Biomedicines

13 pages, 1341 KiB

Open AccessArticle

Risk of Cervical Carcinoma After Unfavorable Behavior and High Genetic Risk in the UK Biobank: A Prospective Nested Case–Control Study

by Shiyi Liu, Yunlong Guan, Shitong Lin, Peng Wu, Qing Zhang, Tian Chu and Ruifen Dong

Biomedicines 2025, 13(2), 464; https://doi.org/10.3390/biomedicines13020464 - 13 Feb 2025

Abstract

Background: Previous studies have established a general understanding of the association between risky sexual behavior, genetic risk, and cervical carcinoma. However, these studies were conducted several years ago and lack systematic analysis using high-quality and population-based data. Methods: We conducted a [...] Read more.

Background: Previous studies have established a general understanding of the association between risky sexual behavior, genetic risk, and cervical carcinoma. However, these studies were conducted several years ago and lack systematic analysis using high-quality and population-based data. Methods: We conducted a prospective nested case–control study to identify risky behaviors and developed a behavior score. Combining the behavior score and genetic risk, we evaluated the effect of sexual and reproductive behavior and PRS on cervical carcinoma through the developed conditional logistic regression models. Results: We verified increased carcinoma risk in individuals with early sexual intercourse (OR: 1.41 [95% CI 1.09 to 1.83], p = 0.0083), non-monogamous sexual partners (OR: 3.13 [95% CI 2.15 to 4.57], p < 0.0001), three or more live births (OR: 1.44 [95% CI 1.12 to 1.84], p = 0.0040), and high PRS (polygenic risk score) (top 25% of PRS, OR: 1.58 [95% CI 1.15 to 2.16], p = 0.0044). The unfavorable sexual and reproductive behavior score we developed was linked to a 151% increased risk (OR: 2.51 [95% CI 1.79 to 3.52], p < 0.0001) after adjusting for PRS. Women with both unfavorable behavior and high genetic risk had a 5.5-fold increased cervical carcinoma risk (OR: 5.45 [95% CI 2.72 to 10.95], p < 0.0001) compared to individuals with favorable behavior and low genetic risk. Conclusions: Unfavorable sexual and reproductive behavior increases the risk of cervical carcinoma, especially in those with a high genetic risk. These findings encourage us to adhere to a healthy sexual and reproductive pattern. Full article

(This article belongs to the Special Issue Advances in Therapeutic Strategies in Gynecological Malignant Tumors—2nd Edition)

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24 pages, 808 KiB

Open AccessReview

Chronic Stress and Headaches: The Role of the HPA Axis and Autonomic Nervous System

by Aleksandar Sic, Marko Bogicevic, Nebojsa Brezic, Clara Nemr and Nebojsa Nick Knezevic

Biomedicines 2025, 13(2), 463; https://doi.org/10.3390/biomedicines13020463 - 13 Feb 2025

Abstract

Chronic stress significantly influences the pathogenesis of headache disorders, affecting millions worldwide. This review explores the intricate relationship between stress and headaches, focusing on the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and autonomic nervous system (ANS). Persistent stress could lead to neuroinflammation, increased [...] Read more.

Chronic stress significantly influences the pathogenesis of headache disorders, affecting millions worldwide. This review explores the intricate relationship between stress and headaches, focusing on the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis and autonomic nervous system (ANS). Persistent stress could lead to neuroinflammation, increased pain sensitivity, and vascular changes that could contribute to headache development and progression. The bidirectional nature of this relationship creates a vicious cycle, with recurrent headaches becoming a source of additional stress. Dysregulation of the HPA axis and ANS imbalance could amplify susceptibility to headaches, intensifying their frequency and severity. While pharmacological interventions remain common, non-pharmacological approaches targeting stress reduction, such as cognitive-behavioral therapy, biofeedback, and relaxation techniques, offer promising avenues for comprehensive headache management. By addressing the underlying stress-related mechanisms, these approaches provide a sustainable strategy to reduce headache frequency and improve patients’ quality of life. Full article

(This article belongs to the Special Issue Autonomic Dysfunction in Neurological Disorders: Novel Mechanisms and Targets)

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19 pages, 1629 KiB

Open AccessReview

Targeting Inflammation and Iron Deficiency in Heart Failure: A Focus on Older Adults

by Daniela Maidana, Andrea Arroyo-Álvarez, Guillermo Barreres-Martín, Andrea Arenas-Loriente, Pedro Cepas-Guillen, Raphaela Tereza Brigolin Garofo, Pedro Caravaca-Pérez and Clara Bonanad

Biomedicines 2025, 13(2), 462; https://doi.org/10.3390/biomedicines13020462 - 13 Feb 2025

Abstract

Background/Objectives: Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with a higher prevalence among older adults. Iron deficiency (ID), affecting up to 50% of HF patients, is closely linked to chronic inflammation, exacerbating HF outcomes. This review aims [...] Read more.

Background/Objectives: Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with a higher prevalence among older adults. Iron deficiency (ID), affecting up to 50% of HF patients, is closely linked to chronic inflammation, exacerbating HF outcomes. This review aims to explore the interplay between inflammation, ID, and HF, focusing on older patients, and to identify therapeutic gaps and emerging treatment strategies. Methods: A comprehensive review of the literature was conducted, emphasizing the pathophysiological mechanisms of inflammation and ID in HF, the challenges of current diagnostic criteria, and the limitations of available treatments. Emerging pharmacological and diagnostic approaches were analyzed. Results: Chronic inflammation in HF, particularly in older adults, promotes functional ID through elevated hepcidin levels, impairing iron availability and worsening anemia. Current diagnostic criteria, relying heavily on ferritin, often misclassify ID due to inflammation. Intravenous (IV) iron therapy shows clinical benefits in patients with <50% left ventricular ejection fraction (LVEF), but the evidence is limited in heart failure with preserved ejection fraction (HFpEF). Emerging therapies, such as Sodium-Glucose Cotransporter-2 inhibitors (SGLT2is) and prolyl hydroxylase inhibitors like Roxadustat, offer promising avenues to improve iron metabolism and outcomes. Conclusions: ID and inflammation significantly impact HF progression, particularly inolder adults. Refining diagnostic criteria and exploring innovative therapies are critical to addressing these challenges. Future research should prioritize personalized approaches targeting inflammation and ID, especially in underrepresented populations, such as HFpEF and elderly patients. Full article

(This article belongs to the Special Issue Acute and Chronic Heart Failure: Pathophysiology and New Therapeutic Developments, 2nd Edition)

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24 pages, 16534 KiB

Open AccessArticle

The Diagnostic Significance of SLC26A2 and Its Potential Role in Ulcerative Colitis

by Lijuan Qian, Shuo Hu, Haizhou Zhao, Ye Han, Chenguang Dai, Xinquan Zan, Qiaoming Zhi and Chunfang Xu

Biomedicines 2025, 13(2), 461; https://doi.org/10.3390/biomedicines13020461 - 13 Feb 2025

Abstract

Background/Objectives: The solute carrier family 26, member 2 (SLC26A2) gene, which belongs to the family of SLC26 transporters, can be detected in multiple tissues. However, the studies of SLC26A2 in colon-related diseases are still limited and incompletely understood, especially in ulcerative colitis (UC). [...] Read more.

Background/Objectives: The solute carrier family 26, member 2 (SLC26A2) gene, which belongs to the family of SLC26 transporters, can be detected in multiple tissues. However, the studies of SLC26A2 in colon-related diseases are still limited and incompletely understood, especially in ulcerative colitis (UC). Methods: In this study, we attempted to search and identify putative UC candidate genes within a large number of known genes by multiple bioinformatics analyses. The potential cellular characteristics and biological functions of SLC26A2 in the pathogenesis of UC were also elucidated. Results: Notably, SLC26A2 was representative and down-regulated in the intestinal mucosa of patients with active UC, compared to healthy controls. Decreased levels of SLC26A2 were proved to have a more value in diagnosis of UC patients, and closely correlated with some UC characteristics, including the Mayo score and Paediatric Ulcerative Colitis Activity Index (PUCAI). Mechanistically, subsequent results from published datasets and our validated clinical data all strongly implied that SLC26A2 was negatively correlated with the IL-17 signaling pathway, and positively associated with the tight junction, which led to abnormal immune cell infiltration and inflammatory injuries. After establishing the UC mice models in vivo by orally administration of DSS in portable water, SLC26A2 was significantly down-regulated at the mRNA or protein level, when compared to that in the control groups. Furthermore, the correlation analyses confirmed that SLC26A2 was positively associated with CLDN3, and negatively correlated with IL-17A expression in colon tissues. In addition, according to the SLC26A2 expression, UC patients were divided into different subgroups. The potential target drugs for UC treatment, such as progesterone, tetradioxin, and dexamethasone, were initially predicted and exerted anti-inflammatory effects via the common molecule-SLC26A2. Conclusions: SLC26A2 might be served as a protective candidate in the UC pathogenesis as well as a potential drug target for UC treatment. Full article

(This article belongs to the Special Issue Crohn's Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches (2nd Edition))

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23 pages, 691 KiB

Open AccessReview

Hallmarks of Brain Plasticity

by Yauhen Statsenko, Nik V. Kuznetsov and Milos Ljubisaljevich

Biomedicines 2025, 13(2), 460; https://doi.org/10.3390/biomedicines13020460 - 13 Feb 2025

Abstract

Cerebral plasticity is the ability of the brain to change and adapt in response to experience or learning. Its hallmarks are developmental flexibility, complex interactions between genetic and environmental influences, and structural–functional changes comprising neurogenesis, axonal sprouting, and synaptic remodeling. Studies on brain [...] Read more.

Cerebral plasticity is the ability of the brain to change and adapt in response to experience or learning. Its hallmarks are developmental flexibility, complex interactions between genetic and environmental influences, and structural–functional changes comprising neurogenesis, axonal sprouting, and synaptic remodeling. Studies on brain plasticity have important practical implications. The molecular characteristics of changes in brain plasticity may reveal disease course and the rehabilitative potential of the patient. Neurological disorders are linked with numerous cerebral non-coding RNAs (ncRNAs), in particular, microRNAs; the discovery of their essential role in gene regulation was recently recognized and awarded a Nobel Prize in Physiology or Medicine in 2024. Herein, we review the association of brain plasticity and its homeostasis with ncRNAs, which make them putative targets for RNA-based diagnostics and therapeutics. New insight into the concept of brain plasticity may provide additional perspectives on functional recovery following brain damage. Knowledge of this phenomenon will enable physicians to exploit the potential of cerebral plasticity and regulate eloquent networks with timely interventions. Future studies may reveal pathophysiological mechanisms of brain plasticity at macro- and microscopic levels to advance rehabilitation strategies and improve quality of life in patients with neurological diseases. Full article

(This article belongs to the Special Issue Neurodegeneration in Cognitive Impairment and Mood Disorders for Experimental, Clinical, and Translational Neuropsychiatry—Second Edition)

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17 pages, 4373 KiB

Open AccessArticle

High-Throughput Whole-Exome Sequencing and Large-Scale Computational Analysis to Identify the Genetic Biomarkers to Predict the Vedolizumab Response Status in Inflammatory Bowel Disease Patients from Saudi Arabia

by Hanin Aljohani, Doaa Anbarserry, Mahmoud Mosli, Amani Ujaimi, Duaa Bakhshwin, Ramu Elango and Sameer Alharthi

Biomedicines 2025, 13(2), 459; https://doi.org/10.3390/biomedicines13020459 - 13 Feb 2025

Abstract

Background/Objectives: Vedolizumab (VDZ) is the new monoclonal drug targeting α4β7 integrin for patients with moderate/severe IBD. Between 30 and 45% of patients fail to respond to VDZ after 14–16 weeks of treatment. The aim of the study was to explore the genetic [...] Read more.

Background/Objectives: Vedolizumab (VDZ) is the new monoclonal drug targeting α4β7 integrin for patients with moderate/severe IBD. Between 30 and 45% of patients fail to respond to VDZ after 14–16 weeks of treatment. The aim of the study was to explore the genetic profile of vedolizumab-treated Arab IBD patients in Saudi Arabia to identify the potential biomarkers to differentiate the responders from non-responders. Methods: A cohort of 16 patients with IBD, including 4 with Crohn’s disease and 12 with ulcerative colitis, were recruited. Following 16 weeks of VDZ treatment, nine were found to be responders and seven non-responders. Blood samples were collected for the whole exome sequencing of DNA from all patients. The variants in the whole-exome sequencing data were analyzed with a variety of bioinformatics tools and databases, such as Polyphen2, Mutation Taster, CADD, FATHMM, Open Target Platform, TOPPFun, STRING, and GTEx. Results: More than 1.6 million variants from 16 samples were analyzed. The rare variant analysis prioritized NOD2, IL23, IL10, IL27, and TRAF1 genes in non-responders. NOD2, IL23, IL10, IL27, and TRAF1 were found to be the significant IBD risk factors in multiple genome-wide association studies, and their pro-inflammatory activity might contribute to the inherent resistance to VDZ. Rare variants of CARD9, TYK2, IL4, and NLRP1 genes present in VDZ responders enhance the anti-inflammatory/immune modulation effects. Conclusions: This investigation is the first to apply whole-exome sequencing to identify the potential drug response biomarkers for the IBD drug VDZ in Saudi Arabia. Full article

(This article belongs to the Special Issue Crohn's Disease and Ulcerative Colitis: From Pathophysiology to Novel Therapeutic Approaches (2nd Edition))

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17 pages, 612 KiB

Open AccessReview

Role of Perinatal Stem Cell Secretome as Potential Therapy for Muscular Dystrophies

by Serafina Pacilio, Sara Lombardi, Roberta Costa, Francesca Paris, Giovannamaria Petrocelli, Pasquale Marrazzo, Giovanna Cenacchi and Francesco Alviano

Biomedicines 2025, 13(2), 458; https://doi.org/10.3390/biomedicines13020458 - 13 Feb 2025

Abstract

Inflammation mechanisms play a critical role in muscle homeostasis, and in Muscular Dystrophies (MDs), the myofiber damage triggers chronic inflammation which significantly controls the disease progression. Immunomodulatory strategies able to target inflammatory pathways and mitigate the immune-mediated damage in MDs may provide new [...] Read more.

Inflammation mechanisms play a critical role in muscle homeostasis, and in Muscular Dystrophies (MDs), the myofiber damage triggers chronic inflammation which significantly controls the disease progression. Immunomodulatory strategies able to target inflammatory pathways and mitigate the immune-mediated damage in MDs may provide new therapeutic options. Owing to its capacity of influencing the immune response and enhancing tissue repair, stem cells’ secretome has been proposed as an adjunct or standalone treatment for MDs. In this review study, we discuss the challenging points related to the inflammation condition characterizing MD pathology and provide a concise summary of the literature supporting the potential of perinatal stem cells in targeting and modulating the MD inflammation. Full article

(This article belongs to the Special Issue Stem Cells and Immunomodulation)

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4 pages, 137 KiB

Open AccessEditorial

Drug-Resistant Bacterial Infections and Alternative Therapies

by Vijay Singh Gondil

Biomedicines 2025, 13(2), 457; https://doi.org/10.3390/biomedicines13020457 - 13 Feb 2025

Abstract

The introduction of antibiotics in clinical use has revolutionized modern medicine practices and significantly contributed to the control of bacterial infections, which were the leading cause of morbidity and mortality throughout human history [...] Full article

(This article belongs to the Special Issue Drug-Resistant Bacterial Infections and Alternative Therapies)

20 pages, 651 KiB

Open AccessReview

The Tight Relationship Between the Tumoral Microenvironment and Radium-223

by Miriam Conte, Miriam Tomaciello, Maria Silvia De Feo, Viviana Frantellizzi, Francesco Marampon, Flaminia De Cristofaro, Giuseppe De Vincentis and Luca Filippi

Biomedicines 2025, 13(2), 456; https://doi.org/10.3390/biomedicines13020456 - 12 Feb 2025

Abstract

Radium-223 (²²³Ra) was the first radioactive isotope approved for treating castration-resistant prostate cancer (CRPC) with symptomatic bone metastases without visceral metastatic disease. To better understand the action of ²²³Ra, its role in the tumor microenvironment represents a crucial aspect. A [...] Read more.

Radium-223 (²²³Ra) was the first radioactive isotope approved for treating castration-resistant prostate cancer (CRPC) with symptomatic bone metastases without visceral metastatic disease. To better understand the action of ²²³Ra, its role in the tumor microenvironment represents a crucial aspect. A literature search was conducted using the PubMed/MEDLINE database and studies regarding the relationship between ²²³Ra and the tumoral microenvironment were considered. The tumoral microenvironment is a complex setting in which complex interactions between cells and molecules occur. Radium-223, as an alpha-emitter, induces double-stranded DNA breaks; to potentiate this effect, it could be used in patients with genetic instability but also in combination with therapies which inhibit DNA repair, modulate the immune response, or control tumor growth. In conclusion, a few studies have taken into consideration the tumoral microenvironment in association with ²²³Ra. However, its understanding is a priority to better comprehend how to effectively exploit ²²³Ra and its action mechanism. Full article

(This article belongs to the Special Issue Feature Reviews in Precision Oncology)

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19 pages, 1549 KiB

Open AccessReview

Everolimus in the Treatment of Neuroendocrine Tumors: Lights and Shadows

by Bianca Medici, Eugenia Caffari, Yuri Maculan, Stefania Benatti, Federico Piacentini, Massimo Dominici and Fabio Gelsomino

Biomedicines 2025, 13(2), 455; https://doi.org/10.3390/biomedicines13020455 - 12 Feb 2025

Abstract

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms that originate from neuroendocrine cells, characterized by their ability to secrete hormones and peptides. Once considered rare, the incidence of NETs has steadily increased due to improved diagnostic modalities. The therapeutic landscape is multifaceted, [...] Read more.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of neoplasms that originate from neuroendocrine cells, characterized by their ability to secrete hormones and peptides. Once considered rare, the incidence of NETs has steadily increased due to improved diagnostic modalities. The therapeutic landscape is multifaceted, ranging from surgery for localized disease to pharmacological interventions for advanced cases. However, the absence of robust predictive biomarkers precludes patient stratification and optimization of therapy. Everolimus, an oral mTOR inhibitor, has emerged as a key therapeutic agent due to its dual role in inhibiting cell proliferation and angiogenesis. Nevertheless, challenges such as resistance mechanisms, toxicity and optimal treatment sequencing remain unresolved. This article provides a comprehensive review of the role of everolimus in the management of NETs, focusing in particular on unresolved issues, from the absence of predictive biomarkers to the unavailability of defined guidelines for determining the correct therapeutic sequence. Full article

(This article belongs to the Special Issue mTOR Signaling in Disease and Therapy)

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40 pages, 3058 KiB

Open AccessReview

Therapeutic Potential of Medicinal Plants and Their Phytoconstituents in Diabetes, Cancer, Infections, Cardiovascular Diseases, Inflammation and Gastrointestinal Disorders

by Prawej Ansari, Alexa D. Reberio, Nushrat J. Ansari, Sandeep Kumar, Joyeeta T. Khan, Suraiya Chowdhury, Fatma Mohamed Abd El-Mordy, J. M. A. Hannan, Peter R. Flatt, Yasser H. A. Abdel-Wahab and Veronique Seidel

Biomedicines 2025, 13(2), 454; https://doi.org/10.3390/biomedicines13020454 - 12 Feb 2025

Abstract

Conditions like diabetes mellitus (DM), cancer, infections, inflammation, cardiovascular diseases (CVDs), and gastrointestinal (GI) disorders continue to have a major global impact on mortality and morbidity. Medicinal plants have been used since ancient times in ethnomedicine (e.g., Ayurveda, Unani, Traditional Chinese Medicine, and [...] Read more.

Conditions like diabetes mellitus (DM), cancer, infections, inflammation, cardiovascular diseases (CVDs), and gastrointestinal (GI) disorders continue to have a major global impact on mortality and morbidity. Medicinal plants have been used since ancient times in ethnomedicine (e.g., Ayurveda, Unani, Traditional Chinese Medicine, and European Traditional Medicine) for the treatment of a wide range of disorders. Plants are a rich source of diverse phytoconstituents with antidiabetic, anticancer, antimicrobial, antihypertensive, antioxidant, antihyperlipidemic, cardioprotective, immunomodulatory, and/or anti-inflammatory activities. This review focuses on the 35 plants most commonly reported for the treatment of these major disorders, with a particular emphasis on their traditional uses, phytoconstituent contents, pharmacological properties, and modes of action. Active phytomolecules with therapeutic potential include cucurbitane triterpenoids, diosgenin, and limonoids (azadiradione and gedunin), which exhibit antidiabetic properties, with cucurbitane triterpenoids specifically activating Glucose Transporter Type 4 (GLUT4) translocation. Capsaicin and curcumin demonstrate anticancer activity by deactivating NF-κB and arresting the cell cycle in the G2 phase. Antimicrobial activities have been observed for piperine, reserpine, berberine, dictamnine, chelerythrine, and allitridin, with the latter two triggering bacterial cell lysis. Quercetin, catechin, and genistein exhibit anti-inflammatory properties, with genistein specifically suppressing CD8+ cytotoxic T cell function. Ginsenoside Rg1 and ginsenoside Rg3 demonstrate potential for treating cardiovascular diseases, with ginsenoside Rg1 activating PPARα promoter, and the PI3K/Akt pathway. In contrast, ternatin, tannins, and quercitrin exhibit potential in gastrointestinal disorders, with quercitrin regulating arachidonic acid metabolism by suppressing cyclooxygenase (COX) and lipoxygenase activity. Further studies are warranted to fully investigate the clinical therapeutic benefits of these plants and their phytoconstituents, as well as to elucidate their underlying molecular mechanisms of action. Full article

(This article belongs to the Special Issue From Molecules to Medicine: Deciphering Obesity and Lipid Metabolism for Translational Insights)

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18 pages, 1792 KiB

Open AccessReview

Ultrasound Assessment in Polycystic Ovary Syndrome Diagnosis: From Origins to Future Perspectives—A Comprehensive Review

by Stefano Di Michele, Anna Maria Fulghesu, Elena Pittui, Martina Cordella, Gilda Sicilia, Giuseppina Mandurino, Maurizio Nicola D’Alterio, Salvatore Giovanni Vitale and Stefano Angioni

Biomedicines 2025, 13(2), 453; https://doi.org/10.3390/biomedicines13020453 - 12 Feb 2025

Abstract

Background: Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of reproductive age, characterized by a broad spectrum of clinical, metabolic, and ultrasound findings. Over time, ultrasound has evolved into a cornerstone for diagnosing polycystic ovarian morphology (PCOM), thanks to [...] Read more.

Background: Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women of reproductive age, characterized by a broad spectrum of clinical, metabolic, and ultrasound findings. Over time, ultrasound has evolved into a cornerstone for diagnosing polycystic ovarian morphology (PCOM), thanks to advances in probe technology, 3D imaging, and novel stromal markers. The recent incorporation of artificial intelligence (AI) further enhances diagnostic precision by reducing operator-related variability. Methods: We conducted a narrative review of English-language articles in PubMed and Embase using the keywords “PCOS”, “polycystic ovary syndrome”, “ultrasound”, “3D ultrasound”, and “ovarian stroma”. Studies on diagnostic criteria, imaging modalities, stromal assessment, and machine-learning algorithms were prioritized. Additional references were identified via citation screening. Results: Conventional 2D ultrasound remains essential in clinical practice, with follicle number per ovary (FNPO) and ovarian volume (OV) functioning as primary diagnostic criteria. However, sensitivity and specificity values vary significantly depending on probe frequency, cut-off thresholds (≥12, ≥20, or ≥25 follicles), and patient characteristics (e.g., adolescence, obesity). Three-dimensional (3D) ultrasound and Doppler techniques refine PCOS diagnosis by enabling automated follicle measurements, stromal/ovarian area ratio assessments, and evaluation of vascular indices correlating strongly with hyperandrogenism. Meanwhile, AI-driven ultrasound analysis has emerged as a promising tool for minimizing observer bias and validating advanced metrics (e.g., SA/OA ratio) that may overcome traditional limitations of stroma-based criteria. Conclusions: The continual evolution of ultrasound, encompassing higher probe frequencies, 3D enhancements, and now AI-assisted algorithms, has expanded our ability to characterize PCOM accurately. Nevertheless, challenges such as operator dependency and inter-observer variability persist despite standardized protocols; the integration of AI holds promise in further enhancing diagnostic accuracy. Future directions should focus on robust AI training datasets, multicenter validation, and age-/BMI-specific cut-offs to optimize the balance between sensitivity and specificity, ultimately facilitating earlier and more precise PCOS diagnoses. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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21 pages, 732 KiB

Open AccessReview

Animal Models for Studying Developmental Origins of Cardiovascular–Kidney–Metabolic Syndrome

by You-Lin Tain, Ying-Jui Lin and Chien-Ning Hsu

Biomedicines 2025, 13(2), 452; https://doi.org/10.3390/biomedicines13020452 - 12 Feb 2025

Abstract

Cardiovascular–kidney–metabolic syndrome (CKMS) has become a significant global health challenge. Since CKMS often originates early in life, as outlined by the developmental origins of health and disease (DOHaD) concept, prevention is a more effective strategy than treatment. Various animal models, classified by environmental [...] Read more.

Cardiovascular–kidney–metabolic syndrome (CKMS) has become a significant global health challenge. Since CKMS often originates early in life, as outlined by the developmental origins of health and disease (DOHaD) concept, prevention is a more effective strategy than treatment. Various animal models, classified by environmental exposures or mechanisms, are used to explore the developmental origins of CKMS. However, no single model can fully replicate all aspects of CKMS or its clinical stages, limiting the advancement of preventive and therapeutic strategies. This review aims to assist researchers by comparing the strengths and limitations of common animal models used in CKMS programming studies and highlighting key considerations for selecting suitable models. Full article

(This article belongs to the Special Issue Animal Models for the Study of Cardiovascular Physiology)

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10 pages, 1076 KiB

Open AccessSystematic Review

The Role of Hyaluronic Acid in Alveolar Ridge Preservation: A Systematic Review of Its Biological and Regenerative Potential According to PRISMA Guidelines and the Cochrane Handbook

by Vincenzo Ronsivalle, Simona Santonocito, Roberta Giudice, Salvatore Bocchieri, Simone Didomenico and Marco Cicciù

Biomedicines 2025, 13(2), 451; https://doi.org/10.3390/biomedicines13020451 - 12 Feb 2025

Abstract

Objectives: This systematic review evaluates the biological activity and regenerative potential of hyaluronic acid (HA) in alveolar ridge preservation (ARP) following tooth extraction, assessing its efficacy in reducing bone resorption and promoting bone regeneration when combined with xenografts. Methods: A comprehensive [...] Read more.

Objectives: This systematic review evaluates the biological activity and regenerative potential of hyaluronic acid (HA) in alveolar ridge preservation (ARP) following tooth extraction, assessing its efficacy in reducing bone resorption and promoting bone regeneration when combined with xenografts. Methods: A comprehensive search was conducted across PubMed, Scopus, Web of Science, and Lilacs databases, adhering to PRISMA guidelines. Studies from 2012 to December 2024 involving human participants were included based on a PECO framework. Four studies met the inclusion criteria, with data extracted and analyzed for clinical and histological outcomes. The risk of bias was assessed using the ROBINS-E tool. Results: The included studies demonstrated that HA combined with xenografts significantly reduced post-extraction bone resorption compared to controls. HA-enhanced grafts showed superior radiographic and histological outcomes, including increased bone density and reduced graft shrinkage. While one randomized controlled trial found no significant differences in wound healing or patient-reported outcomes between HA and control groups, other studies reported improved bone formation and graft stability with HA. Variability in study design and sample size was noted, with a generally moderate to high risk of bias in some studies. Conclusions: The evidence supports the beneficial role of HA as an adjuvant in ARP procedures, enhancing bone regeneration and limiting resorption. However, further research with larger samples and standardized methodologies is required to confirm these findings and optimize clinical protocols. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Approaches for Oral Disorders)

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12 pages, 561 KiB

Open AccessReview

Pharmacological Modulation of Mutant TP53 with Oncotargets Against Esophageal Cancer and Therapy Resistance

by Pei-I Lin, Yu-Cheng Lee, I-Hung Chen and Hsien-Hui Chung

Biomedicines 2025, 13(2), 450; https://doi.org/10.3390/biomedicines13020450 - 12 Feb 2025

Abstract

The prevalence and deaths from esophageal cancer (EC) have recently increased. Although therapeutic strategies depend on the EC stage and recurrence, such as surgical intervention, chemotherapy, radiation therapy, chemoradiation therapy, targeted therapy, and immunotherapy, a more effective and novel treatment for EC is [...] Read more.

The prevalence and deaths from esophageal cancer (EC) have recently increased. Although therapeutic strategies depend on the EC stage and recurrence, such as surgical intervention, chemotherapy, radiation therapy, chemoradiation therapy, targeted therapy, and immunotherapy, a more effective and novel treatment for EC is still required. This review briefly describes and summarizes some insightful oncotargets involved in the metabolic modulation of EC, including (1) cancer stem cells (CSCs) for EC progression, poor prognosis, tumor recurrence, and therapy resistance; (2) retinoic acid receptors (RARs) for esophageal carcinogenesis and regeneration; (3) phosphofructokinase (PFK) for EC-reprogrammed glycolysis; (4) lactate dehydrogenase (LDH) as an EC peripheral blood biomarker; and (5) hypoxia-inducible factor-1 alpha (HIF-1α) for the tumor microenvironment under hypoxic conditions. Moreover, the aforementioned oncotargets can be modulated by mutant TP53 and have their own features in the carcinogenesis, differentiation, proliferation, and metastasis of EC. Thus, the clarification of pharmacological mechanisms regarding the interaction between mutant TP53 and the abovementioned oncotargets could provide precise and perspective opinions for minimizing prediction errors, reducing therapy resistance, and developing novel drugs against EC. Full article

(This article belongs to the Special Issue Advances in Cancer Biology and Experimental Anticancer Therapies (2nd Edition))

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21 pages, 7735 KiB

Open AccessArticle

MicroRNAs Associated with Parenchymal Hematoma After Endovascular Mechanical Reperfusion for Acute Ischemic Stroke in Rats

by Jin-Kun Zhuang, Zhong-Run Huang, Wang Qin, Chang-Luo Li, Qi Li, Chun Xiang, Yong-Hua Tuo, Zhong Liu, Qian-Yu Chen and Zhong-Song Shi

Biomedicines 2025, 13(2), 449; https://doi.org/10.3390/biomedicines13020449 - 12 Feb 2025

Abstract

Background/Objectives: Hemorrhagic transformation after endovascular thrombectomy predicts poor outcomes in acute ischemic stroke with large-vessel occlusion. The roles of microRNAs (miRNAs) in the pathogenesis of parenchymal hematoma (PH) after endovascular thrombectomy still remain unclear. This study aimed to investigate the miRNA and mRNA [...] Read more.

Background/Objectives: Hemorrhagic transformation after endovascular thrombectomy predicts poor outcomes in acute ischemic stroke with large-vessel occlusion. The roles of microRNAs (miRNAs) in the pathogenesis of parenchymal hematoma (PH) after endovascular thrombectomy still remain unclear. This study aimed to investigate the miRNA and mRNA regulatory network associated with PH after mechanical reperfusion in an animal stroke model and an oxygen–glucose deprivation/reoxygenation (OGD/R) model. Methods: Twenty-five miRNAs were assessed in a mechanical reperfusion-induced hemorrhage transformation model in rats under hyperglycemic conditions receiving 5 h middle cerebral artery occlusion. The differentially expressed miRNAs associated with PH were assessed in a neuron, astrocyte, microglia, brain microvascular endothelial cell (BMEC), and pericyte model of OGD/R. The predicted target genes of the differentially expressed miRNAs were further assessed in the animal model. The miRNA-mRNA regulatory network of PH was established. Results: Thirteen down-regulated miRNAs (miRNA-29a-5p, miRNA-29c-3p, miRNA-126a-5p, miRNA-132-3p, miRNA-136-3p, miRNA-142-3p, miRNA-153-5p, miRNA-218a-5p, miRNA-219a-2-3p, miRNA-369-5p, miRNA-376a-5p, miRNA-376b-5p, and miRNA-383-5p) and one up-regulated miRNA (miRNA-195-3p) were found in the rat peri-infarct with PH after mechanical reperfusion. Of these 14 PH-related miRNAs, 10 were significantly differentially expressed in at least two of the five neuron, astrocyte, microglia, BMEC, and pericyte models after OGD/R, consistent with the animal stroke model results. Thirty-one predicted hub target genes were significantly differentially expressed in the rat peri-infarct with PH after mechanical reperfusion. Forty-nine miRNA-mRNA regulatory axes of PH were revealed, and they were related to the mechanisms of inflammation, immunity, oxidative stress, and apoptosis. Conclusions: Fourteen miRNAs were associated with PH after mechanical reperfusion in the rat stroke and the OGD/R models. Simultaneously differentially expressed miRNAs and related genes in several cells of the neurovascular unit may serve as valuable targets for PH after endovascular thrombectomy in acute ischemic stroke. Full article

(This article belongs to the Special Issue Epigenetic Regulation and Its Impact for Medicine (2nd Edition))

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21 pages, 379 KiB

Open AccessReview

Dysbiosis of Oral Microbiome: A Key Player in Oral Carcinogenesis? A Critical Review

by K. Devaraja and Sadhna Aggarwal

Biomedicines 2025, 13(2), 448; https://doi.org/10.3390/biomedicines13020448 - 12 Feb 2025

Abstract

The oral cavity is known to harbor hundreds of microorganisms, belonging to various genera, constituting a peculiar flora called the oral microbiome. The change in the relative distribution of the constituents of this microbial flora, due to any reason, leads to oral dysbiosis. [...] Read more.

The oral cavity is known to harbor hundreds of microorganisms, belonging to various genera, constituting a peculiar flora called the oral microbiome. The change in the relative distribution of the constituents of this microbial flora, due to any reason, leads to oral dysbiosis. For centuries, oral dysbiosis has been linked to the etiopathogenesis of several medical illnesses, both locally and systemically-. However, aided by the recent advent of bio-technological capabilities, several reports have re-emerged that link oral dysbiosis to oral carcinogenesis, and numerous studies are currently exploring their association and plausible mechanisms. Some of the proposed mechanisms of oral dysbiosis-induced carcinogenesis (ODIC) include—a bacteria-induced chronic inflammatory state leading to direct cellular damage, inflammatory-cytokine-mediated promotion of cellular proliferation and invasion, release of bacterial products that are carcinogenic, and suppression of local immunity by alteration of the tumor microenvironment. However, the actual interactions between these cellular mechanisms and their role in carcinogenesis are not yet fully understood. This review provides a comprehensive overview of the various hypotheses and mechanisms implicated in the ODIC, along with the corresponding molecular aberrations. Apart from discussing the usual constituents of the oral microbiome profile, the review also summarizes the various dysbiosis profiles implicated in ODIC. The review also sheds light on the potential clinical implications of the research on oral microbiome in the prevention and management of oral cancer. Full article

(This article belongs to the Special Issue Molecular Mechanisms and Therapeutic Approaches for Oral Disorders)

21 pages, 853 KiB

Open AccessReview

Harnessing Pharmacomultiomics for Precision Medicine in Diabetes: A Comprehensive Review

by Dhoha Dhieb, Dana Mustafa, Maryam Hassiba, May Alasmar, Mohamed Haitham Elsayed, Ameer Musa, Mahmoud Zirie and Kholoud Bastaki

Biomedicines 2025, 13(2), 447; https://doi.org/10.3390/biomedicines13020447 - 12 Feb 2025

Abstract

Type 2 diabetes (T2D) is the fastest-growing non-communicable disease worldwide, accounting for around 90% of all diabetes cases and imposing a significant health burden globally. Due to its phenotypic heterogeneity and composite genetic underpinnings, T2D requires a precision medicine approach personalized to individual [...] Read more.

Type 2 diabetes (T2D) is the fastest-growing non-communicable disease worldwide, accounting for around 90% of all diabetes cases and imposing a significant health burden globally. Due to its phenotypic heterogeneity and composite genetic underpinnings, T2D requires a precision medicine approach personalized to individual molecular profiles, thereby shifting away from the traditional “one-size-fits-all” medical methods. This review advocates for a thorough pharmacomultiomics approach to enhance precision medicine for T2D. It emphasizes personalized treatment strategies that enhance treatment efficacy while minimizing adverse effects by integrating data from genomics, proteomics, metabolomics, transcriptomics, microbiomics, and epigenomics. We summarize key findings on candidate genes impacting diabetic medication responses and explore the potential of pharmacometabolomics in predicting drug efficacy. The role of pharmacoproteomics in prognosis and discovering new therapeutic targets is discussed, along with transcriptomics’ contribution to understanding T2D pathophysiology. Additionally, pharmacomicrobiomics is explored to understand gut microbiota interactions with antidiabetic drugs. Emerging evidence on utilizing epigenomic profiles in improving drug efficacy and personalized treatment is also reviewed, illustrating their implications in personalized medicine. In this paper, we discuss the integration of these layers of omics data, examining recently developed paradigms that leverage complex data to deepen our understanding of diabetes. Such integrative approaches advance precision medicine strategies to tackle the disease by better understanding its complex biology. Full article

(This article belongs to the Special Issue Advancing Pharmacogenetics in Pre-clinical Research: Unveiling New Avenues for Precision Medicine)

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21 pages, 4940 KiB

Open AccessArticle

Metabolic Reprogramming in Gut Microbiota Exposed to Polystyrene Microplastics

by Jinhua Chi, Jeffrey S. Patterson, Yan Jin, Kyle Joohyung Kim, Nicole Lalime, Daniella Hawley, Freeman Lewis, Lingjun Li, Xuan Wang, Matthew J. Campen, Julia Yue Cui and Haiwei Gu

Biomedicines 2025, 13(2), 446; https://doi.org/10.3390/biomedicines13020446 - 12 Feb 2025

Abstract

Background: Microplastics (MPs) are small plastic fragments with diameters less than 5 mm in size and are prevalent in everyday essentials and consumables. Large global plastic production has now led to a flooding of MPs in our natural environment. Due to their [...] Read more.

Background: Microplastics (MPs) are small plastic fragments with diameters less than 5 mm in size and are prevalent in everyday essentials and consumables. Large global plastic production has now led to a flooding of MPs in our natural environment. Due to their detrimental impacts on the planet’s ecosystems and potentially our health, MPs have emerged as a significant public health concern. In this pilot study, we hypothesize that MPs exposure will negatively affect gut microbiota composition and function, in which metabolic reprogramming plays an important role. Methods: Using in vitro experiments, three bacterial strains (Escherichia coli MG1655, Nissle 1917, and Lactobacillus rhamnosus) were selected to investigate the impacts of MPs exposure. The bacterial strains were individually cultured in an anaerobic chamber and exposed to 1 µm polystyrene MPs at various concentrations (0, 10, 20, 50, 100, and 500 µg/mL) in the culture medium. Results: MPs exposure reduced the growth of all three bacterial strains in a dose-dependent manner. Liquid chromatography mass spectrometry (LC-MS)-based untargeted metabolomics revealed significant differences in multiple metabolic pathways, such as sulfur metabolism and amino sugar and nucleotide sugar metabolism. In addition, we extracted gut microbiota from C57BL/6 mice, and 16S rRNA sequencing results showed a significant upregulation of Lactobacillales and a significant reduction in Erysipelotrichales due to MPs exposure. Furthermore, targeted and untargeted metabolomics corroborated the in vitro results and revealed alterations in microbial tryptophan metabolism and energy producing pathways, such as glycolysis/gluconeogenesis and the pentose phosphate pathway. Conclusions: These findings provide evidence that MPs exposure causes comprehensive changes to healthy gut microbiota, which may also provide insights into the mechanistic effects of MPs exposure in humans. Full article

(This article belongs to the Special Issue Metabolomics Technology and Bioinformatics for Precision Medicine)

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15 pages, 2163 KiB

Open AccessArticle

Using a Natural Triterpenoid to Unlock the Antitumor Effects of Autophagy in B-Cell Lymphoma

by Bently P. Doonan, Faisal F. Y. Radwan, Naren L. Banik and Azizul Haque

Biomedicines 2025, 13(2), 445; https://doi.org/10.3390/biomedicines13020445 - 12 Feb 2025

Abstract

Background and Objective: Diffuse large B-cell lymphoma (DLBCL), a subtype of non-Hodgkin’s lymphoma, is the most common lymphoid malignancy in the Western world. Treatment of DLBCL has been greatly improved in recent years with the addition of the monoclonal antibody Rituximab to the [...] Read more.

Background and Objective: Diffuse large B-cell lymphoma (DLBCL), a subtype of non-Hodgkin’s lymphoma, is the most common lymphoid malignancy in the Western world. Treatment of DLBCL has been greatly improved in recent years with the addition of the monoclonal antibody Rituximab to the gold standard CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) chemotherapy regimen, but these treatments are often ineffective in patients with highly aggressive disease or patients of advanced age. While CAR-T cells have further advanced the treatment landscape of DLBCL, these often come at significant costs such as toxicity and financial costs for patients. Thus, research has recently focused on natural products that can selectively target malignant lymphomas while displaying a reduced host toxicity profile. Methods: In vitro cellular and biochemical approaches were used to analyze the effects of a natural extract from the Ganoderma lucidum mushroom (GA-DM) on autophagy and apoptosis in human and mouse B-cell lymphoma lines. In addition, in vivo approaches were applied to determine the effect of GA-DM on tumor growth and metastasis in a mouse model of B-cell lymphoma. Results: Here, we report, for the first time, that GA-DM induces apoptosis in the human B-cell lymphoma cell lines DB and Toledo, and orchestrates autophagy and apoptosis in the murine B-cell lymphoma cell line A20. While GA-DM differentially induced autophagy and apoptosis in mouse and human B-cell lymphomas, blocking apoptosis by the caspase inhibitor Z-VAD-FM reduced anti-proliferative activity in human B-cell lymphoma cells (DB: 71.6 ± 6.2% vs. 56.7 ± 2.4%; Toledo: 53.1 ± 10.6% vs. 14.6 ± 9.3%) in vitro. Antitumor efficacy of GA-DM was also investigated in vivo in a murine B-cell lymphoma model using the A20 cell line, where GA-DM treatment reduced both the number of tumor metastases (control: 5.5 ± 3.2 vs. GA-DM: 1.6 ± 0.87) and the overall tumor burden (control: 3.2 g ± 1.9 vs. GA-DM: 1.70 g ± 0.2) in diseased mice. Conclusions: These findings support the potential use of GA-DM as a novel chemotherapeutic in the treatment of DLBCL and could improve the treatment of higher-risk patients with advanced disease who cannot tolerate current chemotherapy treatments. Full article

(This article belongs to the Special Issue The Development of Cancer Immunotherapy)

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20 pages, 1477 KiB

Open AccessSystematic Review

Prognostic Value of Lectin-like Oxidized Low-Density Lipoprotein Receptor-1 for Future Cardiovascular Disease Risk and Outcome: A Systematic Review and Meta-Analysis

by Amilia Aminuddin, Nazirah Samah, Nur Aishah Che Roos, Shawal Faizal Mohamad, Boon Cong Beh, Adila A. Hamid and Azizah Ugusman

Biomedicines 2025, 13(2), 444; https://doi.org/10.3390/biomedicines13020444 - 12 Feb 2025

Abstract

Cardiovascular disease (CVD) remains a leading cause of mortality globally, underscoring the need for robust predictive biomarkers to enhance risk stratification. Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has emerged as a promising biomarker linked to oxidative stress and endothelial dysfunction, both critical [...] Read more.

Cardiovascular disease (CVD) remains a leading cause of mortality globally, underscoring the need for robust predictive biomarkers to enhance risk stratification. Soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) has emerged as a promising biomarker linked to oxidative stress and endothelial dysfunction, both critical mechanisms in atherogenesis and cardiovascular events. Objectives: This study aimed to evaluate the prognostic value of sLOX-1 in predicting major adverse cardiovascular and cerebrovascular events (MACCEs), myocardial infarction (MI), heart failure (HF), and stroke outcomes through a systematic review and meta-analysis. Methods: A systematic literature search was conducted across PubMed, Scopus, Web of Science, and Ovid databases for studies published between 2014 and October 2024. Eligible studies assessed the association between sLOX-1 levels and future CVD outcomes in adult populations. Meta-analysis pooled hazard ratios (HRs) were assessed using random- and fixed-effects models. Heterogeneity was evaluated using the I² statistic, and study quality was assessed using the Newcastle–Ottawa Scale. Results: Fourteen studies were included, encompassing diverse populations with coronary artery disease (CAD), acute coronary syndrome (ACS), or stroke, with follow-up durations ranging from 30 days to 19.5 years. The meta-analysis of three studies on CAD patients demonstrated a significant association between elevated sLOX-1 levels and increased MACCE risk (HR: 2.3, 95% CI: 0.99–5.33, p = 0.05), albeit with high heterogeneity (I² = 83%). The fixed-effects analysis yielded a more consistent HR of 1.47 (95% CI: 1.19–1.81, p < 0.01). Conclusions: sLOX-1 shows promising potential as a prognostic biomarker for CVD and is associated with an increased risk of MACCEs in CAD patients. However, the high heterogeneity among the included studies highlights the need for standardized protocols and larger, well-designed prospective studies to validate its clinical utility. The integration of sLOX-1 into risk prediction models could improve CVD management by identifying high-risk individuals for targeted interventions. Full article

(This article belongs to the Special Issue Cardiovascular and Metabolic Disease: New Treatment and Future Directions—the 3rd Edition)

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15 pages, 3032 KiB

Open AccessArticle

Antitumor Potential of Different Treatment Approaches Using Cold Atmospheric Pressure Plasma on Oral Squamous Cell Carcinoma Models: In Vitro Study

by Ognjan Pavlović, Miloš Lazarević, Aleksandar Jakovljević, Nikola Škoro, Nevena Puač, Slavko Mojsilović and Maja Miletić

Biomedicines 2025, 13(2), 443; https://doi.org/10.3390/biomedicines13020443 - 11 Feb 2025

Abstract

Background/Objectives: Cold atmospheric plasma (CAP) has shown a strong anticancer effect on a variety of tumors, presenting a new approach for the effective treatment of oral squamous cell carcinoma (OSCC), one of the most prevalent malignant neoplasms with a high mortality rate. Here, [...] Read more.

Background/Objectives: Cold atmospheric plasma (CAP) has shown a strong anticancer effect on a variety of tumors, presenting a new approach for the effective treatment of oral squamous cell carcinoma (OSCC), one of the most prevalent malignant neoplasms with a high mortality rate. Here, we aimed to comprehensively investigate the antitumor potential of two approaches of CAP treatment on both two-dimensional and three-dimensional OSCC cell line models, as well as to analyze whether plasma treatment enhances the sensitivity of OSCC to chemotherapy. Methods: An in-house designed plasma needle, with helium as a working gas, was used to treat the SCC-25 cell line directly or indirectly via plasma-treated medium (PTM). The antitumor effect of CAP was assessed by measuring cell viability, apoptosis, adhesion, and migration. In addition, the combined effect of PTM and cisplatin was analyzed in SCC-25 tumor spheroids, as a more complex and reliable in vitro model. Results: Both plasma treatments showed time-dependent antitumor effects affecting their viability, adhesion, and migration. The rate of apoptosis was higher after incubation with PTM and is mediated by the intrinsic pathway. By utilizing the 3D spheroid carcinoma model, we confirmed the antitumor potential of CAP and additionally demonstrated an increased chemosensitivity of PTM-treated carcinoma cells. Conclusions: The results of our study illustrate a promising avenue for the application of CAP as a therapeutic option for OSCC, either as a standalone treatment or in combination with cisplatin. Full article

(This article belongs to the Special Issue Applications and Perspectives of Cold Electric Discharge Plasmas in Biomedicine and Bioengineering)

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17 pages, 6547 KiB

Open AccessArticle

Preventative Effect of Angiotensin Receptor Blockers on Moderate-to-Severe Cerebral Vasospasm Among Patients Who Received Interventions for Aneurysmal Subarachnoid Hemorrhage

by Si Un Lee, Hyoung Soo Byoun, Min Jai Cho, Jeong-Wook Lim, Chang Hyeun Kim and Jae-Seung Bang

Biomedicines 2025, 13(2), 442; https://doi.org/10.3390/biomedicines13020442 - 11 Feb 2025

Abstract

Objectives: We conducted a retrospective study to investigate the effectiveness of angiotensin receptor blockers (ARBs) in preventing moderate-to-severe cerebral vasospasm, which may influence patient outcomes in cases of subarachnoid hemorrhage resulting from aneurysmal rupture. Methods: Between 2016 and 2020, we treated [...] Read more.

Objectives: We conducted a retrospective study to investigate the effectiveness of angiotensin receptor blockers (ARBs) in preventing moderate-to-severe cerebral vasospasm, which may influence patient outcomes in cases of subarachnoid hemorrhage resulting from aneurysmal rupture. Methods: Between 2016 and 2020, we treated 210 patients with aneurysmal subarachnoid hemorrhage (aSAH) caused by a ruptured cerebral aneurysm. We obtained the clinical and radiological characteristics of patients through medical records and divided them into two groups: those who were administered ARBs (ARB group) and those who were not (no-ARB group). Results: A total of 181 patients aged 19 years or older with aSAH, without vascular abnormalities (including vascular malformations and moyamoya disease), were enrolled in this study. The age of the enrolled patients was 59.01 ± 12.98 (mean ± standard deviation), and the sex ratio of males to females was 66:115, with a higher proportion of females. The ARB group had 29 and the no-ARB group had 152 participants. The overall incidence of moderate-to-severe vasospasm was 33.7%. The incidence of moderate-to-severe vasospasm in each group was 13.8% (4 patients) and 37.5% (57 patients), respectively. The Fisher grade (III–IV) [odds ratio (OR) of 2.732 (95% confidence interval [CI]: 1.343–5.560; p = 0.006)] independently increases the risk of moderate-to-severe vasospasm, while older age [OR = 0.963; 95% CI: 0.938–0.989; p = 0.006] and ARB administration [OR = 0.246; 95% CI: 0.079–0.771; p = 0.016] independently decrease this risk. Conclusions: Despite the potential adverse impacts associated with hypotension, the administration of ARBs may provide therapeutic benefits in preventing moderate-to-severe vasospasm. A multicenter randomized double-blind controlled trial is needed to further investigate the efficacy and safety of ARBs in preventing moderate-to-severe vasospasm in aSAH patients who have undergone interventions and are experiencing acute hypertension. Full article

(This article belongs to the Special Issue Cerebral Hemorrhages: From Pathophysiologic Mechanisms to Therapeutic Strategies)

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15 pages, 6044 KiB

Open AccessArticle

Integrative Analysis of Gene Expression and Promoter Methylation to Differentiate High-Grade Serous Ovarian Cancer from Benign Tumors

by Ieva Vaicekauskaitė, Paulina Kazlauskaitė, Rugilė Gineikaitė, Rūta Čiurlienė, Juozas Rimantas Lazutka and Rasa Sabaliauskaitė

Biomedicines 2025, 13(2), 441; https://doi.org/10.3390/biomedicines13020441 - 11 Feb 2025

Abstract

Background: Ovarian cancer (OC) is the third most common and second most lethal onco-gynecological disease in the world, with high-grade serous ovarian cancer (HGSOC) making up the majority of OC cases worldwide. The current serological biomarkers used for OC diagnosis are lacking sensitivity [...] Read more.

Background: Ovarian cancer (OC) is the third most common and second most lethal onco-gynecological disease in the world, with high-grade serous ovarian cancer (HGSOC) making up the majority of OC cases worldwide. The current serological biomarkers used for OC diagnosis are lacking sensitivity and specificity, thus new biomarkers are greatly needed. Recently, the chromatin remodeling complex gene ARID1A, Notch and Wnt pathway gene expression, as well as HOX-related gene promoter methylation have been linked with promoting OC. Methods: In this pilot study, 10 gene expression biomarkers and 4 promoter methylation biomarkers were examined as potential diagnostic and prognostic indicators of OC in 65 fresh-frozen gynecologic tumor tissues. Results: Out of 10 genes analyzed, the expression of eight biomarkers was significantly reduced in OC cases compared to benign, and HOX-related gene promoter methylation significantly increased in OC tumors. Out of 14 biomarkers, CTNNB1 showed the best single biomarker separation of HGSOC from benign cases (AUC = 0.97), while a combination of the seven Notch pathway-related gene expressions (NOTCH1, NOTCH2, NOTCH3, NOTCH4, DLL1, JAG2, and HES1) demonstrated the best separation of HGSOC from the benign cases (AUC = 1). Conclusions: The combination of multiple gene expression or gene promoter methylation biomarkers shows great promise for the development of an effective biomarker-based diagnostic approach for OC. Full article

(This article belongs to the Special Issue Gynecological Diseases in Cellular and Molecular Perspectives)

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8 pages, 205 KiB

Open AccessBrief Report

The Diagnostic Utility of Oligoclonal Bands in Multiple Sclerosis: A Time-Course Analysis

by Raffaella Candeloro, Caterina Ferri, Michele Laudisi, Eleonora Baldi, Maura Pugliatti and Massimiliano Castellazzi

Biomedicines 2025, 13(2), 440; https://doi.org/10.3390/biomedicines13020440 - 11 Feb 2025

Abstract

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) are a hallmark of MS and reflect intrathecal IgG synthesis and inflammation. This study aims to analyze the temporal distribution [...] Read more.

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). Oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) are a hallmark of MS and reflect intrathecal IgG synthesis and inflammation. This study aims to analyze the temporal distribution of IgG OCBs in the CSF of patients with a definitive diagnosis of MS. Methods: This retrospective study included 500 patients with diagnosed MS. Patients were divided into four groups according to diagnostic epochs: Group 1 (Pre-2001 or Pre-McDonald), Group 2 (2001–2010 or McDonald 2001-Polman 2010), Group 3 (2010–2018 or Polman 2010), and Group 4 (Post-2018 or Thompson 2017). Statistical analyses examined temporal and sex differences in OCB positivity rates. Results: OCB positivity was lower in Group 4 (69.2%) compared to Group 1 (85.4%) in the overall population (p = 0.0022). A decrease in OCB positivity was observed in Groups 3 (62.5%) and 4 (71.8%) compared to Group 1 (92.5%) among males (p = 0.0117 and p = 0.0198, respectively) and in Group 4 (68.1%) compared to Group 1 (82.5%) among females (p = 0.0274). Conclusions: The present study provides valuable insights into temporal trends in CSF positivity among patients diagnosed with MS. There was an overall decrease in OCB positivity rates over the years, particularly in the post-2018 period. Full article

(This article belongs to the Special Issue Biomedical and Biochemical Basis of Neurodegenerative Diseases)

19 pages, 4166 KiB

Open AccessArticle

The Plasma Membrane P-Type ATPase CtpA Is Required for Mycobacterium tuberculosis Virulence in Copper-Activated Macrophages in a Mouse Model of Progressive Tuberculosis

by Marcela López-Ruíz, Jorge Barrios-Payán, Milena Maya-Hoyos, Rogelio Hernández-Pando, Marisol Ocampo, Carlos Y. Soto and Dulce Mata-Espinosa

Biomedicines 2025, 13(2), 439; https://doi.org/10.3390/biomedicines13020439 - 11 Feb 2025

Abstract

Background/Objective: Finding new targets to attenuate Mycobacterium tuberculosis (Mtb) is key in the development of new TB vaccines. In this context, plasma membrane P-type ATPases are relevant for mycobacterial homeostasis and virulence. In this work, we investigate the role of [...] Read more.

Background/Objective: Finding new targets to attenuate Mycobacterium tuberculosis (Mtb) is key in the development of new TB vaccines. In this context, plasma membrane P-type ATPases are relevant for mycobacterial homeostasis and virulence. In this work, we investigate the role of the copper-transporting P-type ATPase CtpA in Mtb virulence. Methods: The impact of CtpA deletion on Mtb’s capacity to overcome redox stress and proliferate in mouse alveolar macrophages (MH-S) was evaluated, as well as its effect on Mtb immunogenicity. Moreover, the influence of CtpA on the pathogenicity of Mtb in a mouse (BALB/c) model of progressive TB was examined. Results: We found that MH-S cells infected with wild-type (MtbH37Rv) or the mutant strain (MtbH37RvΔctpA) showed no difference in Mtb bacterial load. However, the same macrophages under copper activation (50 µM CuSO₄) showed impaired replication of the mutant strain. Furthermore, the mutant MtbΔctpA strain showed an inability to control reactive oxygen species (ROS) induced by PMA addition during MH-S infection. These results, together with the high expression of the Nox2 mRNA observed in MH-S cells infected with the Mtb∆ctpA strain at 3 and 6 days post-infection, suggest a potential role for CtpA in overcoming redox stress under infection conditions. In addition, MtbΔctpA-infected BALB/c mice survived longer with significantly lower lung bacterial loads and tissue damage in their lungs than MtbH37Rv-infected mice. Conclusions: This suggests that CtpA is involved in Mtb virulence and that it may be a target for attenuation. Full article

(This article belongs to the Special Issue Progress in Protein Therapeutics)

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16 pages, 1017 KiB

Open AccessArticle

Alpha-Lipoic Acid Treatment Reduces the Levels of Advanced End Glycation Products in Type 2 Diabetes Patients with Neuropathy

by Sára Csiha, Marcell Hernyák, Ágnes Molnár, Hajnalka Lőrincz, Mónika Katkó, György Paragh, Miklós Bodor, Mariann Harangi, Ferenc Sztanek and Eszter Berta

Biomedicines 2025, 13(2), 438; https://doi.org/10.3390/biomedicines13020438 - 11 Feb 2025

Abstract

Background/Objectives: Type 2 diabetes mellitus (T2DM) and its macro- and microvascular complications are major health concerns with multiple factors, like advanced end glycation products (AGEs), in the background. AGEs induce long-lasting functional modification of the proteins and collagen in the vascular wall and [...] Read more.

Background/Objectives: Type 2 diabetes mellitus (T2DM) and its macro- and microvascular complications are major health concerns with multiple factors, like advanced end glycation products (AGEs), in the background. AGEs induce long-lasting functional modification of the proteins and collagen in the vascular wall and nerve tissue. We investigated the effect of alpha-lipoic acid (ALA) treatment on AGEs, soluble AGE receptor (sRAGE), the AGE/sRAGE ratio, and the parameters of endothelial dysfunction and their correlations. Methods: In our 6-month intervention study, 54 T2DM patients with neuropathy treated according to the actual therapeutic guidelines with unchanged oral antidiabetic drugs were included and treated by daily oral administration of 600 mg ALA. A total of 24 gender and age-matched T2DM patients without neuropathy served as controls. Results: In our work, we first demonstrated the attenuating effect of alpha lipoic acid therapy on AGEs in humans (11.89 (9.44–12.88) to 10.95 (9.81–12.82) AU/μg (p = 0.017)). sRAGE levels or the AGEs/sRAGE ratio were not affected by ALA treatment or by the presence of neuropathy. We found a correlation between the changes of AGEs and the improvement of current perception threshold and progranulin levels, and an inverse correlation with the change of asymmetric dimethylarginine. Conclusions: According to our results, ALA decreases AGEs, which may contribute to the clinically well-known beneficial effect in diabetic neuropathy and improvement of endothelial function. Full article

(This article belongs to the Special Issue Advanced Research in Metabolic Syndrome)

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14 pages, 1702 KiB

Open AccessArticle

Effect of Gender on Patients with Non-Small-Cell Lung Cancer Treated with Immune Checkpoint Inhibitors: A Real-World Study

by Teresa Calleja-Chucla, Patricia Cordeiro González, Alejandro Martínez Pradeda, Sonia Pértega-Díaz, Luis Margusino-Framiñán and Silvia Antolín Novoa

Biomedicines 2025, 13(2), 437; https://doi.org/10.3390/biomedicines13020437 - 11 Feb 2025

Abstract

Objective: To evaluate the differences in overall survival (OS) and progression-free survival (PFS) between men and women with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) in second-line and later treatments. Methods: A retrospective, single-center observational study was conducted on patients [...] Read more.

Objective: To evaluate the differences in overall survival (OS) and progression-free survival (PFS) between men and women with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) in second-line and later treatments. Methods: A retrospective, single-center observational study was conducted on patients with advanced NSCLC treated with ICIs (nivolumab, pembrolizumab, and atezolizumab) from January 2015 to December 2019 (with follow-up until December 2021). Demographic, clinical, and treatment-related variables were collected. OSand PFSwere analyzed using the Kaplan–Meier method and compared between genders using the log-rank test.A multivariate Cox regression analysis was performed to adjust for confounders. Results: A total of 189 patients were included, and 47 (25%) were women. The most common histology was adenocarcinoma (61%). Women began treatment at a younger age (59.8 vs. 66 years, p < 0.001) and had higher rates of active smoking (46.8% vs. 38%, p = 0.001). The median OS was similar between men (9.5 months, 95% CI: 7.1–11.8) and women (9.2 months, 95% CI: 3.3–15.2; p = 0.382) while PFS was significantly higher in males (3.2 months, 95% CI: 2.5–4.0) than in females (2.1 months; 95% CI = 1.6–2.5) (p = 0.002).Women had higher rates of tumor cachexia (BMI < 20).Worse PFS was observed for women both in the <20 kg/m² (median PFS: 1.8 vs. 2.7 months, p = 0.016) and 20–24.9 kg/m² groups (median PFS: 2.2 vs. 3.3 months, p = 0.077), while in patients with a BMI >= 25 kg/m², median OS was higher in women than in men (14.7 months vs. 10.1 months). Women had also a significantly worse PFS than men among those with a cumulative tobacco consumption of <30 packs-year (median PFS: 2.2 vs. 3.2, p = 0.038. In the multivariate analysis, the male sex was significantly associated with a better PFS(HR = 0.59; p = 0.009), without significant differences between sexes in OS (HR = 0.90; p = 0.618). Among the other variables analyzed, only an ECOG >= 2 was significantly associated with both worse OS (HR = 3.53; 95% CI = 1.93–6.47) and PFS (HR = 2.19; 95% CI = 1.23–3.89). Women who discontinued due to toxicity (n = 7) had a median OS of 41.4 months (95% CI: 14.7–68.1) after discontinuation, whereas men (n = 15) had a median OS of 8.8 months (95% CI: 6.9–10.8), (p = 0.045). Conclusions: Sex-based differences were observed in the ICI outcomes. Women had worse PFS, particularly with lower BMI and lower tobacco exposure, despite similar OS between sexes. Women discontinued ICIs due to toxicity earlier but showed longer OS after discontinuation. Poor ECOG status was linked to worse outcomes across all the patients. Full article

(This article belongs to the Special Issue Women’s Special Issue Series: Biomedicines (2nd Edition))

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4 pages, 176 KiB

Open AccessEditorial

Neutrophils, Fast and Strong 2.0: Heterogeneity of Neutrophil Parameters in Health and in Disease

by Galina F. Sud’ina

Biomedicines 2025, 13(2), 436; https://doi.org/10.3390/biomedicines13020436 - 11 Feb 2025

Abstract

Neutrophils are very important cells of the immune system, and every year, new nuances of their functional activity in the body and participation in various pathological processes are discovered [...] Full article

(This article belongs to the Special Issue Neutrophils, Fast and Strong 2.0)

11 pages, 547 KiB

Open AccessArticle

Cardiovascular Risk Factors in Middle-Aged Lithuanian Men: A Comparative Study of an Apparently Resistant Hypertension Group

by Vaida Šileikienė, Vilma Dženkevičiūtė, Alma Čypienė, Martynas Bublys, Roma Puronaitė, Jolita Badarienė, Aleksandras Laucevičius, Eglė Butkevičiūtė and Egidija Rinkūnienė

Biomedicines 2025, 13(2), 435; https://doi.org/10.3390/biomedicines13020435 - 11 Feb 2025

Abstract

Background/Objectives: Hypertension (HTN) is a significant risk factor for cardiovascular disease (CVD), and a subset of patients exhibits apparently resistant hypertension (aRHTN), where blood pressure remains inadequately controlled despite treatment. This study aims to assess the prevalence of cardiovascular risk factors in [...] Read more.

Background/Objectives: Hypertension (HTN) is a significant risk factor for cardiovascular disease (CVD), and a subset of patients exhibits apparently resistant hypertension (aRHTN), where blood pressure remains inadequately controlled despite treatment. This study aims to assess the prevalence of cardiovascular risk factors in middle-aged Lithuanian men with HTN and aRHTN, as well as to evaluate the effectiveness of hypertension management in these groups. Methods: Data from 52,012 men participating in the Lithuanian High Cardiovascular Risk Programme (LitHiR) between 2009 and 2019 were analysed. Participants were categorised into two groups: treated hypertension (HTN) and apparent resistant hypertension (aRHTN). Despite treatment, the aRHTN group included those who failed to achieve their target blood pressure. The prevalence of cardiovascular risk factors (dyslipidaemia, diabetes, metabolic syndrome, obesity, physical inactivity, and an unbalanced diet) was compared between the groups. Results: The overall prevalence of HTN was 47%, with 9.9% of treated hypertensive men having aRHTN. Dyslipidemia was both groups’ most prevalent risk factor (94.1% in HTN vs. 95.5% in aRHTN, p < 0.001). Men with aRHTN exhibited higher rates of diabetes (25.9% vs. 18.5%, p < 0.001), metabolic syndrome (75.3% vs. 66.3%, p < 0.001), and left ventricular hypertrophy (59.4% vs. 43.1%, p < 0.001). Treatment success was significantly lower in the aRHTN group (7.57% vs. 28.4%, p < 0.001). Conclusions: Hypertension affects almost half of the studied population, with 10% of treated hypertensives exhibiting aRHTN. The aRHTN group had a higher number of additional cardiovascular risk factors and lower treatment success rates. Improved management of cardiovascular risk factors is crucial, especially in the aRHTN population, to reduce the burden of CVD. Full article

(This article belongs to the Section Molecular and Translational Medicine)

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Biomedicines, Volume 13, Issue 2 (February 2025) – 217 articles

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