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Open AccessArticle

Effect of Central Injection of Anandamide on LPS-Dependent Suppression of GnRH/LH Secretion in Ewes During the Follicular Phase of the Estrous Cycle

by Karolina Wojtulewicz, Dorota Tomaszewska-Zaremba, Monika Tomczyk, Joanna Bochenek and Andrzej P. Herman

Int. J. Mol. Sci. 2025, 26(23), 11246; https://doi.org/10.3390/ijms262311246 - 21 Nov 2025

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Abstract

The study investigated the effects of intracerebroventricular (ICV) administration of the endocannabinoid anandamide (AEA) on suppression of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) secretion during lipopolysaccharide (LPS)-induced inflammation in ewes at the follicular phase of the estrous cycle. Animals were divided into three groups: [...] Read more.

The study investigated the effects of intracerebroventricular (ICV) administration of the endocannabinoid anandamide (AEA) on suppression of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) secretion during lipopolysaccharide (LPS)-induced inflammation in ewes at the follicular phase of the estrous cycle. Animals were divided into three groups: control, LPS (intravenous, IV; 400 ng/kg), and LPS + AEA (ICV; 100 µM/animal). In LPS-treated ewes, AEA increased GnRH concentration in the preoptic area (POA) and upregulated GnRH mRNA expression in the POA and anterior hypothalamus (AHA). Central administration of AEA decreased the circulating concentration of cortisol in LPS-treated ewes. Moreover, AEA lowered proinflammatory interleukin (IL)-1β and increased anti-inflammatory IL-10 protein expressions in the hypothalamus of LPS-treated ewes. However, ICV AEA did not reverse the inflammation-associated reduction in LH secretion. These findings show that acute central administration of AEA abolishes the inhibitory effect of inflammation on GnRH synthesis in the POA and even stimulates it, likely through attenuation of central inflammation, as reflected by IL-1β and IL-10 changes in the POA. Nevertheless, short-term AEA administration was insufficient to counteract the inflammation-mediated suppression of LH secretion. Further studies are needed to explore the role of endocannabinoids (ECBs) in modulating GnRH/LH secretion under inflammatory conditions, particularly with prolonged exposure. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 5677 KB

Open AccessArticle

Copy Number Alteration Profiling from Plasma cfDNA WES in Advanced NSCLC

by Ho Jang and Mi-Kyung Jeong

Int. J. Mol. Sci. 2025, 26(22), 11111; https://doi.org/10.3390/ijms262211111 - 17 Nov 2025

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Abstract

Circulating cell-free DNA (cfDNA) sequencing offers a minimally invasive approach for profiling tumor genomes, but detecting copy number alterations (CNAs) from cfDNA whole-exome sequencing (WES) remains technically challenging due to noise and guanine–cytosine (GC)-related bias. Building upon our previous study that characterized read [...] Read more.

Circulating cell-free DNA (cfDNA) sequencing offers a minimally invasive approach for profiling tumor genomes, but detecting copy number alterations (CNAs) from cfDNA whole-exome sequencing (WES) remains technically challenging due to noise and guanine–cytosine (GC)-related bias. Building upon our previous study that characterized read count patterns in cfDNA WES data, we developed and evaluated an advanced pipeline for robust CNA detection in patients with advanced non-small cell lung cancer (NSCLC). Read count signals showed strong correlation with GC content, and applying locally estimated scatterplot smoothing (LOESS)-based GC bias correction effectively reduced false positives and improved CNA detection. The resulting cfDNA CNA profiles were reproducible within patients and showed strong concordance with The Cancer Genome Atlas (TCGA) tissue-level patterns for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). These findings demonstrate that cfDNA WES, when combined with appropriate bias correction, can serve as a practical and minimally invasive alternative for genomic characterization of NSCLC. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 3932 KB

Open AccessArticle

Elevated Levels of Active GSK3β in the Blood of Patients with Myotonic Dystrophy Type 1 Correlate with Muscle Weakness

by Katherine Jennings, Cuixia Tian, Rebeccah L. Brown, Paul S. Horn, Benedikt Schoser, Hani Kushlaf, Nikolai A. Timchenko and Lubov Timchenko

Int. J. Mol. Sci. 2025, 26(21), 10760; https://doi.org/10.3390/ijms262110760 - 5 Nov 2025

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Abstract

Myotonic Dystrophy type 1 (DM1) is a complex disease affecting multiple tissues, including skeletal and cardiac muscles, the brain and the eyes. DM1 results from an expansion of CTG repeats in the 3′ UTR of the DMPK gene. Previously, we described that the [...] Read more.

Myotonic Dystrophy type 1 (DM1) is a complex disease affecting multiple tissues, including skeletal and cardiac muscles, the brain and the eyes. DM1 results from an expansion of CTG repeats in the 3′ UTR of the DMPK gene. Previously, we described that the small-molecule inhibitor of GSK3β, tideglusib (TG), reduces DM1 pathology in DM1 cell and mouse models by correcting the GSK3β-CUGBP1 pathway, decreasing the mutant CUG-containing RNA. Respectively, clinical trials using TG showed promising results for patients with congenital DM1 (CDM1). The drug development in DM1 human studies needs specific and noninvasive biomarkers. We examined the blood levels of active GSK3β in different clinical forms of DM1 and found an increase in active GSK3β in the peripheral blood mononuclear cells (PBMCs) in patients with CDM1, juvenile DM1 and adult-onset DM1 vs. unaffected patients. The blood levels of active GSK3β correlate with the length of CTG repeats and severity of muscle weakness. Thrombospondin and TGFβ, linked to the TG-GSK3β pathway in DM1, are also elevated in the DM1 patients’ blood. These findings show that the blood levels of active GSK3β might be developed as a potential noninvasive biomarker of muscle weakness in DM1. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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15 pages, 3604 KB

Open AccessArticle

HIF-2α Interaction with Ataxin-10 Enhances HIF-2α Binding to Its Target Gene Promoters

by Aikaterini Diseri, Ioanna-Maria Gkotinakou, Christina Befani, Ioannis Pappas, Martina Samiotaki, George Panayotou and Panagiotis Liakos

Int. J. Mol. Sci. 2025, 26(21), 10417; https://doi.org/10.3390/ijms262110417 - 27 Oct 2025

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Abstract

The master transcription factors that control cell adaptation under hypoxia are known as hypoxia-inducible factors or HIFs. HIF-2α is the second isoform, which has been studied less extensively, and its expression is limited to particular cell types and is associated with increased malignancy [...] Read more.

The master transcription factors that control cell adaptation under hypoxia are known as hypoxia-inducible factors or HIFs. HIF-2α is the second isoform, which has been studied less extensively, and its expression is limited to particular cell types and is associated with increased malignancy in tumors. Herein, we investigate the interaction of HIF-2α with Ataxin-10, an intracellular protein involved in cell survival and differentiation, as well as the mechanism and the effects of this interaction in cervical cancer (HeLa) and glioma (U-87MG) cells. The interaction was investigated by LC-MS/MS proteomic analysis, immunoprecipitation, and immunoblotting. HIF-2 transcriptional activity was measured by luciferase assays and quantitative RT-PCR of target genes specific to HIF-2. The mechanism of interaction was investigated using immunofluorescence microscopy analysis, subcellular fractionation, siRNA-mediated silencing, quantitative RT-PCR, in vitro binding assays, and chromatin immunoprecipitation (ChIP). Ataxin interacts specifically with HIF2α and binds to the HIF-2α carboxyterminal activation domain. The interaction of HIF-2α with Ataxin-10 increases HIF-2-transcriptional activity under hypoxia through the enhancement of HIF-2α binding to chromatin in Hypoxia Response Elements of HIF-2 specific target genes SERPINE1, CITED-2, and SOD-2. These new data highlight a novel HIF-2 fine-tuning mechanism and may offer new, effective therapeutic approaches for treating cancerous tumors. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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11 pages, 2079 KB

Open AccessArticle

Normal Hematopoietic Stem Cells in Leukemic Bone Marrow Environment Undergo Morphological Changes Identifiable by Artificial Intelligence

by Dongguang Li, Athena Li, Ngoc DeSouza and Shaoguang Li

Int. J. Mol. Sci. 2025, 26(21), 10354; https://doi.org/10.3390/ijms262110354 - 24 Oct 2025

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Abstract

Leukemia stem cells (LSCs) in numerous hematologic malignancies are generally believed to be responsible for disease initiation, progression/relapse and resistance to chemotherapy. It has been shown that non-leukemic hematopoietic cells are affected molecularly and biologically by leukemia cells in the same bone marrow [...] Read more.

Leukemia stem cells (LSCs) in numerous hematologic malignancies are generally believed to be responsible for disease initiation, progression/relapse and resistance to chemotherapy. It has been shown that non-leukemic hematopoietic cells are affected molecularly and biologically by leukemia cells in the same bone marrow environment where both non-leukemic hematopoietic stem cells (HSCs) and LSCs reside. We believe the molecular and biological changes of these non-leukemic HSCs should be accompanied by the morphological changes of these cells. On the other hand, the quantity of these non-leukemic HSCs with morphological changes should reflect disease severity, prognosis and therapy responses. Thus, identification of non-leukemic HSCs in the leukemia bone marrow environment and monitoring of their quantity before, during and after treatments will potentially provide valuable information for correctly handling treatment plans and predicting outcomes. However, we have known that these morphological changes at the stem cell level cannot be extracted and identified by microscopic visualization with human eyes. In this study, we chose polycythemia vera (PV) as a disease model (a type of human myeloproliferative neoplasms derived from a hematopoietic stem cell harboring the JAK2V617F oncogene) to determine whether we can use artificial intelligence (AI) deep learning to identify and quantify non-leukemic HSCs obtained from bone marrow of JAK2V617F knock-in PV mice by analyzing single-cell images. We find that non-JAK2V617F-expressing HSCs are distinguishable from LSCs in the same bone marrow environment by AI with high accuracy (>96%). More importantly, we find that non-JAK2V617F-expressing HSCs from the leukemia bone marrow environment of PV mice are morphologically distinct from normal HSCs from a normal bone marrow environment of normal mice by AI with an accuracy of greater than 98%. These results help us prove the concept that non-leukemic HSCs undergo AI-recognizable morphological changes in the leukemia bone marrow environment and possess unique morphological features distinguishable from normal HSCs, providing a possibility to assess therapy responses and disease prognosis through identifying and quantitating these non-leukemic HSCs in patients. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 2616 KB

Open AccessArticle

GC Content and Thermal Stability of Double-Stranded RNA: Fragments of Microsporidia Vairimorpha ceranae and Nosema bombycis AT-Rich Genes Are Sensitive to Standard Heat Treatment

by Ruslan R. Fadeev, Sergey A. Timofeev, Igor V. Senderskiy and Viacheslav V. Dolgikh

Int. J. Mol. Sci. 2025, 26(21), 10270; https://doi.org/10.3390/ijms262110270 - 22 Oct 2025

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Abstract

Heating at 95 °C or boiling E. coli HT115 (DE3) cells is often used to extract heterologous dsRNA or kill bacteria, although these temperatures cause dsRNA denaturation and destruction. In this study, we examined the risk of degradation of dsRNA fragments of AT-rich [...] Read more.

Heating at 95 °C or boiling E. coli HT115 (DE3) cells is often used to extract heterologous dsRNA or kill bacteria, although these temperatures cause dsRNA denaturation and destruction. In this study, we examined the risk of degradation of dsRNA fragments of AT-rich genes at high temperature. The expression of dsRNA fragments of AT-rich genes encoding DNA replication enzymes from the microsporidia Vairimorpha ceranae and Nosema bombycis in E. coli HT115 (DE3) was accompanied by heating the bacteria at 95 °C for 30 min. In contrast to four control fragments with normal GC content, the AT-rich dsRNAs of microsporidia were destroyed by this treatment. The in vitro synthesis and heating of the studied dsRNAs showed the degradation of both microsporidia and control fragments. The thermal degradation of in vitro-synthesized control dsRNA with a normal GC content of 47.6% was prevented by the addition of 2 × YT media, NaCl, or low concentrations of MgSO₄. This demonstrates the important role of mono- and divalent cations in stabilizing heated fragments and helps explain the preservation of their integrity and RNAi-initiating activity despite the treatment of bacteria at temperatures that denature dsRNA. Feeding Colorado potato beetle larvae with the same in vitro-synthesized dsRNA containing fragments of three Leptinotarsa decemlineata genes showed that their thermal destruction was accompanied by a decrease in pest-suppressing activity. No dsRNA degradation was observed at 80 °C or after E. coli sonication, and these treatments, as well as increasing cation content, may help to avoid the degradation of heat-sensitive dsRNA. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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22 pages, 4166 KB

Open AccessArticle

Characterization of Recombinant Human Type II Collagen from CHO Cells, Functional Assessment of Chondrocytes and Alleviation of Cartilage Degeneration

by Chuan Wang, Zhijie Zhang, Zhengqi Zha, Chunyang Lu, Hang Wang, Long Yue and Hongping Yin

Int. J. Mol. Sci. 2025, 26(20), 10232; https://doi.org/10.3390/ijms262010232 - 21 Oct 2025

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Abstract

Type II collagen (Col2), a crucial structural protein in hyaline cartilage, is essential for cartilage integrity and facilitating injury repair. However, research on recombinant type II collagen still faces many challenges, such as structure and yield, which limit the application of recombinant Col2 [...] Read more.

Type II collagen (Col2), a crucial structural protein in hyaline cartilage, is essential for cartilage integrity and facilitating injury repair. However, research on recombinant type II collagen still faces many challenges, such as structure and yield, which limit the application of recombinant Col2 in biomedical fields. In this study, we achieved high-yield expression of full-length human Col2 (rhCol2) in CHO cells. The physical and chemical properties of rhCol2 were very close to native Col2, including molecular weight, triple helix structure, thermal stability and self-assembly capacity. Functional assays of primary chondrocytes have demonstrated that rhCol2 can effectively promote chondrocyte proliferation and increase the expression levels of cartilage-specific genes (Col2a1, Aggrecan, and Sox-9). Moreover, a cartilage defect model was surgically created in SD rats demonstrated that rhCol2 significantly enhanced cartilage repair, and the severity of the defect was assessed through histological and micro-CT analyses. Human chondrocytes were utilized to compare the effects of different collagens and verified through a series of functional experiments. In conclusion, these findings indicate that rhCol2 is an effective biomaterial and is expected to promote the application of recombinant collagen in the field of cartilage repair. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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20 pages, 1105 KB

Open AccessArticle

Does Genetic Variation in Detoxification Capacity Influence Hepatic Biomarker Responses to a Liver Support Supplementation Regimen?

by Markus Schauer, Susanne Mair, Michael Keiner, Christian Werner, Florian Kainz and Mohamad Motevalli

Int. J. Mol. Sci. 2025, 26(20), 10209; https://doi.org/10.3390/ijms262010209 - 20 Oct 2025

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Abstract

Genetic polymorphisms contribute to inter-individual variation in liver detoxification, influencing susceptibility to exposures and responses to interventions. While urinary biomarkers reflect Phase II activity, the impact of genotype on supplementation response remains unclear. In a pilot, prospective, open-label cohort study, 30 Austrian adults [...] Read more.

Genetic polymorphisms contribute to inter-individual variation in liver detoxification, influencing susceptibility to exposures and responses to interventions. While urinary biomarkers reflect Phase II activity, the impact of genotype on supplementation response remains unclear. In a pilot, prospective, open-label cohort study, 30 Austrian adults completed an 8-week multi-ingredient liver support supplementation regimen (e.g., glutathione, N-acetylcysteine, α-lipoic acid). First-morning urine was collected at baseline and follow-up for measurement of D-glucaric acid, mercapturic acids, and creatinine. Dried blood spots were genotyped for polymorphisms in detoxification genes (CYP1A1, GSTM1, GSTP1, GSTT1, and NQO1), and participants were stratified into normal (NDC) or limited (LDC) detoxification capacity groups. Adherence was monitored through logs, mid-study interviews, and product counts. The intervention led to modest reductions in body weight (−0.87 kg, p < 0.05) and BMI (−0.31 kg/m², p < 0.05), and significant increases in urinary D-glucaric acid (p < 0.05) and mercapturic acids (p < 0.01), with consistent responses across detoxification genotype groups (p > 0.05). The pattern of biomarker responses based on clinically defined categories did not differ significantly between the study groups (adjusted odds ratio = 2.88, p > 0.05). The observed increases in urinary biomarkers and reductions in weight and BMI are consistent with potential modulation of detoxification pathways following liver support supplementation, independent of genetic polymorphisms influencing detoxification capacity. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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13 pages, 334 KB

Open AccessArticle

The Prevalence of Second Neoplasms in Patients with Non-Aldosterone Producing Adrenocortical Lesions

by Paraskevi Tripolitsioti, Ariadni Spyroglou, Odysseas Violetis, Panagiota Konstantakou, Eleni Chouliara, Grigoria Betsi, Konstantinos Iliakopoulos, Eleni Memi, Konstantinos Bramis, Denise Kolomodi, Paraskevi Xekouki, Manousos Konstadoulakis, George Mastorakos and Krystallenia I Alexandraki

Int. J. Mol. Sci. 2025, 26(20), 10167; https://doi.org/10.3390/ijms262010167 - 19 Oct 2025

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Abstract

Over the last few decades, due to improvement in imaging techniques, the increased detection of adrenal incidentalomas is observed. Non-aldosterone producing adrenal adenomas (NAPACAs) often co-exist with second benign or malignant lesions. In the present study, we aimed to assess the presence of [...] Read more.

Over the last few decades, due to improvement in imaging techniques, the increased detection of adrenal incidentalomas is observed. Non-aldosterone producing adrenal adenomas (NAPACAs) often co-exist with second benign or malignant lesions. In the present study, we aimed to assess the presence of second neoplasms, both benign and malignant, in patients with NAPACAs, and to investigate possible correlations with clinical parameters, hormonal characteristics and the emergence of comorbidities. A total of 130 NAPACA patients were included in this single-center retrospective study. In this cohort, 35.4% of NAPACA patients carried any second neoplasm (either benign or malignant) whereas, 26.9% had a second malignant neoplasm. Cortisol levels after 1 mg overnight dexamethasone suppression test (F-ODS) were significantly higher in patients without a second neoplasm (p = 0.02), and this finding was consistent even when categorizing patients with and without malignancies (p = 0.02). In line with this observation, ACTH/F-ODS levels were significantly higher in patients with second malignancies (p < 0.05). Interestingly, the presence of mild autonomous cortisol secretion tended to be lower in patients with second malignancies (p = 0.08). No remarkable differences in the comorbidities of NAPACA patients with and without a second neoplasm were documented. Further prospective studies will be needed to elucidate the role of mild hypercortisolemia on the development of these second tumors in NAPACA patients. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 1827 KB

Open AccessArticle

Utility of Serum HBV RNA Measurement During Nucleoside/Nucleotide Analog Therapy in Chronic Hepatitis B Patients

by Keiichi Hiraoka, Masataka Tsuge, Michihiko Kawahara, Hatsue Fujino, Yasutoshi Fujii, Atsushi Ono, Eisuke Murakami, Tomokazu Kawaoka, Daiki Miki, C. Nelson Hayes, Seiya Kashiyama, Sho Mokuda, Shinichi Yamazaki and Shiro Oka

Int. J. Mol. Sci. 2025, 26(20), 10141; https://doi.org/10.3390/ijms262010141 - 18 Oct 2025

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Abstract

Hepatitis B virus (HBV) particles containing HBV RNA are secreted into the blood; these RNA-containing particles are non-infectious byproducts of the replication cycle and are distinct from mature, DNA-containing virions. The proportion of these particles increases during nucleoside/nucleotide analog therapy, but the clinical [...] Read more.

Hepatitis B virus (HBV) particles containing HBV RNA are secreted into the blood; these RNA-containing particles are non-infectious byproducts of the replication cycle and are distinct from mature, DNA-containing virions. The proportion of these particles increases during nucleoside/nucleotide analog therapy, but the clinical significance of serum HBV RNA remains unclear. We evaluated longitudinal changes in serum HBV RNA and their association with the antiviral efficacy of nucleoside/nucleotide analog therapy. Eighty-six patients with chronic HBV infection (baseline HBV DNA ≥ 5.0 Log IU/mL and ALT < 500 U/L) treated with entecavir (ETV, N = 80) or tenofovir alafenamide (TAF, N = 6) were included. Serum HBV RNA was quantified using Cobas HBV RNA (RUO) at baseline, week 12, and week 48. Associations with clinical variables and treatment response were analyzed. Baseline HBV RNA correlated with HBsAg, HBV DNA, and hepatitis B core-related antigen. Both HBV DNA and RNA tended to decrease with advanced liver fibrosis. HBV DNA and RNA declines did not differ between HBeAg-positive and -negative patients, but the HBV RNA/DNA ratio at week 48 was significantly higher in HBeAg-positive cases (p < 0.001). Patients with baseline ALT ≥ 100 U/L showed significantly lower RNA levels at weeks 12 and 48 (p = 0.004, p < 0.001). While HBV DNA decline was similar between ETV and TAF (p = 0.076), RNA decline was significantly greater with TAF at week 12 (p = 0.027). Serum HBV RNA reflects intrahepatic viral replication and may not be influenced by fibrosis progression. HBV RNA decline during nucleoside/nucleotide analog therapy differed between ETV and TAF, suggesting drug-specific effects on viral RNA dynamics. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 9834 KB

Open AccessArticle

Cardiac Troponin I Antibodies Induce Cardiomyocyte Damage and Alter Cell Morphology

by Jennifer Furkel, Vanessa A. Zirkenbach, Maximilian Knoll, Renate Öttl, Katrin Rein, Amir Abdollahi, Norbert Frey, Mathias H. Konstandin and Ziya Kaya

Int. J. Mol. Sci. 2025, 26(20), 10005; https://doi.org/10.3390/ijms262010005 - 14 Oct 2025

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Abstract

Circulating heart-reactive autoantibodies (aAbs) detected in a variety of heart diseases (e.g., myocarditis, dilated cardiomyopathy, and myocardial infarction) have been associated with the progression of heart failure and a poor prognosis. However, the underlying mechanisms remain largely unknown. We investigated the effects of [...] Read more.

Circulating heart-reactive autoantibodies (aAbs) detected in a variety of heart diseases (e.g., myocarditis, dilated cardiomyopathy, and myocardial infarction) have been associated with the progression of heart failure and a poor prognosis. However, the underlying mechanisms remain largely unknown. We investigated the effects of murine plasma containing aAbs against cardiac troponin I (cTnI) on neonatal rat cardiomyocytes (NRCMs). An autoimmune response to cTnI in A/J mice was induced, and anti-cTnI-aAbs were quantified. After 21 days, cardiac function, inflammation, fibrosis, and apoptosis were evaluated. In complementary in vitro liquid biopsy experiments, NRCMs were incubated with murine plasma containing high anti-cTnI-aAb levels or corresponding controls. Morphological phenotyping was performed using the C-MORE fluorescent image-based analysis workflow. Immunization with cTnI resulted in high anti-cTnI-aAb production, followed by myocardial inflammation, fibrosis, and impaired ejection fraction. NRCMs exposed to anti-cTnI-aAb-containing plasma showed reduced cell size, altered shape and radius, and elevated rate of dead cells in cell cycle analysis (p < 0.01, for 20% plasma). Together, these findings suggest a direct interaction of anti-cTnI-aAbs on cardiomyocytes, likely promoting adverse myocardial remodeling in vivo. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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29 pages, 4696 KB

Open AccessArticle

Exploring the Role of Heat Shock Proteins in Neuroimmune Modulation in Rheumatoid Arthritis: Insights from a Rat Model

by Malak Fouani, Federica Scalia, Giuseppe Donato Mangano, Francesca Rappa, Wassim Abou-Kheir, Angelo Leone, Nada Lawand and Rosario Barone

Int. J. Mol. Sci. 2025, 26(19), 9743; https://doi.org/10.3390/ijms26199743 - 7 Oct 2025

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Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joints, with neurogenic inflammation involving the nervous system being a hallmark of the condition. Treatments include medications such as disease-modifying antirheumatic drugs (DMARDs), corticosteroids, and biologics targeting inflammatory pathways. Yet, these treatments [...] Read more.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joints, with neurogenic inflammation involving the nervous system being a hallmark of the condition. Treatments include medications such as disease-modifying antirheumatic drugs (DMARDs), corticosteroids, and biologics targeting inflammatory pathways. Yet, these treatments are not curative for RA. Heat Shock Proteins (HSPs) are molecular chaperones with immunoregulatory properties; however, their role is not yet fully understood, as these molecules may play a dual, pro- and anti-inflammatory role. In this study, we evaluated the protein expression levels of HSPs 27, 60, 70, and 90 in the synovial membrane and spinal cord of the RA rats’ model to determine their roles during the disease course, both on the neurological and immunological levels. Furthermore, HSP levels have been evaluated in the spinal cord of control and RA rats’ model after high and low doses of ketamine injection. Significant changes in Hsp60, 70, and 90 expression levels were observed only in the spinal cord of RA rats. We demonstrated that blocking N-methyl-D-aspartate receptors with ketamine can modulate spinal cord HSPs expression in RA rats and subsequently impact neurogenic inflammation and adult neurogenesis. This suggests that HSPs may be a promising target for RA treatment due to their complex immunomodulatory effects and potential interactions with the nervous system. Further research is needed to explore their therapeutic potential and develop effective interventions for RA. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 3367 KB

Open AccessArticle

Effect of Chronic Social Defeat Stress on the Small-Intestinal Environment, Including the Gut Flora, Immune System, and Mucosal Barrier Integrity

by Soichi Yagi, Hirokazu Fukui, Tetsuya Shiraishi, Koji Kaku, Midori Wakita, Yasuhiro Takagi, Maiko Ikenouchi, Toshiyuki Sato, Mikio Kawai, Yoko Yokoyama, Tetsuya Takagawa, Toshihiko Tomita, Shiho Kitaoka and Shinichiro Shinzaki

Int. J. Mol. Sci. 2025, 26(19), 9359; https://doi.org/10.3390/ijms26199359 - 25 Sep 2025

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Abstract

Psychological stress is deeply involved in the pathophysiology of gastrointestinal diseases. We investigated the effect of psychological stress on the small-intestinal environment, including gut flora, immune system, and mucosal integrity in mice subjected to chronic social defeat stress (CSDS). CSDS mice were established [...] Read more.

Psychological stress is deeply involved in the pathophysiology of gastrointestinal diseases. We investigated the effect of psychological stress on the small-intestinal environment, including gut flora, immune system, and mucosal integrity in mice subjected to chronic social defeat stress (CSDS). CSDS mice were established by exposing a C57BL/6N mouse to an ICR aggressor mouse. Stool samples were obtained to investigate its properties and the gut microbiome profile. Using small-intestinal tissues, the expression of cytokines, antimicrobial peptides, and tight junction proteins (TJPs) were examined by real-time RT-PCR and immunohistochemistry. Small-intestinal permeability was evaluated by transepithelial electrical resistance assay. For stool properties, mean Bristol scale score and fecal water content were significantly lower in the CSDS group. Pseudomonadota and Patescibacteria were significantly more abundant in the stools from CSDS mice. Among TJPs and antimicrobial peptides, the expression of Occludin, Claudin-4, and Regenerating gene IIIγ was significantly decreased in the small intestine epithelium of CSDS mice. The small-intestinal permeability was significantly increased in CSDS mice. Lipopolysaccharide immunoreactivity, the number of macrophages, and proinflammatory IL-1β expression were significantly increased in the small intestine of CSDS mice. These findings suggest that psychological stress is associated with mucosal barrier dysfunction and microinflammation in small-intestinal tissues. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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20 pages, 6242 KB

Open AccessArticle

Non-Canonical Compartmentalization of DROSHA Protein at the Golgi Apparatus: miRNA Biogenesis-Independent Functionality in Human Cancer Cells of Diverse Tissue Origin

by Eleni I. Theotoki, Panos Kakoulidis, Kostas A. Papavassiliou, Konstantinos-Stylianos Nikolakopoulos, Eleni N. Vlachou, Efthimia K. Basdra, Athanasios G. Papavassiliou, Ourania E. Tsitsilonis, Gerassimos E. Voutsinas, Athanassios D. Velentzas, Ema Anastasiadou and Dimitrios J. Stravopodis

Int. J. Mol. Sci. 2025, 26(19), 9319; https://doi.org/10.3390/ijms26199319 - 24 Sep 2025

Cited by 1 | Viewed by 3035

Abstract

DROSHA protein is widely known for its essential role in the microRNA (miRNA/miR) biogenesis pathway where, together with its co-factor DGCR8, it forms the “Microprocessor” complex and catalyzes the primary miRNA (pri-miRNA) processing in the nucleus. Nevertheless, DROSHA also seems to participate in [...] Read more.

DROSHA protein is widely known for its essential role in the microRNA (miRNA/miR) biogenesis pathway where, together with its co-factor DGCR8, it forms the “Microprocessor” complex and catalyzes the primary miRNA (pri-miRNA) processing in the nucleus. Nevertheless, DROSHA also seems to participate in several miRNA-independent cellular mechanisms, such as transcriptional regulation, RNA processing and genome integrity maintenance. Hence, the present study aims to further investigate novel miRNA-independent activities of DROSHA protein, with potentially regulatory roles in the oncogenesis of human cancer cells. Our results reveal a new, strong profile of microprocessor-independent DROSHA localization at the Golgi apparatus in several human cancer cell lines of different tissue origin, with hepatic carcinoma, thyroid cancer, urothelial bladder cancer, colon carcinoma and melanoma being the cellular model systems herein examined. Notably, oncogenic activity, malignancy grade and metastatic capacity are shown to be strongly associated with DROSHA’s compartmentalization at Golgi, a phenotype that does not seem to rely on p53 protein’s functionality. Taken together, through employment of advanced confocal laser scanning microscopy (CLSM) and molecular modeling, we herein unveil the ability of DROSHA, but not AGO2 and DICER, to reside at Golgi, where DROSHA can physically interact with the GM130 Golgi-specific component, thus indicating DROSHA’s engagement in non-canonical and miRNA-independent—but also Golgi apparatus-dependent—novel mechanisms that can be tightly coupled with malignancy dynamics and beneficially utilized as potential biomarkers and therapeutic targets for human cancer. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 6419 KB

Open AccessArticle

Lactiplantibacillus plantarum HY7715 Alleviates Restraint Stress-Induced Anxiety-like Behaviors by Modulating Oxidative Stress, Apoptosis, and Mitochondrial Function

by Kippuem Lee, Daehyeop Lee, Haeryn Jeong, Joo Yun Kim, Jae Jung Shim and Jae Hwan Lee

Int. J. Mol. Sci. 2025, 26(18), 9251; https://doi.org/10.3390/ijms26189251 - 22 Sep 2025

Viewed by 784

Abstract

Anxiety disorders are closely associated with oxidative stress-mediated neuronal damage, mitochondrial dysfunction, and apoptosis. In this study, we investigated the neuroprotective effects of Lactiplantibacillus plantarum HY7715 in a mouse model of restraint stress-induced anxiety, and in neuronal cell models (HT-22 mouse hippocampal neuroblast [...] Read more.

Anxiety disorders are closely associated with oxidative stress-mediated neuronal damage, mitochondrial dysfunction, and apoptosis. In this study, we investigated the neuroprotective effects of Lactiplantibacillus plantarum HY7715 in a mouse model of restraint stress-induced anxiety, and in neuronal cell models (HT-22 mouse hippocampal neuroblast cell and SH-SY5Y human neuroblastoma cells). Oral administration of HY7715 (1 × 10⁹ CFU/kg/day) alleviated anxiety-like behaviors significantly, as shown by increased central exploration in the open field test and prolonged open-arm activity in the elevated plus maze. HY7715 reduced serum norepinephrine levels elevated by stress, and restored hippocampal expression of brain-derived neurotrophic factor, while suppressing pro-inflammatory (NF-κB, IL-6) and pro-apoptotic (BAX, caspase-3) markers. It also increased expression of mitochondrial regulatory genes (SIRT1, mTOR), and decreased that of cytochrome c, in brain tissue. Histological analysis revealed that HY7715 preserved neuronal integrity in the CA1 and CA3 hippocampal regions. In vitro, HY7715 attenuated oxidative stress-induced cytotoxicity, decreased intracellular ROS accumulation, maintained mitochondrial activity, and inhibited apoptosis of both neuronal cell types, showing greater efficacy than the strain type L. plantarum KCTC3108. These findings suggest that HY7715 exerts neuroprotective effects by modulating oxidative stress/apoptosis/mitochondrial pathways, and highlight its potential as a psychobiotic for stress-related neuropsychiatric disorders. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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40 pages, 3769 KB

Open AccessArticle

Deciphering European Sea Bass (Dicentrarchus labrax) Resistance to Nervous Necrosis Virus by Transcriptome Analysis from Early Infection Towards Establishment of Virus Carrier State

by Dimitra K. Toubanaki, Odysseas-Panagiotis Tzortzatos, Antonia Efstathiou, Vasileios Bakopoulos and Evdokia Karagouni

Int. J. Mol. Sci. 2025, 26(18), 9220; https://doi.org/10.3390/ijms26189220 - 21 Sep 2025

Viewed by 930

Abstract

Viral nervous necrosis, caused by the nervous necrosis virus (NNV), is an important threat to aquaculture, causing great economic losses and a high environmental burden. European sea bass (Dicentrarchus labrax) is highly affected by NNV, and selective breeding programs for disease [...] Read more.

Viral nervous necrosis, caused by the nervous necrosis virus (NNV), is an important threat to aquaculture, causing great economic losses and a high environmental burden. European sea bass (Dicentrarchus labrax) is highly affected by NNV, and selective breeding programs for disease resistance have been established in order to achieve a sustainable aquaculture and minimize the need for vaccines, drugs and antibiotics. Resistant and susceptible European sea bass were experimentally challenged with NNV and their head kidney transcriptomes were analyzed at three time points, i.e., 3 hpi, 2 dpi and 14 dpi. Numerous differentially expressed genes (DEGs) were identified in the head kidneys of resistant and susceptible infected vs. non-infected sea bass. Gene ontology enrichment, pathway, and protein–protein interaction analyses revealed that the NNV-resistant fish control their response to viral infection more efficiently, utilizing different mechanisms compared to the susceptible fish. Resistant fish displayed higher levels of interferon-related elements, cytokines, antigen presentation, T-cell activity, apoptosis, and programmed cell death combined with a controlled inflammatory response and more active proteasome and lysosome functions. The susceptible fish appeared to have high immune responses at the early infection stages, accompanied by high expressions of inflammatory, complement and coagulation pathways. Insulin metabolism was better regulated in the resistant fish and the control of lipid metabolism was less effective in the susceptible family. The cytoskeleton- and cell adhesion-related pathways were mostly down-regulated in the susceptible fish, and the intracellular transport and motor proteins were utilized more efficiently by the resistant fish. The present study represents a thorough transcriptomic analysis of NNV infection effects on a resistant and a susceptible European sea bass head kidney. The obtained results provide valuable information on the mechanisms that offers pathogen resistance to a host, with many aspects that can be exploited to develop more efficient approaches to fighting viral diseases in aquaculture. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 1626 KB

Open AccessArticle

Temporal and Spatial Dynamics in the Regulation of Myocardial Metabolism During the Ischemia-Reperfusion Process

by Elena de Dios, Maria J. Forteza, Nerea Perez-Sole, Tamara Molina-Garcia, Jose Gavara, Victor Marcos-Garces, Manuel Jimenez-Navarro, Amparo Ruiz-Sauri, Cesar Rios-Navarro and Vicente Bodi

Int. J. Mol. Sci. 2025, 26(18), 8820; https://doi.org/10.3390/ijms26188820 - 10 Sep 2025

Cited by 1 | Viewed by 670

Abstract

Although cardiac metabolic adaptation has been observed in response to the ischemia–reperfusion, the specific temporal and spatial changes occurring in the main regulators of myocardial glucolipid metabolism in the infarcted heart have not been fully characterized. Myocardial infarction (MI) was induced in female [...] Read more.

Although cardiac metabolic adaptation has been observed in response to the ischemia–reperfusion, the specific temporal and spatial changes occurring in the main regulators of myocardial glucolipid metabolism in the infarcted heart have not been fully characterized. Myocardial infarction (MI) was induced in female swine by transient coronary occlusion. The study design consisted of one control and four MI groups (no reperfusion, 1 min, 1 week, and 1 month after reperfusion). Metabolites obtained from the coronary sinus were determined at baseline, during ischemia, and after coronary reperfusion. mRNA expression of genes related to beta-oxidation and glucose transport were quantified in the five experimental groups and in three myocardial regions (infarcted, adjacent, and remote). In the coronary sinus, reduced glucose and increased lactate levels were detected during ischemia and soon after reperfusion. However, non-esterified fatty acids increased during reperfusion. A general upregulation of genes implicated in glycolysis and beta-oxidation occurred during ischemia and few minutes after reperfusion. Contrarily, heightened mRNA expression of glucose transporters and decay in regulators of beta-oxidation were observed one week after coronary reperfusion. Glycolysis and beta-oxidation are activated during ischemia and few minutes after coronary reopening, while a shift from beta-oxidation to glycolysis is evidenced a few days afterwards. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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27 pages, 3474 KB

Open AccessArticle

A ‘Spicy’ Mechanotransduction Switch: Capsaicin-Activated TRPV1 Receptor Modulates Osteosarcoma Cell Behavior and Drug Sensitivity

by Arianna Buglione, David Becerril Rodriguez, Simone Dogali, Giulia Alloisio, Chiara Ciaccio, Marco Luce, Stefano Marini, Luisa Campagnolo, Antonio Cricenti and Magda Gioia

Int. J. Mol. Sci. 2025, 26(18), 8816; https://doi.org/10.3390/ijms26188816 - 10 Sep 2025

Cited by 1 | Viewed by 1002

Abstract

Osteosarcoma (OS), the most common primary malignant bone tumor, arises in highly mechanosensitive tissue and exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. Here, we identify [...] Read more.

Osteosarcoma (OS), the most common primary malignant bone tumor, arises in highly mechanosensitive tissue and exhibits marked heterogeneity and resistance to conventional therapies. While molecular drivers have been extensively characterized, the role of mechanical stimuli in OS progression remains underexplored. Here, we identify the transient receptor potential vanilloid 1 (TRPV1) channel as a key regulator of mechanotransduction and drug responsiveness in OS cells. Using uniaxial cyclic stretch, we show that aggressive U-2 OS cells undergo TRPV1-dependent perpendicular reorientation, unlike the inert SAOS-2 cells. Confocal microscopy, immunohistochemistry, and atomic force microscopy reveal that nanomolar concentrations of capsaicin—a well-characterized TRPV1 agonist—chemically mimic this mechanical phenotype, altering metastatic traits including adhesion, edge architecture, migration, nuclear-to-cytoplasmic ratio, and sensitivity to doxorubicin and cisplatin. TRPV1 activation, whether mechanical or chemical, induces subtype-specific effects absent in healthy hFOB osteoblasts. Notably, it differentially regulates nuclear localization of the proto-oncogene Src in U-2 OS versus SAOS-2 cells. Corresponding changes in Src and acetylated histone H3 (acH3) levels support a role for TRPV1 in modulating the Src–acH3 mechanosignaling axis. These effects are tumor-specific, positioning TRPV1 as a mechanosensitive signaling hub that integrates mechanical and chemical cues to drive epigenetic remodeling and phenotypic plasticity in OS, with potential as a therapeutic target in aggressive, drug-resistant subtypes Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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21 pages, 2258 KB

Open AccessArticle

Neurotransmitter Genes in the Nucleus Accumbens That Are Involved in the Development of a Behavioral Pathology After Positive Fighting Experiences and Their Deprivation: A Conceptual Paradigm for Data Analysis

by Natalia N. Kudryavtseva, Dmitry A. Smagin, Olga E. Redina, Irina L. Kovalenko, Anna G. Galyamina and Vladimir N. Babenko

Int. J. Mol. Sci. 2025, 26(17), 8580; https://doi.org/10.3390/ijms26178580 - 3 Sep 2025

Viewed by 920

Abstract

It has been shown previously that repeated positive fighting experience in daily agonistic interactions is accompanied by the development of psychosis-like behavior, with signs of an addiction-like state associated with changes in the expression of genes encoding the proteins involved in the main [...] Read more.

It has been shown previously that repeated positive fighting experience in daily agonistic interactions is accompanied by the development of psychosis-like behavior, with signs of an addiction-like state associated with changes in the expression of genes encoding the proteins involved in the main neurotransmitter events in some brain regions of aggressive male mice. Fighting deprivation (a no-fight period of 2 weeks) causes a significant increase in their aggressiveness. This paper is aimed at studying—after a period of fighting deprivation—the involvement of genes (associated with neurotransmitter systems within the nucleus accumbens) in the above phenomena. The nucleus accumbens is known to participate in reward-related mechanisms of aggression. We found the following differentially expressed genes (DEGs), whose expression significantly differed from that in controls and/or mice with positive fighting experience in daily agonistic interactions followed by fighting deprivation: catecholaminergic genes Th, Drd1, Drd2, Adra2c, Ppp1r1b, and Maoa; serotonergic genes Maoa, Htr1a, Htr1f, and Htr3a; opioidergic genes Oprk1, Pdyn, and Penk; and glutamatergic genes Grid1, Grik4, Grik5, Grin3a, Grm2, Grm5, Grm7, and Gad1. The expression of DEGs encoding proteins of the GABAergic system in experienced aggressive male mice mostly returned to control levels after fighting deprivation, except for Gabra5. In light of the conceptual paradigm for analyzing data that was chosen in our study, the aforementioned DEGs associated with the behavioral pathology can be considered responsible for consequences of aggression followed by fighting deprivation, including mechanisms of an aggression relapse. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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13 pages, 802 KB

Open AccessArticle

Salivary Protein Profile in Patients with Recurrent Aphthous Stomatitis: A Pilot Proteomic Study

by Francesco Franco, Nima Namarvari, Alessio Gambino, Federica Romano, Barbara Pergolizzi, Jianjian Zhang, Giuliana Abbadessa, Barbara Mognetti, Adriano Ceccarelli, Paolo Giacomo Arduino and Giovanni Nicolao Berta

Int. J. Mol. Sci. 2025, 26(16), 7878; https://doi.org/10.3390/ijms26167878 - 15 Aug 2025

Viewed by 951

Abstract

Recurrent aphthous stomatitis (RAS) is the most common ulcerative disorder of the oral cavity, although its etiology is still unknown. The present study aimed to identify the proteomic profile associated with the RAS inflammatory process, thereby enhancing our understanding of its etiopathogenesis. We [...] Read more.

Recurrent aphthous stomatitis (RAS) is the most common ulcerative disorder of the oral cavity, although its etiology is still unknown. The present study aimed to identify the proteomic profile associated with the RAS inflammatory process, thereby enhancing our understanding of its etiopathogenesis. We compared salivary protein profiles of RAS patients during an active episode of oral ulceration (30 patients, mean age 36.9) to those from healthy donors without a history of RAS (30 healthy subjects, mean age 37.9). Using 2D-electrophoresis and mass spectrometry (MALDI-TOF) analysis, we identified 17 proteins that were differentially expressed in the two groups. Notably, Cystatin SN (CST1) appeared to be significantly downregulated in RAS patients. These findings were validated by Western blot analysis: CST1 was detected in only 3 of the 30 RAS cases, while it was strongly expressed in all the healthy subjects. Although preliminary, our results suggest a potential role for CST1 in the etiopathogenesis of RAS. Interestingly, the relative absence of CST1 in RAS patients seems to align with some clinical and molecular features of this disease. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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Review

Jump to: Research

36 pages, 2407 KB

Open AccessReview

Emerging Breast Cancer Subpopulations: Functional Heterogeneity Beyond the Classical Subtypes

by Amalia Kotsifaki, Georgia Kalouda, Efthymios Karalexis, Martha Stathaki, Georgios Metaxas and Athanasios Armakolas

Int. J. Mol. Sci. 2025, 26(23), 11599; https://doi.org/10.3390/ijms262311599 - 29 Nov 2025

Viewed by 105

Abstract

Breast cancer (BC) is increasingly recognized as a heterogeneous disease, with complexity that extends beyond the classical luminal A/B, HER2-enriched, and triple-negative framework. Advances in molecular and functional profiling have uncovered emerging subpopulations, including HER2-low, claudin-low, BRCA-deficient (“BRCAness”), and refined TNBC subsets, such [...] Read more.

Breast cancer (BC) is increasingly recognized as a heterogeneous disease, with complexity that extends beyond the classical luminal A/B, HER2-enriched, and triple-negative framework. Advances in molecular and functional profiling have uncovered emerging subpopulations, including HER2-low, claudin-low, BRCA-deficient (“BRCAness”), and refined TNBC subsets, such as luminal AR (LAR) and basal-like immune variants, that extend beyond traditional taxonomies. These novel classifications provide additional resolutions, offering both prognostic insight and therapeutic opportunities. In this comprehensive review, we integrate evidence from genomic, epigenetic, proteomic, immune-related, and liquid biopsy biomarkers, underscoring how they define the biology of these subgroups and predict responses to targeted therapies, such as antibody–drug conjugates, PARP inhibitors, and immune checkpoint blockade. We further highlight the role of the tumor microenvironment (TME) and intratumoral heterogeneity in shaping these entities. Collectively, recognition of emerging subtypes as clinically actionable groups represents a paradigm shift from static receptor-based models to dynamic, biomarker-driven frameworks that refine prognosis, enable patient stratification, and support precision oncology in aggressive BC. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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27 pages, 1578 KB

Open AccessReview

Comprehensive Liquid Biopsy Approaches for the Clinical Management of Lung Cancer Using Multiple Biological Matrices

by Areti Strati, Martha Zavridou, Kostas A. Papavassiliou and Athanasios G. Papavassiliou

Int. J. Mol. Sci. 2025, 26(23), 11304; https://doi.org/10.3390/ijms262311304 - 22 Nov 2025

Viewed by 296

Abstract

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related mortality in both men and women. It is broadly classified into two main histological subtypes, with non-small cell lung cancer (NSCLC) being the most prevalent, accounting for approximately 85–90% [...] Read more.

Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related mortality in both men and women. It is broadly classified into two main histological subtypes, with non-small cell lung cancer (NSCLC) being the most prevalent, accounting for approximately 85–90% of all cases. Liquid biopsy refers to the analysis of tumor-derived material circulating in body fluids. This minimally invasive technique can be performed repeatedly over time and enables the detection of a tumor’s genomic profile without tissue samples. Liquid biopsies have the potential to identify biomarkers across different lung cancer subtypes that may be associated with early detection, prognosis, and prediction of response to targeted therapies. In this context, bioinformatics tools play a critical role in analyzing large-scale, high-dimensional omics datasets, which can be transformed into clinically meaningful insights. This article emphasizes the significance of prognostic, predictive, and diagnostic biomarkers in lung cancer, which can be detected in various biological fluids. Furthermore, it highlights how integrating bioinformatics approaches can facilitate the development of a personalized molecular profile, ultimately supporting individualized treatment strategies for each patient. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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28 pages, 1765 KB

Open AccessReview

The Role of mRNA Alternative Processing in Mammalian Neurodevelopment

by Xian Liu, Jian Zuo, Guicheng Zhang, Xiaoyu Han and Yao Tian

Int. J. Mol. Sci. 2025, 26(22), 11075; https://doi.org/10.3390/ijms262211075 - 16 Nov 2025

Viewed by 519

Abstract

The mammalian brain undergoes a series of orderly developmental events, including neurogenesis, neuronal migration, axon guidance, and synaptic connection. These neurodevelopmental mechanisms have traditionally been characterized through studies focused on transcriptional control; however, a growing body of evidence highlights the critical roles of [...] Read more.

The mammalian brain undergoes a series of orderly developmental events, including neurogenesis, neuronal migration, axon guidance, and synaptic connection. These neurodevelopmental mechanisms have traditionally been characterized through studies focused on transcriptional control; however, a growing body of evidence highlights the critical roles of co- or post-transcriptional steps like alternative splicing, alternative polyadenylation, and RNA chemical modification in orchestrating brain development. This review discusses the recent progress made toward understanding the influence of alternative mRNA processing on neurodevelopment, including three aspects: the key mRNA processing events that drive neuronal differentiation from stem/progenitor cells; the regulatory mechanisms that govern cell-type and stage-specific mRNA-processing patterns; and the neuropathological consequences of mRNA-processing dysregulation. By integrating these insights, we aim to deepen the understanding of how mRNA alternative processing influences neurodevelopment and its implications for neurological health. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 544 KB

Open AccessReview

MicroRNAs in Uterine Leiomyosarcoma: From Molecular Mechanisms to Clinical Applications

by Areti Kourti, Ioannis Kalogiannidis, Kali Makedou and Elisavet Georgiou

Int. J. Mol. Sci. 2025, 26(22), 10952; https://doi.org/10.3390/ijms262210952 - 12 Nov 2025

Viewed by 313

Abstract

Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive malignancy of uterine smooth muscle, associated with early metastasis, frequent recurrence, and poor prognosis. Accurate preoperative diagnosis remains difficult given that clinical and radiologic features often overlap with benign leiomyomas, and no reliable biomarkers are [...] Read more.

Uterine leiomyosarcoma (uLMS) is a rare, highly aggressive malignancy of uterine smooth muscle, associated with early metastasis, frequent recurrence, and poor prognosis. Accurate preoperative diagnosis remains difficult given that clinical and radiologic features often overlap with benign leiomyomas, and no reliable biomarkers are currently available. This review summarizes recent evidence on the role of microRNAs (miRNAs) in the biology and clinical management of uLMS. Literature from molecular and translational studies was examined to identify dysregulated miRNAs, their target pathways, and potential diagnostic and therapeutic applications. uLMS displays a characteristic miRNA profile, including downregulation of tumor-suppressive miRNAs such as the miR-29 and miR-200 families and upregulation of oncogenic miRNAs including miR-21 and the miR-183~96~182 cluster, leading to activation of PI3K/AKT/mTOR signaling and epithelial–mesenchymal transition (EMT). Circulating and tissue miRNAs show promise as minimally invasive biomarkers for differentiating uLMS from leiomyomas, predicting prognosis, and guiding therapy. Emerging therapeutic approaches aim to restore the tumor-suppressive miRNAs or inhibit oncogenic ones using mimics or antagomiRs. Overall miRNAs represent critical regulators of uLMS pathogenesis and hold significant potential for precision diagnosis, prognostication, and targeted therapy, though larger validation studies and improved delivery systems are required before clinical translation. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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26 pages, 1431 KB

Open AccessReview

Molecular and Clinical Insights into TP53-Mutated MDS and AML

by Erotokritos Georgantzinos and Theodoros Karantanos

Int. J. Mol. Sci. 2025, 26(22), 10818; https://doi.org/10.3390/ijms262210818 - 7 Nov 2025

Viewed by 1525

Abstract

TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprise a distinct subgroup of myeloid neoplasms with unique biological and clinical features. The molecular alterations linked to TP53 mutations drive genomic instability and treatment resistance and ultimately lead to poor survival outcomes. [...] Read more.

TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprise a distinct subgroup of myeloid neoplasms with unique biological and clinical features. The molecular alterations linked to TP53 mutations drive genomic instability and treatment resistance and ultimately lead to poor survival outcomes. The disease biology is further shaped by alterations in immune response within the bone marrow microenvironment and significant changes in cellular metabolism. Conventional treatments, including chemotherapy and hypomethylating agents +/− venetoclax, offer limited benefit, with high relapse rates and short remissions. Allogeneic bone marrow transplantation is the only curative approach, but the vast majority of patients relapse. Novel therapeutic approaches—ranging from p53 reactivation strategies to immunotherapy and targeted inhibition of specific signaling pathways—are under active investigation. Our review summarizes current knowledge on the molecular pathogenesis, prognostic implications, and therapeutic landscape of TP53-mutated MDS/AML and discusses ongoing challenges and opportunities for improving patient outcomes. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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13 pages, 1931 KB

Open AccessReview

Factor VII-Activating Protease (FSAP) and Its Importance in Hemostasis—Part II: A Link Between FSAP, Blood Coagulation, and Fibrinolysis: A Narrative Review

by Iga Schachta, Ewa Żekanowska, Jan Styczyński, Joanna Murawska, Simona Lattanzi, Andrea M. Alexandre and Artur Słomka

Int. J. Mol. Sci. 2025, 26(21), 10709; https://doi.org/10.3390/ijms262110709 - 3 Nov 2025

Viewed by 406

Abstract

As a continuation of Part I on the structure and regulation of factor VII-activating protease (FSAP), this narrative review synthesizes mechanistic, translational, and limited clinical evidence to delineate FSAP’s roles at the interface of coagulation and fibrinolysis. Current evidence indicates that FSAP enhances [...] Read more.

As a continuation of Part I on the structure and regulation of factor VII-activating protease (FSAP), this narrative review synthesizes mechanistic, translational, and limited clinical evidence to delineate FSAP’s roles at the interface of coagulation and fibrinolysis. Current evidence indicates that FSAP enhances thrombin generation primarily via proteolytic inactivation of tissue factor pathway inhibitor (TFPI), whereas direct activation of factor VII (FVII) by FSAP appears weak or context-restricted. Beyond plasma proteins, FSAP can upregulate tissue factor (TF) in human macrophages, while platelet-related effects remain insufficiently substantiated. On the fibrinolytic axis, FSAP indirectly accelerates clot lysis by converting single-chain urokinase (scuPA) to its active two-chain form (tcuPA) and, less efficiently, by processing tissue-type plasminogen activator (tPA); in addition, selective cleavage of fibrinogen Aα and Bβ chains remodels clot architecture, yielding thinner fibers with higher density and increased susceptibility to proteolysis. Collectively, the data position FSAP as a context-sensitive modulator of thrombin generation and fibrin turnover. Key gaps include isoform specificity, in vivo cellular targets, and the quantitative contribution of the FSAP-TFPI and FSAP–fibrinogen–urokinase/tPA axes in human pathophysiology, which warrant focused mechanistic and clinical studies. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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22 pages, 862 KB

Open AccessReview

Diagnostic Value of Serum Biomarkers in Endocrine Dysfunction, Neuronal Injury, and Inflammation Following Traumatic Brain Injury

by Maria Bouta and Martha Assimakopoulou

Int. J. Mol. Sci. 2025, 26(21), 10702; https://doi.org/10.3390/ijms262110702 - 3 Nov 2025

Viewed by 472

Abstract

Traumatic brain injury (TBI) constitutes one of the primary causes of mortality globally. While many survivors fully recover, others experience several chronic complications that, if left untreated, negatively affect the patient’s quality of life. Among these, post-traumatic hypopituitarism (PTHP) represents a common yet [...] Read more.

Traumatic brain injury (TBI) constitutes one of the primary causes of mortality globally. While many survivors fully recover, others experience several chronic complications that, if left untreated, negatively affect the patient’s quality of life. Among these, post-traumatic hypopituitarism (PTHP) represents a common yet poorly recognized condition. The subtle, non-specific nature of pituitary dysfunction symptomatology, its overlap with similar disorders subsequent to TBI, and the lack of sensitive diagnostic tools are the main factors resulting in underdiagnosis of PTHP. The aim of this review is to summarize the existing knowledge, potential clinical utility, and limitations of serum biomarkers that may serve as reliable, minimally invasive tools for assessing pituitary function in the post-TBI period or even predicting late-onset deficiencies. These biomarkers, originating from neuronal damage or the inflammatory response following pituitary injury, can be co-evaluated with basal levels of pituitary and target organs hormones to accurately establish the diagnosis of the condition. Additionally, this review also provides an overview of emerging biomarkers that are currently under investigation and may be incorporated into clinical practice in the future. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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28 pages, 1429 KB

Open AccessReview

Natural Compounds Targeting MAPK, PI3K/Akt, and JAK/STAT Signaling in Papillary Thyroid Cancer

by Michelle Carnazza, Nan Yang, Raj K. Tiwari, Jan Geliebter and Xiu-Min Li

Int. J. Mol. Sci. 2025, 26(21), 10498; https://doi.org/10.3390/ijms262110498 - 29 Oct 2025

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Abstract

Thyroid cancer (TC) represents the most prevalent endocrine malignancy, with papillary thyroid cancer (PTC) comprising approximately 80% of cases and accounting for the majority of annual incidence and mortality. PTC is generally confined to the thyroid gland and demonstrates an excellent prognosis after [...] Read more.

Thyroid cancer (TC) represents the most prevalent endocrine malignancy, with papillary thyroid cancer (PTC) comprising approximately 80% of cases and accounting for the majority of annual incidence and mortality. PTC is generally confined to the thyroid gland and demonstrates an excellent prognosis after surgery, with a five-year survival rate exceeding 90%. Nevertheless, recurrence can occur, and the ten-year survival rate for the advanced PTC is below 50%. Even after effective successful surgical intervention, many still require ongoing surveillance, additional treatment, and lifelong thyroid hormone replacement, while facing the potential adverse effects such as hormone fluctuations, surgical complications, and sequelae of radioactive iodine exposure. Naturally occurring compounds have demonstrated anti-cancer properties and hence the potential to be used as therapeutic options, impacting the same drivers and pathways involved in the tumorigenesis of thyroid cancer. This narrative review focuses on the natural compounds’ convergence on molecular nodes of PI3K/Akt, MAPK, and JAK/STAT to overcome therapeutic resistance and restore apoptosis, highlighting their potential in advanced and recurrent PTC. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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26 pages, 4226 KB

Open AccessReview

Molecular Mechanisms of the Microbiota–Gut–Brain Axis in the Onset and Progression of Stroke

by Javier Caballero-Villarraso, Sara Pons-Villarta, Jerónimo Cruces-Párraga, Ainoa Navarrete-Pérez, Antonio Camargo, Juan Antonio Moreno, Isaac Túnez and Eduardo Agüera-Morales

Int. J. Mol. Sci. 2025, 26(20), 10071; https://doi.org/10.3390/ijms262010071 - 16 Oct 2025

Cited by 1 | Viewed by 1421

Abstract

The bidirectional relationship between the brain and gut microbiota has led to the concept of the microbiota–gut–brain axis. It refers to a system of bilateral communication that integrates neuronal, immunological, and metabolic signals, whose disruption has been linked to the pathogenesis of digestive, [...] Read more.

The bidirectional relationship between the brain and gut microbiota has led to the concept of the microbiota–gut–brain axis. It refers to a system of bilateral communication that integrates neuronal, immunological, and metabolic signals, whose disruption has been linked to the pathogenesis of digestive, metabolic, and neurological disorders, among others. Intestinal dysbiosis (an imbalance in the gut microbiota) can promote a proinflammatory and prothrombotic state, as well as dyslipidaemia and dysglycemia, that increase atherogenic risk and consequently the risk of stroke. Dysbiosis can also lead to neuroinflammatory and neurodegenerative effects, compromising the integrity of the blood–brain barrier and exacerbating brain injury after stroke. Specific bacterial profiles have been associated with varying levels of stroke risk, emphasising the role of gut microbiota-derived vasoactive metabolites such as Trimethylamine N-Oxide (TMAO), phenylacetylglnutamine (PAGln), and short-chain fatty acids (SCFAs), which may serve as biomarkers for stroke risk and severity. Gut microbiota also influences neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF), involved in recovery after stroke. Research has explored the potential to modify the gut microbiota to either prevent stroke (by reducing risk) or improve outcomes (by decreasing severity and sequelae). Current scientific evidence supports the role of gut microbiota as a potential diagnostic and prognostic biomarker, as well as a therapeutic target. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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17 pages, 1827 KB

Open AccessReview

The Role of Cadherin 17 (CDH17) in Cancer Progression via Wnt/β-Catenin Signalling Pathway: A Systematic Review and Meta-Analysis

by Bipusha Tha Shrestha, Yahui Feng, Aaron Lad, Anthony Bates, Jing Chen, Karen Brown, Feier Zeng and Ning Wang

Int. J. Mol. Sci. 2025, 26(20), 9838; https://doi.org/10.3390/ijms26209838 - 10 Oct 2025

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Abstract

Cadherin 17 (CDH17) is a cell adhesion glycoprotein essential for epithelial integrity. It is frequently overexpressed in various cancers, where it is associated with aggressive behaviour. While evidence indicates that CDH17 functions as an upstream regulator of Wnt/β-catenin signalling, findings are inconsistent across [...] Read more.

Cadherin 17 (CDH17) is a cell adhesion glycoprotein essential for epithelial integrity. It is frequently overexpressed in various cancers, where it is associated with aggressive behaviour. While evidence indicates that CDH17 functions as an upstream regulator of Wnt/β-catenin signalling, findings are inconsistent across tumour types, limiting the assessment of CDH17 as a biomarker or therapeutic target for Wnt pathway in cancer. In this study, we systematically review and meta-analyse the relationship between CDH17 and Wnt/β-catenin signalling in human cancers and evaluate whether CDH17 modulation affects tumour behaviour through Wnt-related mechanisms. Our search of Medline, Web of Science and Scopus identified five studies examining CDH17 expression in the Wnt/β-catenin pathway in vitro and in vivo. All five studies identified CDH17 as a key driver of canonical Wnt signalling, directly influencing cancer progression in hepatocellular carcinoma (HCC), gastric cancer (GC), and colorectal cancer (CRC). Meta-analysis (MA) showed that CDH17 inhibition consistently reduced Wnt/β-catenin downstream T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcriptional activity (MD = −1.32, 95% CI: −1.64 to −0.99, p < 0.00001). Narrative synthesis found that CDH17 suppression decreased total and nuclear β-catenin, phosphorylated glycogen synthase kinase-3 beta (GSK-3β), and cyclin D1 while increasing tumour suppressors, retinoblastoma (Rb) and p53/p21. These changes were associated with reduced proliferation, colony formation, migration, invasion and cell cycle arrest. In vivo, CDH17 suppression resulted in 80–95% tumour growth suppression (Mean Difference (MD) = −96.67, 95% CI: [−144.35, −48.98], p < 0.0001), with immunohistochemistry confirming cytoplasmic β-catenin sequestration and lower cyclin D1 levels. Collectively, these findings show CDH17 as a critical upstream effector sustaining Wnt/β-catenin signalling, cancer progression, tumour proliferation, stem cell properties, and metastasis, and support CDH17 inhibition as a promising therapeutic target across multiple cancer types. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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14 pages, 818 KB

Open AccessReview

Stem Cells and Cell-Free Therapies for Olfactory Epithelium Regeneration: Insights from Experimental Models

by Keun-Ik Yi, Ji-Hwan Park, Sung-Dong Kim, Sue Jean Mun and Kyu-Sup Cho

Int. J. Mol. Sci. 2025, 26(18), 9024; https://doi.org/10.3390/ijms26189024 - 16 Sep 2025

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Abstract

Olfactory impairment is one of the most common diseases of the sense organs, and it is closely related to quality life. Although the molecular mechanism of olfaction was recently brought to light, the pathophysiology and effective treatments for olfactory dysfunction still remain challenging. [...] Read more.

Olfactory impairment is one of the most common diseases of the sense organs, and it is closely related to quality life. Although the molecular mechanism of olfaction was recently brought to light, the pathophysiology and effective treatments for olfactory dysfunction still remain challenging. Olfactory impairment can be caused by the degeneration of olfactory receptor neurons in the nose and also by the degeneration of the olfactory bulb of the olfactory cortex. Several studies have shown that stem cells promote the regeneration of the olfactory neuroepithelium after permanent damage in anosmic mice. Transplanted adipose stem cells differentiated into olfactory receptor neurons and endothelial cells. Recently, cell-free approaches using stem cell-derived secretome and extracellular vesicles (EVs) have emerged as a safer, more controllable alternative. These vesicles contain biologically active cargo such as neurotrophins, cytokines, and microRNAs that promote neurogenesis and modulate inflammation. Although direct application in anosmia models remains limited, findings from related neural injury models suggest that secretome- and EV-based therapies may achieve comparable regenerative efficacy to stem cell transplantation. This review summarizes current evidence on the regenerative capacity of stem cells and their secretome or EVs as therapeutic strategies for olfactory epithelium regeneration. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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21 pages, 820 KB

Open AccessReview

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: Pathophysiology, Clinical Patterns, and Therapeutic Challenges of Intractable and Severe Forms

by Tatsuro Misu

Int. J. Mol. Sci. 2025, 26(17), 8538; https://doi.org/10.3390/ijms26178538 - 2 Sep 2025

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Abstract

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is characterized by the predominance of optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis, and can be diagnosed by the presence of pathogenic immunoglobulin G (IgG) antibodies targeting the extracellular domain of MOG in [...] Read more.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is characterized by the predominance of optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), and cortical encephalitis, and can be diagnosed by the presence of pathogenic immunoglobulin G (IgG) antibodies targeting the extracellular domain of MOG in the serum and cerebrospinal fluid (CSF). Initially considered a variant of multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), it is now widely recognized as a separate entity, supported by converging evidence from serological, pathological, and clinical studies. Patients with MOGAD often exhibit better recovery from acute attacks; however, their clinical and pathological features vary based on the immunological role of MOG-IgG via antibody- or complement-mediated perivenous demyelinating pathology, in addition to MOG-specific cellular immunity, resulting in heterogeneous demyelinated lesions from vanishing benign forms to tissue necrosis, even though MOGAD is not a mild disease. The key is the immunological mechanism of devastating lesion coalescence and long-term degenerating mechanisms, which may still accrue, particularly in the relapsing, progressing, and aggressive clinical course of encephalomyelitis. The warning features of the severe clinical forms are: (1) fulminant acute multifocal lesions or multiphasic ADEM transitioning to diffuse (Schilder-type) or tumefactive lesions; (2) cortical or subcortical lesions related to brain atrophy and/or refractory epilepsy (Rasmussen-type); (3) longitudinally extended spinal cord lesions severely affected with residual symptoms. In addition, it is cautious for patients refractory to acute stage early 1st treatment including intravenous methylprednisolone treatment and apheresis with residual symptoms and relapse activity with immunoglobulin and other 2nd line treatments including B cell depletion therapy. Persistent MOG-IgG high titration, intrathecal production of MOG-IgG, and suggestive markers of higher disease activity, such as cerebrospinal fluid interleukin-6 and complement C5b-9, could be identified as promising markers of higher disease activity, worsening of disability, and poor prognosis, and used to identify signs of escalating treatment strategies. It is promising of currently ongoing investigational antibodies against anti-interleukin-6 receptor and the neonatal Fc receptor. Moreover, due to possible refractory issues such as the intrathecal production of autoantibody and the involvement of complement in the worsening of the lesion, further developments of other mechanisms of action such as chimeric antigen receptor T-cell (CAR-T) and anti-complement therapies are warranted in the future. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Pathology, Diagnostics, and Therapeutics)

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