustainable LAL production depends on collection buffers that prevent amebocyte degranulation while preserving these clotting factors. We previously showed that caffeine buffer inhibits degranulation, but caffeine-collected pellets aggregated upon resuspension in 5 mM CaCl, unlike phosphate-buffered saline (PBS). We therefore developed a PBS-caffeine collection solution and compared it with caffeine buffer. Over one bleeding season, 121 crabs were bled; blood was collected in caffeine, PBS-caffeine, or PBS-caffeine supplemented with EDTA, EGTA, or both, and LAL activity was measured by chromogenic and turbidimetric assays. Both buffers prevented degranulation and gave comparable LAL activity, but PBS-caffeine reduced aggregation and clotting. Treating PBS-caffeine LAL with 10% PEG-8000 selectively abolished endotoxin-sensitive Factor C activity while preserving (1,3)-β-D-glucan-sensitive Factor G activity, and the resulting Factor G lysate, formulated in 20 mM acetate (pH 5.6), remained stable for 27 months. These results define an improved collection buffer and identify conditions that selectively stabilize Factor G zymogen in liquid form.
Curcumin and Its Derivatives as Anticancer Agents in Head and Neck Cancer: Molecular Mechanisms and Preclinical Evidence.
Pinto L, Silva JPN, Monteiro L … +1 more , Silva PMA
Int J Mol Sci · 2026 Jun · PMID 42353340 · Full text
Head and neck cancer (HNC), particularly oral squamous cell carcinoma (OSCC), remains a major clinical challenge due to its aggressive behavior, high recurrence rates, and frequent resistance to conventional therapies. N...
Head and neck cancer (HNC), particularly oral squamous cell carcinoma (OSCC), remains a major clinical challenge due to its aggressive behavior, high recurrence rates, and frequent resistance to conventional therapies. Natural compounds, especially curcumin and its derivatives, have gained increasing attention as potential anticancer agents due to their ability to target multiple molecular pathways involved in tumor progression. This review critically evaluates the current preclinical and translational evidence supporting curcumin and its derivatives as monotherapeutic agents in HNC, with particular emphasis on oral cancer. We integrate the available evidence to assess the biological rationale, therapeutic potential, and current limitations of curcumin-based approaches. The molecular mechanisms underlying their antitumor activity are discussed, including modulation of EGFR/ERK and PI3K/Akt signaling pathways, inhibition of NF-κB and STAT3 activation, induction of apoptosis, regulation of oxidative stress, and suppression of epithelial-mesenchymal transition and tumor invasiveness. In addition, we address the impact of curcumin on the tumor microenvironment and its role in overcoming intrinsic cellular resistance mechanisms. The review also highlights advances in drug delivery strategies, such as nanoformulations, that are designed to improve curcumin's bioavailability and therapeutic efficacy. By critically integrating current evidence, this review highlights both the promise and the challenges associated with curcumin-based monotherapy in HNC, emphasizing the need for more robust and clinically relevant studies to support future translation.
Deubiquitinating Enzymes as Therapeutic Candidates in Hepatocellular Carcinoma and Other Liver Disease.
Jeong YH, Lee HH, Kim YJ … +2 more , Lee HR, Lim KH
Int J Mol Sci · 2026 Jun · PMID 42353339 · Full text
Hepatocellular carcinoma is challenging to detect at an early stage, and its severity increases over time. Recently, the incidence of hepatocellular carcinoma has increased, partly due to lifestyle-related factors such a...
Hepatocellular carcinoma is challenging to detect at an early stage, and its severity increases over time. Recently, the incidence of hepatocellular carcinoma has increased, partly due to lifestyle-related factors such as excessive alcohol intake, sedentary behavior, and diets high in fat, which contribute to the growing prevalence of fatty liver and hepatitis. Various therapeutic strategies are being explored for hepatocellular carcinoma, among which therapies targeting deubiquitinating enzymes (DUBs) have attracted growing attention. Ubiquitination acts as a crucial modulator in the regulation of intracellular signaling across many diseases. E3 ligase recognizes the target protein and transfers ubiquitin, received from the E2 enzyme, to the lysine residues of the substrate, thereby conferring specificity to the ubiquitination process. Once a ubiquitin chain is attached to a target protein by an E3 ligase, the protein is directed to the ubiquitin-proteasome system (UPS) for degradation. In this process, the 26S proteasome complex recognizes the ubiquitin chain and degrades the target protein, thereby serving as a major mechanism for maintaining protein homeostasis. Through this pathway, cells regulate signal transduction, eliminate abnormal proteins, and perform various essential functions. On the other hand, deubiquitinating enzymes (DUBs) recognize the ubiquitin chains on target proteins and remove them by hydrolyzing the isopeptide bonds of ubiquitin, thereby enabling the target proteins to evade degradation by the proteasome system. Furthermore, deubiquitinating enzymes independently remove ubiquitin from proteins and can serve as central regulators in signaling pathways related to hepatocellular carcinoma.
Liraglutide, a GLP-1 Receptor Agonist, Mitigates LPS-Induced Osteoclastogenesis and Bone Loss by Downregulating Macrophage TNF-α Expression.
Murakami K, Kitaura H, Ohori F … +8 more , Marahleh A, Lin A, Fan Z, Narita K, Ishiyama T, Hu J, Zheng H, Kanetaka H
Int J Mol Sci · 2026 Jun · PMID 42353338 · Full text
Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, restores hyperglycemic conditions in patients with type 2 diabetes and has recently shown promising anti-inflammatory properties. In this study, we explore...
Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, restores hyperglycemic conditions in patients with type 2 diabetes and has recently shown promising anti-inflammatory properties. In this study, we explored its potential to suppress osteoclast formation and bone loss triggered by lipopolysaccharide (LPS), an inflammatory agent. In animal models, the co-administration of liraglutide with LPS on the calvaria regions in mice markedly reduced osteoclast numbers and bone resorption areas relative to treatment with LPS alone. Furthermore, the expression levels of receptor activators of the NF-κB ligand (RANKL) and tumor necrosis factor (TNF)-α mRNA were notably lower in the group receiving liraglutide and LPS compared to treatment with LPS alone. Moreover, in vitro tests revealed that liraglutide has no direct inhibitory effect on RANKL-induced osteoclastogenesis and TNF-α-induced osteoclastogenesis. In addition, liraglutide had no direct inhibitory effect on LPS-stimulated RANKL expression in osteoblasts. Moreover, liraglutide effectively suppressed TNF-α mRNA expression in macrophages stimulated by LPS. These findings suggest that liraglutide prevents inflammatory bone destruction not by targeting osteoclast formation directly but by inhibiting the production of TNF-α within macrophages.
A Systematic Review on the Association Between Water Fluoride Levels and Dental Fluorosis: Exploring the 'Halo Effect' and Confounding Environmental Factors.
Funcuza M, Magunga BT, Rathebe PC … +1 more , Mbonane TP
Int J Mol Sci · 2026 Jun · PMID 42353337 · Full text
Dental fluorosis (DF) remains a global public health challenge traditionally attributed to elevated water fluoride F. However, the Halo Effect and environmental factors now complicate this dose-response relationship. Fol...
Dental fluorosis (DF) remains a global public health challenge traditionally attributed to elevated water fluoride F. However, the Halo Effect and environmental factors now complicate this dose-response relationship. Following PRISMA 2020 guidelines, this systematic review identified 20 observational studies ( = 21,780) via PubMed, Scopus, and Web of Science. Inclusion logic utilized the PICOS framework, specifically selecting human studies that reported quantitative water F levels alongside environmental or dietary confounders. Quality was assessed via the Newcastle-Ottawa Scale. Synthesis revealed that in optimal fluoridated areas (0.7 mg/L), mild DF prevalence reached 15-20% in cohorts with high "Halo Effect" exposure (infant formula, processed beverages) a twofold increase over historical benchmarks. High altitude (>2000 m) and arid climates further exacerbated toxicity by altering renal clearance. These factors sustain systemic fluoride levels that inhibit protease activity (MMP-20/KLK4) and induce endoplasmic reticulum stress during enamel maturation, causing hypomineralization. Current water-centric monitoring is insufficient for modern risk assessment. A transition toward Total Daily Intake (TDI) models and context-specific standards accounting for altitude and dietary diffusion is essential to balance caries prevention with systemic safety.
Synergistic Induction of Caspase-8-Mediated Leukaemic Cell Death by Fisetin and Pinocembrin.
Kaewthawee N, Sharma A, Brimson JM … +1 more , Brimson S
Int J Mol Sci · 2026 Jun · PMID 42353336 · Full text
Fisetin is a bioactive flavanol with reported anticancer activity, although its mechanisms in leukaemia and potential for combination therapy remain incompletely understood. This study investigated the cytotoxic and mech...
Fisetin is a bioactive flavanol with reported anticancer activity, although its mechanisms in leukaemia and potential for combination therapy remain incompletely understood. This study investigated the cytotoxic and mechanistic effects of fisetin, alone and combined with pinocembrin, in human leukaemia cells. Cell viability, apoptosis, and cell cycle progression were assessed by flow cytometry; protein expression in Jurkat cells was assessed by Western blotting; and molecular docking was used to evaluate interactions with the Fas receptor. Drug interactions were quantified using ZIP synergy analysis, and cytotoxicity and clonogenic survival were evaluated using soft-agar colony formation assays in K562 cells. Fisetin significantly reduced cell viability and induced apoptosis, accompanied by caspase-8 cleavage, p62 accumulation, and CDK4 downregulation, consistent with activation of extrinsic apoptosis, impaired autophagic flux, and cell cycle inhibition in Jurkat cells. Docking analysis supported a potential interaction with the Fas receptor, which was confirmed using the Fas receptor antagonist Met-12. Co-treatment with pinocembrin enhanced fisetin-mediated cytotoxicity and produced synergistic effects, particularly in Jurkat cells (ZIP score > 10), while synergistic interactions at specific sub-IC concentrations were also observed in K562 cells. Combination treatment further enhanced caspase-8 activation, reduced CDK4 expression in Jurkat cells, and significantly suppressed clonogenic survival in K562 cells compared with single-agent treatments. These findings suggest that fisetin promotes caspase-8-dependent apoptosis, potentially involving Fas-associated signalling, and highlight fisetin-pinocembrin combination therapy as a promising strategy for leukaemia treatment.
Isothiocyanates as Multi-Target Natural Compounds in Leukemia: Mechanisms, Selectivity, and Therapeutic Potential.
Yoldi Vergara A, Simonicova K, Bertova A … +3 more , Sulova Z, Breier A, Imrichova D
Int J Mol Sci · 2026 Jun · PMID 42353335 · Full text
Natural compounds are increasingly explored as complementary strategies to enhance the effectiveness of chemotherapy and reduce toxicity. Among these are isothiocyanates (ITCs), bioactive metabolites derived from glucosi...
Natural compounds are increasingly explored as complementary strategies to enhance the effectiveness of chemotherapy and reduce toxicity. Among these are isothiocyanates (ITCs), bioactive metabolites derived from glucosinolates in cruciferous vegetables, which have gained substantial attention for their chemopreventive and antileukemic potential. ITCs exert diverse biological effects driven by the high reactivity of the -NCS group, enabling covalent modification of key cellular proteins and modulation of signaling pathways. Well-studied representatives, including sulforaphane (SFN), allyl isothiocyanate (AITC), 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC), benzyl isothiocyanate (BITC), and phenethyl isothiocyanate (PEITC), exhibit diverse antileukemic activities, including cytotoxic, pro-apoptotic, differentiation-inducing, and cell-cycle-modulating effects. Although individual compounds differ in their relative potency and predominant biological responses, their activities are generally mediated through multiple interconnected mechanisms including oxidative stress modulation, mitochondrial dysfunction, regulation of apoptosis-related proteins, and interference with key signaling pathways. In addition to apoptosis, several ITCs have also been reported to induce autophagy, ferroptosis, or cellular differentiation in leukemic cells. Taken together, the existing evidence highlights ITCs as promising candidates for leukemia chemoprevention or therapy, acting through multi-targeted mechanisms that may complement conventional treatment strategies. Further studies are needed to clarify their selectivity, mechanistic diversity, and translational potential.
Effects of Nonionizing Millimeter-Wave on Spheroid-like Irradiated Non-Small-Cell Lung Cancer (NSCLC) Cells.
Tuchinsky H, Litvak B, Freydin V … +6 more , Simaan F, Said R, Patel D, Pinhasi Y, Yahalom A, Liberman-Aronov S
Int J Mol Sci · 2026 Jun · PMID 42353334 · Full text
Non-thermal millimeter-wave (MMW) irradiation represents a promising non-invasive strategy for cancer therapy, yet its effects in physiologically relevant 3D systems remain poorly defined. Here, we evaluated the biologic...
Non-thermal millimeter-wave (MMW) irradiation represents a promising non-invasive strategy for cancer therapy, yet its effects in physiologically relevant 3D systems remain poorly defined. Here, we evaluated the biological impact of MMW exposure in 3D non-small-cell lung cancer (NSCLC) spheroids (NCI-H1299, A549) and normal WI-38 fibroblasts under active cooling to suppress bulk heating. We demonstrate that cellular responses are governed primarily by power density (PD), irradiation geometry, and genotype-dependent susceptibility. High-PD pyramidal horn (PH) irradiation (~4.9 mW/cm) induced rapid apoptosis, metabolic collapse, and near-complete loss of clonogenic survival, whereas lower-PD waveguide (WG) irradiation (~0.6 mW/cm) produced depth-limited, cumulative cytotoxicity. Surviving cancer cells exhibited robust senescence-associated growth arrest, particularly in p53-deficient NCI-H1299 cells, indicating a dual apoptotic-senescent anti-proliferative response. In contrast, WI-38 fibroblasts showed minimal apoptosis and only transient stress-associated senescence, confirming selective tumor vulnerability. Mechanistic modeling suggests that MMW energy couples to glycan-rich membrane domains, generating localized electromagnetic hotspots that trigger calcium influx, mitochondrial dysfunction, and depth-dependent apoptosis. These findings establish a mechanistic basis for selective, non-thermal MMW-induced cytotoxicity in 3D NSCLC models and support further preclinical development of MMW-based therapeutic strategies.
Aortic Single-Cell Transcriptome Analysis Reveals ApoE-Isoform-Specific Influences on Vascular Disease.
Hui DY, Alagarsamy J, Haller A … +2 more , Medvedovic M, Jaeschke A
Int J Mol Sci · 2026 Jun · PMID 42353333 · Full text
The human gene is polymorphic with three major alleles that encode apolipoprotein (apo) E2, apoE3, and apoE4. Both apoE2 and apoE4 are associated with increased atherosclerosis risk. This study utilized human , , and g...
The human gene is polymorphic with three major alleles that encode apolipoprotein (apo) E2, apoE3, and apoE4. Both apoE2 and apoE4 are associated with increased atherosclerosis risk. This study utilized human , , and gene replacement mice and single-cell RNA sequencing approach to delineate the mechanisms underlying this association. The human , , and mice were fed a Western-type high fat-cholesterol diet for 16 weeks. Hyperlipidemia and significant atherosclerosis were observed in mice but not in or mice. However, increased vascular inflammation was observed in both and mice. Single-cell RNA sequencing followed by cluster analysis identified 25 major cell types in the aorta that include various immune cell types, endothelial cells, and various vascular mural cell subsets. Results showed that cells from the mice were enriched with genes associated with intracellular lipid accumulation and inflammation, whereas cells from the mice displayed elevated oxidative- and/or endoplasmic reticulum-stress and inflammatory response. Thus, apoE2 accelerates atherosclerosis by inducing diet-induced hyperlipidemia and inflammation, while apoE4 does not induce hyperlipidemia but enhances inflammation that may prime the vasculature for atherosclerosis development. The distinct mechanisms by which apoE2 and apoE4 promote atherosclerosis underscore the importance of including apoE genotype information in the design of therapeutics for atherosclerosis intervention.
High-Level Secretory Expression of Recombinant Type XVII Human-like Collagen in .
Jia Y, Yue J, Wu W … +5 more , Zhao W, Hu S, Mei L, Wei P, Lyu C
Int J Mol Sci · 2026 Jun · PMID 42353332 · Full text
Type XVII collagen (COL17) is crucial for skin integrity but difficult to produce. To achieve high-level secretory expression, a human COL17 segment was designed and cloned into the pPIC9K vector with six different α-mat...
Type XVII collagen (COL17) is crucial for skin integrity but difficult to produce. To achieve high-level secretory expression, a human COL17 segment was designed and cloned into the pPIC9K vector with six different α-mating factor signal peptides and integrated into GS115. Fed-batch fermentation in a 5 L bioreactor yielded 4.7 g/L of recombinant COL17. Functional assays showed that it promoted the proliferation of human skin fibroblast (HFF) and immortalized keratinocytes (HaCaT), upregulated , , and in HFF cells, and enhanced skin barrier-related genes (, , , , , , ) in HaCaT cells. In a UVB-induced photoaging model, COL17 reduced reactive oxygen species (ROS) and matrix metalloproteinase 3 (MMP3) activity. This recombinant collagen exhibits photoprotective, regenerative, and barrier-enhancing activities, offering potential for skincare and tissue engineering.
Therapeutic Effects of Glucagon-like Peptide-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: A Systematic Review.
Mahoon D, Kellany F, Khan I … +2 more , Khan S, Butler AE
Int J Mol Sci · 2026 Jun · PMID 42353331 · Full text
Non-alcoholic fatty liver disease (NAFLD), now increasingly termed metabolic dysfunction-associated steatotic liver disease (MASLD), is a growing cause of chronic liver disease with limited treatment options. Glucagon-li...
Non-alcoholic fatty liver disease (NAFLD), now increasingly termed metabolic dysfunction-associated steatotic liver disease (MASLD), is a growing cause of chronic liver disease with limited treatment options. Glucagon-like peptide-1 (GLP-1) receptor agonists, approved for type 2 diabetes and obesity, possess metabolic effects that may render them suitable for treating NAFLD and metabolic dysfunction-associated steatohepatitis (MASH). To evaluate the therapeutic effects of GLP-1 receptor agonists in adults with NAFLD, non-alcoholic steatohepatitis (NASH), MASLD, or MASH. PubMed, Scopus, Embase, and the Cochrane Library were systematically searched using keywords related to NAFLD and GLP-1 receptor agonists. Given heterogeneity in populations, designs, and outcomes, findings were synthesized narratively. The review is registered with PROSPERO (CRD420261337353). Twelve studies met the inclusion criteria. The most consistent outcome was a reduction in hepatic fat, seen with semaglutide, liraglutide, dulaglutide, and beinaglutide. Improvements in liver enzymes, particularly alanine aminotransferase, were less consistent and best regarded as supportive rather than definitive evidence of histological improvement. Histological benefits were strongest for steatohepatitis resolution in non-cirrhotic MASH. Fibrosis findings were mixed, with the greatest benefit in F2-F3 MASH and limited improvement in established cirrhosis. GLP-1 receptor agonists were generally well tolerated, with gastrointestinal symptoms the most common adverse effects. GLP-1 receptor agonists show promising liver-related benefits in NAFLD and MASH, particularly in obesity, type 2 diabetes, or earlier-stage disease. Their effects on advanced fibrosis and long-term outcomes remain uncertain, warranting larger, longer-term studies.
Associative Analysis of lncRNA/circRNA-miRNA-mRNA Expression Profiles in Iron-Overloaded HT-1080 Fibrosarcoma Cells.
Teng Y, Zhang Q, Ding H … +1 more , Feng J
Int J Mol Sci · 2026 Jun · PMID 42353330 · Full text
Iron overload disrupts cellular homeostasis and drives ferroptosis through dysregulated iron metabolism. Non-coding RNAs (ncRNAs) are considered as key regulators of various biological functions and targets for a new gen...
Iron overload disrupts cellular homeostasis and drives ferroptosis through dysregulated iron metabolism. Non-coding RNAs (ncRNAs) are considered as key regulators of various biological functions and targets for a new generation of RNA therapeutics and biomarkers. However, few studies have investigated the regulatory roles of ncRNAs, particularly competitive endogenous RNAs (ceRNAs) in iron overload. This study performed whole-transcriptome sequencing to characterize the ceRNA network in ferric ammonium citrate (FAC)-induced iron-overloaded HT-1080 fibrosarcoma cells. A total of 208 differentially expressed mRNAs, 83 lncRNAs, and 170 circRNAs ( < 0.05) were identified, with hierarchical clustering revealing distinct expression patterns between control and iron-treated groups. KEGG enrichment implicated vitamin B6 metabolism ( < 0.001) and lysine degradation ( < 0.001) as key disrupted pathways. ceRNA network was conducted and further demonstrated lncRNA/circRNA-mediated regulation of ferroptosis genes via shared miRNA response elements. Notably, was implicated in the regulation of both ferritin heavy chain () and sequestosome 1 (), two ferroptosis-associated mRNAs. upregulation mitigates iron toxicity through ferroxidase activity, while modulates lipid peroxidation in ferroptosis. These findings provide a preliminary transcriptomic landscape for hypothesis generation regarding ncRNA-mediated regulatory mechanisms in iron overload-induced ferroptosis and offer a computational foundation for future functional and therapeutic investigations.
Bidirectional Interactions Between Cervicovaginal Microbiota and Human Papillomavirus Drive Persistence and Disease Progression.
Suárez-Rico DO, Rizo de la Torre LDC, Zermeño-Ruiz M … +4 more , Balleza-Alejandri LR, García-Galindo JJ, Montoya-Fuentes H, Beltrán-Ramírez A
Int J Mol Sci · 2026 Jun · PMID 42353329 · Full text
Persistent high-risk human papillomavirus infection is a critical prerequisite for cervical intraepithelial neoplasia and cervical cancer, yet viral factors alone do not fully explain why most infections clear while a su...
Persistent high-risk human papillomavirus infection is a critical prerequisite for cervical intraepithelial neoplasia and cervical cancer, yet viral factors alone do not fully explain why most infections clear while a subset persists and progresses. Emerging longitudinal, multi-omics, and mechanistic evidence supports a plausible model in which the cervicovaginal microbiota is not a passive bystander but a functional determinant of mucosal immunity, epithelial barrier integrity, and local metabolic tone. -dominant community states, particularly those enriched in , are generally associated with lower pH, regulated inflammatory signaling, stronger barrier function, and a higher likelihood of HPV clearance. In contrast, anaerobe-enriched dysbiosis is linked to elevated pro-inflammatory cytokines, altered antigen presentation, immune checkpoint signatures consistent with T-cell dysfunction, and metabolic shifts involving lactate depletion and accumulation of short-chain fatty acids and other metabolites that can influence epithelial and immune-cell programs. Importantly, the interaction is bidirectional: hrHPV can remodel the microenvironment by suppressing host defense peptides and perturbing mucosal barriers, thereby reducing fitness and reinforcing dysbiosis in a feed-forward loop that favors persistence and oncogenic progression. This review integrates functional ecology, longitudinal clinical evidence, immunological and metabolic mechanisms, and translational implications, highlighting opportunities for microbiome-informed risk stratification and adjunctive interventions, as well as key gaps requiring standardized longitudinal multi-omics and rigorously designed clinical trials.
Early Flowering () Gene Integrates Vegetative Growth, Flowering Regulation, and Reproductive Development in .
Jan R, Iqbal S, Ali S … +5 more , Almalki MA, Alfredan M, Ibrahim RIH, Asaf S, Kim KM
Int J Mol Sci · 2026 Jun · PMID 42353328 · Full text
Early flowering-related factors play pivotal roles in coordinating plant growth and reproductive development. In this study, we investigated the biological function of early flowering gene () in using CRISPR/Cas9-mediat...
Early flowering-related factors play pivotal roles in coordinating plant growth and reproductive development. In this study, we investigated the biological function of early flowering gene () in using CRISPR/Cas9-mediated genome editing and construction of overexpression approaches. Two independent overexpression () and genome-edited () lines were generated and systemically analyzed. overexpression significantly enhanced early seedling performance, increasing germination rate and seedling fresh weight by up to 8.7%, while genome-edited lines exhibited a marked reduction. Root growth was strongly promoted in plants, with root length increase of 85% and 75%, whereas lines showed a reduction of up to 48%. At later developmental stages, plants displayed enhanced vegetative growth, including increased leaf length (32%), leaf area (91%), and accelerated flowering (21% earlier than wild type). In contrast, delayed flowering by up to 25% and resulted in compact plant architecture. Reproductive development was severely compromised in plants, which exhibited malformed inflorescences, reduced pollen germination, shortened silique (45%), and a drastic decrease in seed number per silique (70%). Conversely, plants showed increased silique number and seed per silique. Molecular analysis revealed that positively regulates key flowering-related genes, including , , , and , which correlated strongly with growth and reproductive traits. Our results demonstrate that functions as a central regulator integrating vegetative growth, floral development, male fertility, and seed production in .
Building Disease Models for Endometriosis: iPSCs as Game-Changers.
Kahar KH, E-Anjum B, Nordin F … +5 more , Ng AMH, Abd Aziz NH, Mohd Idris I, Tye GJ, Wan Kamarul Zaman WS
Int J Mol Sci · 2026 Jun · PMID 42353327 · Full text
This review aims to evaluate the potential of endometriosis models, especially patient-derived iPSC models, to gain deeper insights into the disease, thereby advancing our understanding and treatment of endometriosis. Th...
This review aims to evaluate the potential of endometriosis models, especially patient-derived iPSC models, to gain deeper insights into the disease, thereby advancing our understanding and treatment of endometriosis. This comprehensive narrative review utilized a structured search of the PubMed, Scopus, and Web of Science databases, primarily covering literature published between January 2000 and May 2025. An expansive search strategy was employed to capture the full breadth of the field using keywords such as "endometriosis," "induced pluripotent stem cells (iPSCs)," "patient-derived organoids," "disease modeling," and "epigenetics" without restrictive filtering, ensuring the integration of both foundational theories and emerging biotechnological advances. In total, over 170 peer-reviewed publications were analyzed, ranging from landmark genomic meta-analyses that have identified significant risk loci to state-of-the-art 3D-culture systems for modeling patient-specific endometrial disease. By synthesizing these diverse sources, the review bridges the gap between traditional anatomical classifications and modern molecular modeling to evaluate the potential of iPSC platforms for personalized medicine and therapeutic discovery. Endometriosis is a multifactorial gynecological condition that affects 176 million women worldwide and can significantly impair quality of life. It occurs when endometrium-like tissue grows outside the uterus, responsive to ovarian hormones, causing inflammation, pain, and discomfort, and leading to fibrotic tissue. World Health Organization estimates indicate that 6-10% of women suffer from this disorder, which can cause infertility and increase the risk of developing various types of cancer and autoimmune disorders. The use of patient-derived iPSC models serves to gain deeper insights into the disease by mimicking the endometrial tissue or lesions observed in affected individuals, thereby advancing our understanding and treatment of endometriosis.
The Versatile Applications of Antisense Oligonucleotides in Modern Medicine.
Liang XH, Zhang L
Int J Mol Sci · 2026 Jun · PMID 42353326 · Full text
Antisense oligonucleotides (ASOs) are a class of nucleic acid therapeutics that modulate gene expression through diverse mechanisms. Since their initial demonstration in inhibiting viral genes, advances in medicinal chem...
Antisense oligonucleotides (ASOs) are a class of nucleic acid therapeutics that modulate gene expression through diverse mechanisms. Since their initial demonstration in inhibiting viral genes, advances in medicinal chemistry, pharmacology, and delivery have enabled robust and durable target engagement across multiple tissues. Chemical modifications to the backbone, ribose, and nucleobases have improved nuclease resistance, binding affinity, and pharmacokinetics, while conjugation and delivery technologies have expanded tissue accessibility. Beyond classical RNase H-mediated RNA degradation, ASOs regulate gene expression via splicing modulation, microRNA inhibition, transcriptional activation, and translation modulation, supporting both gene silencing and upregulation strategies. Multiple ASO drugs are now approved, particularly for genetic diseases, with many more in clinical development. This review outlines the evolution of antisense technology, key chemical and delivery innovations, ASO pharmacokinetics and intracellular trafficking, the mechanisms underlying gene regulation, and current clinical applications and future opportunities.
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