Biomedicines

9 pages, 630 KiB

Open AccessArticle

Copper and Zinc Levels, Prevalence of Common Variants of Genes Involved in Their Metabolism and Psoriasis Disease

by Tadeusz Dębniak, Piotr Baszuk, Ewa Duchnik, Karolina Rowińska, Magdalena Boer, Magdalena Kiedrowicz, Mariola Marchlewicz, Cezary Cybulski, Martyna Feherpataky, Róża Derkacz, Anna Dębniak, Emilia Rogoża-Janiszewska, Wojciech Marciniak, Marcin Lener, Jan Lubiński, Rodney J. Scott and Jacek Gronwald

Biomedicines 2025, 13(2), 529; https://doi.org/10.3390/biomedicines13020529 - 19 Feb 2025

Abstract

Background: The pathogenesis of psoriasis is poorly understood. Increased reactive oxygen species (ROS) and lipid peroxidation are crucial in the inflammatory processes, including psoriasis. Thus, microelements, such as zinc and copper, may play a significant role in this disease’s development. Methods: Due to [...] Read more.

Background: The pathogenesis of psoriasis is poorly understood. Increased reactive oxygen species (ROS) and lipid peroxidation are crucial in the inflammatory processes, including psoriasis. Thus, microelements, such as zinc and copper, may play a significant role in this disease’s development. Methods: Due to the paucity and inconsistency of literature data, we studied the levels of copper and zinc in blood and serum from 301 unselected psoriatic patients and 301 matched healthy controls and examined any associations among the microelements and clinical course or SOD2 (rs4880), CAT (rs1001179), GPX1 (rs1050450), and DMGDH (rs921943) DNA variants. Results: The mean blood copper levels were 864.94 µg/L and 907.24 µg/L, respectively, for controls and psoriasis patients (p < 0.001). The mean serum copper levels were 1,104.14 µg/L and 1191.72 µg/L, respectively, for controls and psoriasis patients (p < 0.001). The psoriasis risk was highest the among participants with the highest blood levels (>950.02 µg/L, OR: 2.36; 95% CI: 1.31–4.26; p = 0.004) and the highest serum concentrations (>1276.98 µg/L, OR: 3.08; 95% CI: 1.77–5.36; p < 0.001). The mean serum zinc levels were significantly lower (p < 0.001) among patients (910.87 µg/L) when compared to controls (979.68 µg/L). The mean blood zinc levels were not significantly different in cases and controls. Subjects with the lowest serum zinc levels (<843.68 µg/L) were affected more frequently (OR: 3.85; 95% CI: 2.24–6.60; p < 0.001). We found positive correlations between copper levels and PASI and inverse correlations of serum zinc levels with PASI and NAPSI scores. There were no associations between the levels of microelements and studied DNA variants. Conclusions: Our results support the thesis of an association between psoriasis onset and altered course of the disease with upset levels of copper and zinc. Future prospective studies might focus on optimization of the concentration of these trace elements for prophylaxis and to support the treatment of psoriasis. Full article

(This article belongs to the Section Molecular Genetics and Genetic Diseases)

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4 pages, 171 KiB

Open AccessEditorial

Perspectives, Challenges, and Advances in Therapeutic Strategies for Gynecological Malignant Tumors

by Alberto Farolfi, Daniela Montanari, Chiara Casadei and Antonino Musolino

Biomedicines 2025, 13(2), 528; https://doi.org/10.3390/biomedicines13020528 - 19 Feb 2025

Abstract

For years, treatment options for advanced gynecological malignancies have been limited, with the combination of carboplatin and paclitaxel being the preferred first-line therapeutic approach, regardless of disease type [...] Full article

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

22 pages, 7554 KiB

Open AccessArticle

Bioactive Carbon Dots from Clove Residue: Synthesis, Characterization, and Osteogenic Properties

by Hye-Sun Hong, Hee-Jung Park, Ji-Min Lee, Zu-Yu Chen, Tae-Woo Kim, Yong-Seok Seo, Jun-Won Kang and Young-Kwon Seo

Biomedicines 2025, 13(2), 527; https://doi.org/10.3390/biomedicines13020527 - 19 Feb 2025

Abstract

Background/Objectives: Bone regeneration using nanomaterial-based approaches shows promise for treating critical bone defects. However, developing sustainable and cost-effective therapeutic materials remains challenging. This study investigates the osteogenic potential of clove-derived carbon dots (C-CDs) for bone regeneration applications. Methods: C-CDs were synthesized [...] Read more.

Background/Objectives: Bone regeneration using nanomaterial-based approaches shows promise for treating critical bone defects. However, developing sustainable and cost-effective therapeutic materials remains challenging. This study investigates the osteogenic potential of clove-derived carbon dots (C-CDs) for bone regeneration applications. Methods: C-CDs were synthesized using a green hydrothermal method. The osteogenic potential was evaluated in human bone marrow-derived mesenchymal stem cells (hBM-MSCs) and validated using ectopic bone formation and calvarial defect models. Results: C-CDs demonstrated uniform morphology (~10 nm) with efficient cellular uptake. In vitro studies showed successful osteogenic differentiation through the upregulation of RUNX2, ALP, COL1A1, and BMP-2 mediated by Wnt/β-catenin/GSK3β and BMP signaling pathways. In vivo models have also demonstrated that C-CDs are effective in promoting bone regeneration. Conclusions: These findings establish C-CDs as promising candidates for bone regeneration therapy, offering a sustainable alternative to current treatments. While optimization is needed, their demonstrated osteogenic properties warrant further development for regenerative medicine applications. Full article

(This article belongs to the Special Issue Antioxidant Materials with Additional Biological Properties)

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19 pages, 2600 KiB

Open AccessReview

Microbiota and Radiotherapy: Unlocking the Potential for Improved Gastrointestinal Cancer Treatment

by Damir Vučinić, Arnela Redžović, Goran Hauser and Ivana Mikolašević

Biomedicines 2025, 13(2), 526; https://doi.org/10.3390/biomedicines13020526 - 19 Feb 2025

Abstract

Radiotherapy (RT) is one of the major cornerstones in managing gastrointestinal (GI) cancers. However, several side effects, such as intestinal inflammation, mucosal injury, and dysbiosis, often compromise this. The gut microbiota increasingly attracts much interest as an essential modulator of RT effects influencing [...] Read more.

Radiotherapy (RT) is one of the major cornerstones in managing gastrointestinal (GI) cancers. However, several side effects, such as intestinal inflammation, mucosal injury, and dysbiosis, often compromise this. The gut microbiota increasingly attracts much interest as an essential modulator of RT effects influencing immune responses and tissue repair. Through short-chain fatty acids such as butyrate, representatives of certain bacterial species play a crucial role under normal conditions, keeping the mucosal integrity intact and reducing oxidative stress-mediated damage. Dysbiosis, a state where diminished microbial diversity and increased pathogenic species in the microbiota are seen, amplifies RT-induced toxicity in patients. Clinical investigations highlight that microbiota-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation, hold the means to augment RT efficacy and lessen toxicity. Increased microflora diversity and specific microbial profiles have yielded serious patient improvements. Advanced RT methods use stereotactic body radiotherapy combined with microbiota modulation as a promising technique to shield healthy tissue and maximize immune-mediated antitumor effects. Additionally, there is an implication in tumor behavior regulated by the intratumoral microbiota regarding the response to radiotherapy. Notably, the modulation of gut and tumor microbiota provides an avenue to optimize RT benefits in GI cancers, underscoring the importance of personalized therapy. Full article

(This article belongs to the Special Issue Digestive Disorders: Translation and Bridging the Gap Between Research, Diagnosis, and Treatment)

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16 pages, 3250 KiB

Open AccessArticle

Histological Alterations and Interferon-Gamma and AKT-mTOR Expression in an Experimental Model of Achilles Tendinopathy—A Comparison of Stem Cell and Amniotic Membrane Treatment

by Guilherme Vieira Cavalcante, Rosangela Fedato, Lucia de Noronha, Seigo Nagashima, Ana Paula Camargo Martins, Márcia Olandoski, Ricardo Pinho, Aline Takejima, Rossana Simeoni, Julio Cesar Francisco and Luiz César Guarita Souza

Biomedicines 2025, 13(2), 525; https://doi.org/10.3390/biomedicines13020525 - 19 Feb 2025

Abstract

Achilles tendon injuries are extremely common and have a significant impact on the physical and mental health of individuals. Both conservative and surgical treatments have unsatisfactory results. The search for new therapeutic tools, using cell therapies with stem cells (SC) and biological tissues, [...] Read more.

Achilles tendon injuries are extremely common and have a significant impact on the physical and mental health of individuals. Both conservative and surgical treatments have unsatisfactory results. The search for new therapeutic tools, using cell therapies with stem cells (SC) and biological tissues, such as amniotic membranes (AM), has proved useful for the regeneration of injured tendons. Background/Objectives: This research was carried out to assess the capacity of tissue repair in animal models of Achilles tendinopathy, in which rats were submitted to complete sections of the tendon, and the effects of using bone marrow SC and/or AM graft are evaluated. Methods: Thirty-seven Wistar rats, submitted to complete surgical section of the Achilles tendon and subsequent tenorrhaphy, were randomized into four groups: Control Group (CG), received saline solution; SC Group (SCG) received an injection of SC infiltrated directly into the tendon; AM Group (AMG), the tendon was covered with an AM graft; SC + AM Group (SC+AMG), has been treated with an AM graft and SC local injection. Six weeks later, the Achilles tendons were evaluated using a histological score and immunohistochemical pro-healing markers such as Interferon-γ, AKT, and mTOR. Results: There were no differences between morphometric histological when evaluating the Achilles tendons of the samples. No significant differences were found regarding the expression of AKT-2 and mTOR markers between the study groups. The main finding was the presence of a higher concentration of Interferon-γ in the group treated with SC and AM. Conclusions: The isolated use of SC, AM, or the combination of SC-AM did not produce significant changes in tendon healing when the histological score was evaluated. Similarly, no difference was observed in the expression of AKT-2 and mTOR markers. An increase in the expression of Interferon-γ was observed in SC+AMG. This suggests that such therapies may be potentially beneficial for the regeneration of injured tendons. However, as tendon repair mechanisms are very complex, further studies should be carried out to verify the benefits of the tendon structure and function. Full article

(This article belongs to the Special Issue Advances in Immune Cell Biology: Insights from Molecular Perspectives)

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13 pages, 2507 KiB

Open AccessArticle

Expression of E-CADHERIN and miR-200b in Different Forms of Endometriosis

by Konstantinos Ntzeros, Charalampos Voros, Despoina Mavrogianni, Nikolaos Kathopoulis, Konstantinos Kypriotis, Antonia Varthaliti, Menelaos Darlas, Athanasios Douligeris and Athanasios Protopapas

Biomedicines 2025, 13(2), 524; https://doi.org/10.3390/biomedicines13020524 - 19 Feb 2025

Abstract

Background/Objectives: Epithelial–Mesenchymal Transition (EMT) is the process by which epithelial cells acquire mesenchymal properties, which helps endometriotic cells migrate and invade. This study looks at the expression of E-CADHERIN, a critical epithelial marker, and miR-200b, an EMT regulator, in several types [...] Read more.

Background/Objectives: Epithelial–Mesenchymal Transition (EMT) is the process by which epithelial cells acquire mesenchymal properties, which helps endometriotic cells migrate and invade. This study looks at the expression of E-CADHERIN, a critical epithelial marker, and miR-200b, an EMT regulator, in several types of endometriosis, including endometriomas and deep infiltrating endometriotic (DIE) nodules. Methods: We examined 19 individuals with endometriosis (9 with just endometriotic cysts and 10 with both DIE and endometriotic cysts) and 8 controls with benign gynecological abnormalities. Tissue samples were taken during laparoscopic surgery, and E-CADHERIN and miR-200b expression were measured using Real-Time PCR, with G6PD and U6 as controls. Results:E-CADHERIN expression was maintained in the eutopic endometrium of both ovarian and DIE types, but it was considerably reduced in endometriotic cysts, indicating heightened mesenchymal features. miR-200b was downregulated in the eutopic endometrium of ovarian endometriosis but upregulated in DIE. Endometriotic cysts in both groups had greater miR-200b expression than their corresponding eutopic endometrium. E-CADHERIN and miR-200b expression in DIE lesions was similar to that found in matched eutopic endometrium. Conclusions: The regulation of E-CADHERIN and miR-200b varies across ovarian and DIE lesions. The miR-200b-ZEB1 feedback loop is increased in DIE eutopic endometrium but downregulated in ovarian endometriosis. E-CADHERIN downregulation in endometriotic cysts indicates heightened mesenchymal dynamics, whereas DIE nodules have gene expression patterns similar to eutopic endometrium. These findings emphasize the distinct regulatory processes that govern endometriotic lesions. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis 4.0)

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23 pages, 1278 KiB

Open AccessReview

Advances and Challenges in Modeling Autosomal Dominant Polycystic Kidney Disease: A Focus on Kidney Organoids

by Jinglan Gu, Fei Liu, Lu Li and Jianhua Mao

Biomedicines 2025, 13(2), 523; https://doi.org/10.3390/biomedicines13020523 - 19 Feb 2025

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent hereditary disorder characterized by distinct phenotypic variability that has posed challenges for advancing in-depth research. Recent advancements in kidney organoid construction technologies have enabled researchers to simulate kidney development and create simplified in vitro [...] Read more.

Autosomal dominant polycystic kidney disease (ADPKD) is a prevalent hereditary disorder characterized by distinct phenotypic variability that has posed challenges for advancing in-depth research. Recent advancements in kidney organoid construction technologies have enabled researchers to simulate kidney development and create simplified in vitro experimental environments, allowing for more direct observation of how genetic mutations drive pathological phenotypes and disrupt physiological functions. Emerging technologies, such as microfluidic bioreactor culture systems and single-cell transcriptomics, have further supported the development of complex ADPKD organoids, offering robust models for exploring disease mechanisms and facilitating drug discovery. Nevertheless, significant challenges remain in constructing more accurate ADPKD disease models. This review will summarize recent advances in ADPKD organoid construction, focusing on the limitations of the current techniques and the critical issues that need to be addressed for future breakthroughs. New and Noteworthy: This review presents recent advancements in ADPKD organoid construction, particularly iPSC-derived models, offering new insights into disease mechanisms and drug discovery. It focuses on challenges such as limited vascularization and maturity, proposing potential solutions through emerging technologies. The ongoing optimization of ADPKD organoid models is expected to enhance understanding of the disease and drive breakthroughs in disease mechanisms and targeted therapy development. Full article

(This article belongs to the Special Issue Glomerular Disease and Cystic Kidney Disease: From Pathogenesis to Novel Therapeutic Approaches)

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9 pages, 199 KiB

Open AccessCommentary

Should We Accept the Epiligament Theory About the Differences in the Healing Potential of the Medial Collateral and the Anterior Cruciate Ligament?

by Georgi P. Georgiev, Lyubomir Gaydarski and Boycho Landzhov

Biomedicines 2025, 13(2), 522; https://doi.org/10.3390/biomedicines13020522 - 19 Feb 2025

Abstract

The epiligament (EL), described in 1990 as a connective tissue layer distinguishable from the ligament proper, has only recently gained recognition for its critical role in ligament function and repair. Previously overlooked, the EL is now understood to be a dynamic structure, particularly [...] Read more.

The epiligament (EL), described in 1990 as a connective tissue layer distinguishable from the ligament proper, has only recently gained recognition for its critical role in ligament function and repair. Previously overlooked, the EL is now understood to be a dynamic structure, particularly in the context of medial collateral ligament (MCL) healing. Rat model studies demonstrate that the EL actively contributes to ligament repair by serving as a source of cells and blood vessels, findings later corroborated in human studies. The EL’s role in spontaneous MCL healing highlights its importance, raising the question of whether differences in EL morphology and activity contribute to the poor healing capacity of the anterior cruciate ligament (ACL). Comparative studies reveal significant disparities in EL cellularity and activity between the ACL and MCL. The EL of the MCL is hypercellular, with robust expression markers like α-smooth muscle actin (α-SMA) and collagen types III and V, essential for tissue remodeling and structural integrity. Conversely, the ACL’s EL is less vascularized and exhibits weaker expression of these markers. While vascular endothelial growth factor (VEGF) promotes angiogenesis, its effectiveness is limited in the ACL due to restricted vascularization. Similarly, CD34, a progenitor cell marker, is more prominently expressed in the MCL’s EL, further supporting its superior healing potential. These findings suggest that the EL’s distinct structural and functional attributes are key determinants of ligament healing. Targeting the EL’s regenerative properties offers a promising therapeutic strategy, particularly for improving ACL repair outcomes. Further research is necessary to validate and expand these findings. Full article

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

16 pages, 3095 KiB

Open AccessArticle

Long-Term Outcomes of Patients with Poor Prognostic Factors Following Transanal Endoscopic Microsurgery (TEMS) for Early Rectal Cancer

by Muneeb Ul Haq, Khaled Noureldin, David Mark Pritchard, Arthur Sun Myint, Carrie A. Duckworth, Ngu Wah Than, David M. Hughes, Shakil Ahmed and Muhammad Ahsan Javed

Biomedicines 2025, 13(2), 521; https://doi.org/10.3390/biomedicines13020521 - 19 Feb 2025

Abstract

Background: Transanal endoscopic microsurgery (TEMS) is an organ-preserving approach for treatment of early rectal cancer (ERC). However, adverse histopathological features identified post-TEMS often necessitate adjuvant therapy. This study aims to compare the long-term oncological outcomes of patients who underwent TEMS and were offered [...] Read more.

Background: Transanal endoscopic microsurgery (TEMS) is an organ-preserving approach for treatment of early rectal cancer (ERC). However, adverse histopathological features identified post-TEMS often necessitate adjuvant therapy. This study aims to compare the long-term oncological outcomes of patients who underwent TEMS and were offered adjuvant treatments with total mesorectal excision (TME), chemoradiotherapy (CRT), radiotherapy (RT), active surveillance, or dose escalation with contact X-ray brachytherapy (CXB). Methods: This study included patients treated with TEMS for ERC between September 2012 and December 2022, with follow-up until December 2023. Patients with adverse histopathological features (extra-mural venous invasion, lympho-vascular invasion, R1 margins, tumour budding) were assigned to adjuvant treatments. Inverse probability of treatment weighting (IPTW) was applied to mitigate selection bias. Results: Of the 117 patients, 24 underwent TME, 17 received CRT, 25 received RT, 14 underwent active surveillance, and 37 patients received CXB boost along with CRT. The median follow-up was 60 months (IQR 52–73). During this time, 29 patients developed recurrence, and 15 died. The 5-year overall survival (OS) was 78.6%, and disease-free survival (DFS) was 70.9%. Compared to CXB, the mortality risk for CRT (HR = 0.81; 95% CI: 0.20–3.28; p = 0.77) and TME (HR = 3.68; 95% CI: 0.46–29.79; p = 0.22) was not significantly different. However, TME was associated with a significantly higher recurrence risk compared to CXB (HR = 7.57; 95% CI: 1.23–46.84; p = 0.029). Conclusions: An organ-preserving strategy with CRT or CRT combined with a CXB boost may offer comparable long-term outcomes and reduced recurrence risks for patients undergoing TEMS for ERC with poor prognostic features. Further research with larger cohorts is needed to validate these results. Full article

(This article belongs to the Special Issue Pancreatic, Liver, Biliary Tract and Intestinal Diseases: Pathogenesis, Diagnostics and Therapy)

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14 pages, 655 KiB

Open AccessArticle

Combination of Cannabidiol with Cisplatin or Paclitaxel Analysis Using the Chou–Talalay Method and Chemo-Sensitization Evaluation in Platinum-Resistant Ovarian Cancer Cells

by Jana Ismail, Wassim Shebaby, Shirine Azar Atallah, Robin I. Taleb, Sara Kawrani, Wissam Faour and Mohamad Mroueh

Biomedicines 2025, 13(2), 520; https://doi.org/10.3390/biomedicines13020520 - 19 Feb 2025

Abstract

Background/Objectives: Cannabidiol (CBD) is known for its anti-cancer properties in preclinical models and is increasingly used alongside conventional chemotherapy in cancer treatment. This study aims to evaluate the anti-cancer activity of CBD from Lebanese Cannabis sativa as a monotherapy and in combination with [...] Read more.

Background/Objectives: Cannabidiol (CBD) is known for its anti-cancer properties in preclinical models and is increasingly used alongside conventional chemotherapy in cancer treatment. This study aims to evaluate the anti-cancer activity of CBD from Lebanese Cannabis sativa as a monotherapy and in combination with cisplatin or paclitaxel on human ovarian adenocarcinoma cells. Methods: Cytotoxicity of CBD was tested on OVCAR-3 and SK-OV-3 cell lines using the MTS assay. The Chou–Talalay method and CompuSyn software were used to determine the combination indices (CIs) for predicting interactions between CBD and chemotherapeutic agents. CBD showed dose-dependent tumor growth inhibition at 72 h with comparable IC₅₀ values for both cell lines. Results: The combination of CBD with cisplatin or paclitaxel showed significant antagonistic interaction in SK-OV-3 cells (CI > 1), but mild synergism (CI < 1) at high growth inhibition rates (95% and 97%) was observed in SK-OV-3 cells with CBD/cisplatin. Pure antagonism was found in OVCAR-3 cells with CBD/cisplatin. Priming SK-OV-3 cells with CBD reduced the IC₅₀ values of both drugs significantly, with a similar effect seen when cells were primed with cisplatin or paclitaxel before CBD treatment. Conclusions: Integrating CBD with chemotherapy could improve cancer therapy and address drug resistance. Sequential administration of CBD and chemotherapeutic agents is more beneficial than simultaneous administration. Further in vivo studies are necessary to validate these findings and understand CBD’s interactions with other drugs fully. Full article

(This article belongs to the Special Issue Compounds from Natural Products as Sources for Drug Discovery)

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16 pages, 785 KiB

Open AccessReview

Exploring the Utility of Renal Resistive Index in Critical Care: Insights into ARDS and Cardiac Failure

by Giuseppe Cuttone, Giulio Geraci, Luigi La Via, Massimiliano Sorbello, Federico Pappalardo and Caterina Carollo

Biomedicines 2025, 13(2), 519; https://doi.org/10.3390/biomedicines13020519 - 19 Feb 2025

Abstract

The renal resistive index (RRI), a Doppler ultrasound-derived parameter measuring renal vascular resistance, has emerged as a promising non-invasive tool to evaluate renal hemodynamics in critically ill patients, particularly those with acute respiratory distress syndrome (ARDS) and heart failure (HF). This narrative review [...] Read more.

The renal resistive index (RRI), a Doppler ultrasound-derived parameter measuring renal vascular resistance, has emerged as a promising non-invasive tool to evaluate renal hemodynamics in critically ill patients, particularly those with acute respiratory distress syndrome (ARDS) and heart failure (HF). This narrative review examines the current evidence for RRI measurement in these conditions, exploring its physiological bases, methodology, clinical applications, and limitations. In ARDS, RRI reflects the complex interactions between positive pressure ventilation, hypoxemia, and systemic inflammation, showing a role in predicting acute kidney injury and monitoring response to interventions. In HF, RRI is able to assess venous congestion and cardiorenal interactions and can also serve as a prognostic indicator. Many studies have shown RRI’s superiority or complementarity to traditional biomarkers in predicting renal dysfunction, although its interpretation requires consideration of multiple patient-related factors. Key challenges include operator dependency, lack of standardization, and complex interpretation in multi-organ dysfunction. Future research should focus on measurement standardization, development of automated techniques, investigation of novel applications like intraparenchymal renal resistive index variation, and validation of RRI-guided management strategies. Despite its limitations, RRI represents a valuable tool that offers bedside and real-time insights into renal hemodynamics and potential guidance for therapeutic interventions. Further research is needed to fully clarify its clinical potential and address current limitations, particularly in critical care settings involving multiple organ dysfunction. Full article

(This article belongs to the Special Issue Kidney Diseases in Critical Ill Patients)

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5 pages, 171 KiB

Open AccessEditorial

New Advances in Chronic Kidney Disease: Biology, Diagnosis and Therapy

by Susana Coimbra and Alice Santos-Silva

Biomedicines 2025, 13(2), 518; https://doi.org/10.3390/biomedicines13020518 - 19 Feb 2025

Abstract

Chronic kidney disease (CKD) is characterized by a progressive and usually irreversible deterioration of renal function [...] Full article

(This article belongs to the Special Issue New Advances in Chronic Kidney Disease: Biology, Diagnosis and Therapy)

12 pages, 571 KiB

Open AccessArticle

Low-Burden Oligometastatic Disease of the Lung Treated with Robotic Stereotactic Ablative Radiotherapy: A Retrospective Study

by Anna Zygogianni, Ioannis M. Koukourakis, Zoi Liakouli, Dimitra Desse, Ioannis Georgakopoulos, Christina Armpilia, Georgia Lymperopoulou and Vasileios Kouloulias

Biomedicines 2025, 13(2), 517; https://doi.org/10.3390/biomedicines13020517 - 19 Feb 2025

Abstract

Background/Objectives: The lung is the most common site of metastases, regardless of the cancer subtype. Treating oligometastatic disease with surgery or stereotactic ablative radiotherapy (SABR) may improve patient survival. Methods: We retrospectively analyzed 41 patients with limited (one or two lesions, [...] Read more.

Background/Objectives: The lung is the most common site of metastases, regardless of the cancer subtype. Treating oligometastatic disease with surgery or stereotactic ablative radiotherapy (SABR) may improve patient survival. Methods: We retrospectively analyzed 41 patients with limited (one or two lesions, max dimension <3 cm) lung-only metastatic disease that were treated with the CK M6 robotic radiosurgery system in our Department, in terms of treatment efficacy and toxicity. Results: Acute and late toxicity was negligible (4 out of 41 patients developed grade 2 or 3 lung fibrosis). Six months post-SABR, complete response was achieved in 18 out of 41 patients (43.9%), while the rest of the cases exhibited major responses. A biological effective dose (BED_α/β=10) in the range of 100 Gy appears to be equally effective with higher doses. Within a median follow-up of 34 months, only three patients (7.3%) progressed locally, while three patients progressed to distal sites. Two-year local progression-free survival (LPFS) rates were 92.6% (95% CI 78.5–97%). Conclusions: SABR for low-burden lung oligometastases is an effective treatment modality that yields high local control and survival rates. Toxicity is negligible, regardless of the performance status of patients. Early referral of such patients to radiation oncology departments may be critical for patient survival and quality of life. Full article

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

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21 pages, 1385 KiB

Open AccessArticle

The New Occurrence of Antiphospholipid Syndrome in Severe COVID-19 Cases with Pneumonia and Vascular Thrombosis Could Explain the Post-COVID Syndrome

by Mirjana Zlatković-Švenda, Melanija Rašić, Milica Ovuka, Slavica Pavlov-Dolijanović, Marija Atanasković Popović, Manca Ogrič, Polona Žigon, Snežna Sodin-Šemrl, Marija Zdravković and Goran Radunović

Biomedicines 2025, 13(2), 516; https://doi.org/10.3390/biomedicines13020516 - 19 Feb 2025

Abstract

Introduction: The classification of antiphospholipid syndrome (APS) comprises clinical criteria (vascular thrombosis or obstetric complications throughout life) and laboratory criteria (antiphospholipid antibodies (aPLs) positivity, confirmed at least twice at 12-week interval). Methods: In 100 patients admitted to the hospital with COVID-19 pneumonia, thrombosis [...] Read more.

Introduction: The classification of antiphospholipid syndrome (APS) comprises clinical criteria (vascular thrombosis or obstetric complications throughout life) and laboratory criteria (antiphospholipid antibodies (aPLs) positivity, confirmed at least twice at 12-week interval). Methods: In 100 patients admitted to the hospital with COVID-19 pneumonia, thrombosis and pregnancy complications were recorded during the hospital stay and in personal medical history. They were tested for nine types of aPLs at four time points (admission, deterioration, discharge, and 3-month follow-up): anticardiolipin (aCL), anti-β2-glycoproteinI (anti-β2GPI), and antiphosphatidylserine/prothrombin (aPS/PT) isotypes IgM/IgG/IgA. Results: During hospitalization, aPLs were detected at least once in 51% of patients. All 7% of deceased patients tested negative for aPLs upon admission, and only one patient became aCL IgG positive as his condition worsened. In 83.3% of patients, intrahospital thrombosis was not related to aPLs. One patient with pulmonary artery and cerebral artery thrombosis was given an APS diagnosis (triple aPLs positivity on admission, double on follow-up). Personal anamnesis (PA) for thromboembolism was verified in 10 patients, all of whom tested negative for aPLs at admission; however, transition to aPLs positivity at discharge (as the disease subsided) was seen in 60% of patients: three of six with arterial thrombosis (at follow-up, two did not appear, and one was negativized) and three of four with deep vein thrombosis (one was confirmed at follow-up and diagnosed with APS, one was negativized, and one did not appear). At admission, the majority of the aPLs were of the aCL IgG class (58.8%). Unexpectedly, as the COVID-19 disease decreased, anti-β2GPI IgG antibodies (linked with thromboses) became newly positive at discharge (14.9%), as confirmed at follow-up (20.8%). Conclusion: The incidence of APS in our cohort was 2.0%, whereas in the general population, it ranges from 0.000001% to 0.000002%. The incidence might have increased even more if the four aPLs-positive patients with intrahospital thrombosis/history of thrombosis had attended follow-up. Recommendation: All patients with severe COVID-19 or post-COVID syndrome should be evaluated for current/previous thrombosis and tested for aPLs at least twice: at admission to the hospital and at discharge, then retested 3 months later in positive cases in order to be given the appropriate therapy. Full article

(This article belongs to the Special Issue Emerging Trends in Pathophysiology and Therapy of COVID-19)

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14 pages, 2401 KiB

Open AccessArticle

Treatments and Outcomes in Neuroendocrine Patients Treated with Long-Acting Somatostatin Analogues: An Italian Real-World Propensity Score-Matched Cohort Study

by Nicoletta Ranallo, Andrea Roncadori, Nicola Gentili, William Balzi, Mattia Altini, Virginia Ghini, Roberta Maltoni, Alice Andalò, Martina Cavallucci, Maddalena Sansovini, Valentina Fausti, Maria Teresa Montella, Ilaria Massa and Valentina Danesi

Biomedicines 2025, 13(2), 515; https://doi.org/10.3390/biomedicines13020515 - 19 Feb 2025

Abstract

Objectives: The aim of this study was to investigate the treatment patterns and outcomes in two propensity score-matched cohorts of patients with neuroendocrine tumours (NETs) treated with first-line somatostatin analogue (SSA). Methods: Metastatic NET patients treated with first-line SSA (2009–2022) were [...] Read more.

Objectives: The aim of this study was to investigate the treatment patterns and outcomes in two propensity score-matched cohorts of patients with neuroendocrine tumours (NETs) treated with first-line somatostatin analogue (SSA). Methods: Metastatic NET patients treated with first-line SSA (2009–2022) were retrospectively examined. First-line lanreotide vs. octreotide cohorts were matched 1:1 by propensity scores for demographics, tumour characteristics, and diagnosis year. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan–Meier analysis and the Cox proportional hazards model. Results: Among 441 patients, 310 were matched (155 in both the octreotide and lanreotide groups). First-line SSA was monotherapy (63.5%) or combination with other medications (36.5%). A total of 77% of second-line patients (188/244) maintained their initial SSA medication in combination with other therapies. Radioligand therapy with lanreotide (N = 72; 29.5%) or octreotide (N = 70; 28.7%) was the most common second-line treatment. First-line lanreotide and octreotide cohorts had similar median PFS (15.5; 95% CI: 13.6–19.1 vs. 14.0; 95% CI: 12.0–15.8 months), despite octreotide having a 36% higher likelihood of moving to the second line than lanreotide (95% CI: 1.05–1.76, p = 0.018). Multiple metastases (HR = 1.45; p = 0.004, 95% CI: 1.13–1.87) and Ki-67 > 20% (HR = 2.34; p < 0.001, 95% CI: 1.43–3.83) were significantly associated with the worst PFS. First-line lanreotide patients had a median OS of 10.4 years (95% CI: 7.5-NA) and octreotide 9.2 years (95% CI: 7.3-NA) (p = 0.537). Bone metastases increased death risk by 91% (p = 0.014; 95% CI: 1.14–3.20). Conclusions: SSA monotherapy is the main first-line treatment and most subsequent treatments include SSA with additional medications. Cohorts had similar PFS/OS, but octreotide demonstrated a 36% significantly higher likelihood of moving to the second-line treatment. Full article

(This article belongs to the Special Issue Neuroendocrine Neoplasia and Endocrine Tumors: Pathogenic Features, Prognostic Markers and New Therapeutic Approaches)

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18 pages, 3855 KiB

Open AccessArticle

Differential Pattern of Circulating MicroRNA Expression in Patients with Intracranial Atherosclerosis

by Marine M. Tanashyan, Anton A. Raskurazhev, Alla A. Shabalina, Andrey S. Mazur, Vladislav A. Annushkin, Polina I. Kuznetsova, Sergey N. Illarioshkin and Mikhail A. Piradov

Biomedicines 2025, 13(2), 514; https://doi.org/10.3390/biomedicines13020514 - 19 Feb 2025

Abstract

Background: Intracranial atherosclerosis (ICAS) is a major cause of ischemic stroke, yet fundamental studies regarding epigenetic regulation of ICAS are lacking. We hypothesized that, due to anatomical and/or functional differences, extracranial atherosclerosis is distinct from ICAS, which may explain the clinical variability as [...] Read more.

Background: Intracranial atherosclerosis (ICAS) is a major cause of ischemic stroke, yet fundamental studies regarding epigenetic regulation of ICAS are lacking. We hypothesized that, due to anatomical and/or functional differences, extracranial atherosclerosis is distinct from ICAS, which may explain the clinical variability as well. Methods: We chose a number of miRNAs involved in various steps of atherogenesis (namely, miR-712/205-5p/-3p, miR-106b-3p/-5p, miR-146a-3p/-5p, miR-100-3p/miR-5p, miR-200c-3p/-5p, miR-532-3p/-5p, and miR-126-3p/-5p) and examined their plasma levels in a cohort of patients with carotid stenosis > 50% (n = 35, mean age: 65 years, 54% male; 12 patients had ICAS). Results: A differential pattern of circulating miR expression was found in ICAS patients: there was an overexpression of miR-712/205-5p, miR-106b-5p, miR-146a-5p, miR-200c-5p, miR-532-3p, and miR-126-3p. The following miRs were underexpressed in intracranial atherosclerosis—miR-712/205-3p and miR-100-3p. These changes represent a plethora of atherogenic mechanisms: smooth muscle cell migration (miR-712/205, miR-532), foam cell formation (miR-106b, miR-146a), endothelial dysfunction (miR-200c), low-density lipoprotein-induced vascular damage (miR-100), and leukocyte recruitment (miR-126). In symptomatic ICAS patients, we observed a statistically significant upregulation of miR-712/205-3p and miR-146a-5p. Conclusions: Overall, the findings of our pilot study revealed several new and interesting associations: (1) intracranial atherosclerosis seems to have a different epigenetic profile (regarding circulating microRNA expression) than isolated extracranial vessel involvement; (2) ischemic stroke in ICAS may be potentiated by other pathophysiologic mechanisms than in extracranial-only atherosclerosis (ECAS). Certain miRs (e.g., miR-712/205) seem to have a larger impact on ICAS than on extracranial atherosclerosis; this may be potentially linked to difference between extra- and intracranial artery morphology and physiology, and/or may lead to the said differences. This underscores the importance of making a distinction in future epigenetic studies between ECAS and ICAS, as the mechanisms of atherogenesis are likely to vary. Full article

(This article belongs to the Special Issue MicroRNA and Its Role in Human Health, 2nd Edition)

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19 pages, 5478 KiB

Open AccessArticle

Causal Relationships Between Environmental Exposures, Iron Metabolism, Hematuria Markers, and Rheumatoid Arthritis: An Investigation Using Mendelian Randomization

by Chao Wang, Wenqing Xie, Chenggong Wang, Yong Zhu and Da Zhong

Biomedicines 2025, 13(2), 513; https://doi.org/10.3390/biomedicines13020513 - 19 Feb 2025

Abstract

Background: Rheumatoid arthritis (RA) is a globally prevalent chronic inflammatory disease. Environmental exposures, such as air pollution and smoking, are considered potential risk factors. However, the causal relationships and underlying mechanisms between these factors and RA are not fully understood. Methods: This study [...] Read more.

Background: Rheumatoid arthritis (RA) is a globally prevalent chronic inflammatory disease. Environmental exposures, such as air pollution and smoking, are considered potential risk factors. However, the causal relationships and underlying mechanisms between these factors and RA are not fully understood. Methods: This study utilized large-scale genome-wide association studies (GWASs) from European ethnic backgrounds and employed bidirectional two-sample Mendelian randomization (MR) to investigate the relationships between air pollution, smoking, and RA. Genetic correlations were assessed using linkage disequilibrium score regression (LDSC). Furthermore, mediation analysis was conducted to evaluate the potential mediating roles of iron metabolism and urinary biomarkers in these relationships. Results: The MR analysis revealed that genetically predicted lifetime smoking intensity was associated with an 85% increased risk of RA. Subgroup analysis differentiating between seropositive RA (SPRA) and seronegative RA (SNRA) showed a causal association with SPRA, but not with SNRA. C-reactive protein was identified as a mediator in the relationship between lifetime smoking and both RA and SPRA, mediating 18.23% and 32.45% of the effects, respectively. Genetic correlation analysis further confirmed a positive genetic association between smoking and both RA and SPRA. Conclusions: This study provides significant insights into the genetic and causal connections between air pollution, smoking, and the development of RA, highlighting the mediating role of C-reactive protein. These findings not only offer new perspectives on how smoking might enhance RA risk through inflammatory pathways but also underscore the importance of reducing smoking exposure in public health strategies. Full article

(This article belongs to the Section Cell Biology and Pathology)

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20 pages, 616 KiB

Open AccessReview

The Advances in Antipsychotics-Induced Dyskinesia Rodent Models: Benefits of Antioxidant Supplementation

by Uros Velickovic, Dragica Selakovic, Nemanja Jovicic, Marina Mitrovic, Vladimir Janjic, Sara Rosic, Suzana Randjelovic, Dragan Milovanovic and Gvozden Rosic

Biomedicines 2025, 13(2), 512; https://doi.org/10.3390/biomedicines13020512 - 18 Feb 2025

Abstract

After 70 years of clinical practice with antipsychotics in the treatment of some specific serious mental disorders, much information has been accumulated considering their efficiency as a first-line evidence-based schizophrenia therapy, but also on their adverse effects within the range from minor to [...] Read more.

After 70 years of clinical practice with antipsychotics in the treatment of some specific serious mental disorders, much information has been accumulated considering their efficiency as a first-line evidence-based schizophrenia therapy, but also on their adverse effects within the range from minor to life-threatening issues. In this paper, we highlight motor impairment as a frequent limiting factor. Despite the diversity of side effects following antipsychotics usage, many of those who suffer share the same pathophysiological background issues, such as oxidative damage, neuroinflammation, apoptosis, and neurodegeneration (observed in the brain regions involved in motor control). The obvious need to solve these limitations is facing restraints in clinical studies due to the ethical issues. Therefore, it seems reasonable to address the importance of preclinical investigations to overcome the adverse effects of antipsychotics. For that purpose, we analyzed the antipsychotics-induced dyskinesia seen in rodent models, with a special focus on attempts to highlight the benefits of antioxidant supplementation. Our analysis has revealed that antioxidant supplementation, with various antioxidant-rich compounds, confirms the clear neuroprotective effects of the therapy of this iatrogenic dyskinesia. Given their accessibility and safety, it seems that the administration of antioxidant-rich compounds in various forms, as an adjuvant therapy, may be beneficial in patients by lowering the risk of secondary Parkinsonism. Also, it seems that the strategy for further investigations in this field of preclinical studies should be standardized and should include more antipsychotics employed in the clinical practice. Full article

(This article belongs to the Special Issue Animal Models of Neurological Disorders: Where Are We Now? (2nd Edition))

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17 pages, 5763 KiB

Open AccessArticle

Assessment of the Interdependencies Between High-Speed Videoendoscopy and Simultaneously Recorded Audio Data in Various Glottal Pathologies

by Magdalena M. Pietrzak, Wioletta Pietruszewska, Magda Barańska, Aleksander Rycerz, Konrad Stawiski and Ewa Niebudek-Bogusz

Biomedicines 2025, 13(2), 511; https://doi.org/10.3390/biomedicines13020511 - 18 Feb 2025

Abstract

Background: This study aimed to investigate the relationships between kymographic parameters derived from high-speed videoendoscopy (HSV) and simultaneously recorded acoustic signals. The research provides insights into the vibratory dynamics of various glottal pathologies, assessed across different glottal widths, and their mutual relations [...] Read more.

Background: This study aimed to investigate the relationships between kymographic parameters derived from high-speed videoendoscopy (HSV) and simultaneously recorded acoustic signals. The research provides insights into the vibratory dynamics of various glottal pathologies, assessed across different glottal widths, and their mutual relations with audio data. Methods: The study included 192 participants categorized as normophonic or having functional or organic lesions (benign, premalignant, and malignant). Parameters describing vocal fold oscillations were calculated using HSV kymography for three glottal widths, along with corresponding acoustic data. Initially, linear correlations between these parameters were assessed. Next, the consistency in cycle detection and its influence on the correlation levels were evaluated. Results: The fundamental frequency (F0) and mean Jitter (Jita) showed the highest correlations between the HSV- and audio-determined parameters (F0: 0.97, Jita: 0.40–0.70), with even stronger correlations when the number of detected cycles was consistent (F0: 0.99, Jita: 0.68–0.98). The correlations for other parameters ranged from low to moderate, with no significant differences observed between the diagnostic subgroups (functional changes and benign and malignant glottal lesions). However, in the premalignant lesions group, high correlations (0.77–0.9) were observed between the HSV and audio parameters, but only for measures describing period perturbations. Beyond F0 and mean Jitter, consistency in cycle detection did not significantly affect correlation levels. Conclusions: The simultaneous audio signal proved useful in verifying the accuracy of HSV quantification measures, particularly for F0, which showed strong agreement between the methods. Discrepancies in other parameters and low correlations between HSV-derived kymography and audio data may suggest the influence of the throat, mouth, and nose resonators, which are added to the glottal signal. While the kymographic analysis based on HSV provides detailed descriptions of vocal fold oscillations, it does not fully capture the three-dimensional structure and complex functionality of the vocal folds. Full article

(This article belongs to the Section Biomedical Engineering and Materials)

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11 pages, 1196 KiB

Open AccessArticle

Circulating Microvesicles Enriched in miR–126–5p and miR–223–3p: Potential Biomarkers in Acute Coronary Syndrome

by José Rubicel Hernández-López, Mirthala Flores-García, Esbeidy García-Flores, Benny Giovanni Cazarín-Santos, Marco Antonio Peña-Duque, Fausto Sánchez-Muñoz, Martha Alicia Ballinas-Verdugo, Hilda Delgadillo-Rodríguez, Marco Antonio Martínez-Ríos, Eduardo Angles-Cano and Aurora de la Peña-Díaz

Biomedicines 2025, 13(2), 510; https://doi.org/10.3390/biomedicines13020510 - 18 Feb 2025

Abstract

Background. The molecular mechanisms underlying acute coronary syndrome (ACS) have been extensively investigated, with a particular focus on the role of circulating microvesicles (MVs) as carriers of regulatory elements that influence hemodynamic changes and coronary flow. Endothelial and platelet dysfunction during ACS alters [...] Read more.

Background. The molecular mechanisms underlying acute coronary syndrome (ACS) have been extensively investigated, with a particular focus on the role of circulating microvesicles (MVs) as carriers of regulatory elements that influence hemodynamic changes and coronary flow. Endothelial and platelet dysfunction during ACS alters MV composition, impacting clinical outcomes. This study explores the levels of miR–126–5p and miR–223–3p in circulating MVs and their association with the Thrombolysis in Myocardial Infarction (TIMI) coronary flow classification scale, proposing their potential as biomarkers. Methods. Bioinformatic tools identified miRNAs linked to ACS. Plasma MVs were isolated from ACS patients and healthy controls through high-speed centrifugation. miRNA levels were quantified using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and compared across TIMI 0 and TIMI 3 groups. Diagnostic efficacy was assessed via receiver operating characteristic (ROC) curve analysis. Results. The bioinformatic analysis identified miR–126 and miR–223 present in ACS. miR–126–5p and miR–223–3p were significantly reduced in MVs from TIMI 0 patients compared to TIMI 3. ROC analysis showed high diagnostic accuracy for miR–126–5p (AUC = 0.918; 95% CI: 0.818–1.00; p = 0.001) and miR–223–3p (AUC = 1.00; 95% CI: 1.00–1.00; p < 0.001). Conclusions. Reduced levels of miR–126–5p and miR–223–3p in circulating MVs are strongly associated with impaired coronary flow, positioning these miRNAs as potential biomarkers for ACS risk stratification and therapeutic targeting. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: From Pathophysiology to Novel Therapeutic Approaches)

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41 pages, 1709 KiB

Open AccessReview

A Narrative Review on Manufacturing Methods Employed in the Production of Mesenchymal Stromal Cells for Knee Osteoarthritis Therapy

by Rasmus Roost Aabling, Maria Rusan, Anaïs Marie Julie Møller, Naija Munk-Pedersen, Carsten Holm, Brian Elmengaard, Michael Pedersen and Bjarne Kuno Møller

Biomedicines 2025, 13(2), 509; https://doi.org/10.3390/biomedicines13020509 - 18 Feb 2025

Abstract

Knee osteoarthritis (OA) is a chronic, progressive, inflammatory, and degenerative whole-joint disease. Early-stage OA treatments typically include physiotherapy, weight-loss, pain relief medications, and intra-articular knee injections, such as corticosteroids, hyaluronic acid, or platelet-rich plasma. These treatments primarily provide symptomatic relief rather than reversing [...] Read more.

Knee osteoarthritis (OA) is a chronic, progressive, inflammatory, and degenerative whole-joint disease. Early-stage OA treatments typically include physiotherapy, weight-loss, pain relief medications, and intra-articular knee injections, such as corticosteroids, hyaluronic acid, or platelet-rich plasma. These treatments primarily provide symptomatic relief rather than reversing or halting disease progression. Recently, mesenchymal stromal cell (MSC) injections have garnered attention due to their immunomodulatory and regenerative capacities. MSCs, which can be derived from sources such as bone marrow, umbilical cord, or adipose tissue, and can be allogeneic or autologous, have demonstrated promising results in both animal models and several human studies. However, different protocols have been employed, presenting challenges for comparing outcomes. In this review, we address these variable settings, evaluate current practices, and identify key factors critical in optimizing MSC-based therapies by critically reviewing clinical trials of ex vivo expanded MSC therapies for OA undertaken between 2008 and 2023. Specific attention was given to two key aspects: (1) the cell culture process employed in manufacturing of autologous or allogeneic MSC products, and (2) the post-culture methods employed in storage, reconstitution and administration of the MSCs. Our findings suggest that standardizing MSC production for clinical applications remains a significant challenge, primarily due to variations in tissue sources, harvesting techniques, and manufacturing protocols, and due to broad discrepancies in reporting. Thus, we propose a set of minimal reporting criteria to guide future clinical trials. A common reporting guideline is a critical step towards a more standardized MSC production across different laboratories and clinical settings, thereby enhancing reproducibility and advancing the field of regenerative medicine for knee OA, as well as other disease settings. Full article

(This article belongs to the Section Cell Biology and Pathology)

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22 pages, 4928 KiB

Open AccessArticle

Honey, Gellan Gum, and Hyaluronic Acid as Therapeutic Approaches for Skin Regeneration

by Patrícia Sousa, Alicia Moreira, Bruna Lopes, Ana Catarina Sousa, André Coelho, Alexandra Rêma, Maria Balça, Luís Atayde, Carla Mendonça, Lucília P. da Silva, Cristiana Costa, Alexandra P. Marques, Irina Amorim, Rui Alvites, Filipa Batista, Filipa Mata, João Transmontano and Ana Colette Maurício

Biomedicines 2025, 13(2), 508; https://doi.org/10.3390/biomedicines13020508 - 18 Feb 2025

Abstract

Background/Objectives: Chronic wounds pose a significant health concern, with their prevalence increasing due to various etiologies. The global aging population further contributes to this rise, placing a substantial burden on healthcare systems in developed countries. This work aimed to develop new therapeutic [...] Read more.

Background/Objectives: Chronic wounds pose a significant health concern, with their prevalence increasing due to various etiologies. The global aging population further contributes to this rise, placing a substantial burden on healthcare systems in developed countries. This work aimed to develop new therapeutic options in the form of creams and dressings based on honey, gellan gum, and hyaluronic acid for preventing and treating chronic wounds across all stages. Methods: To address this, after the formulations were developed, in vitro cytocompatibility was determined. To confirm biocompatibility, an ovine wound model was used: full-thickness excisional wounds were treated with three formulations, namely gellan gum and honey sponges (GG-HNY), gellan gum, honey and hyaluronic acid sponges (GG-HA-HNY) and a honey-based cream (cream FB002). Daily assessments, including visual evaluation and wound scoring, were conducted for 30 days. Following the study period, tissues were collected for histological analyses. Results: The macroscopic examination revealed that all therapeutic groups facilitated lesion closure. Lesion size reduction, granulation tissue disappearance, and scar tissue development were consistent across all groups, with the group receiving cream demonstrating an advanced stage of healing. All groups achieved substantial wound closure by day 30, with no significant differences. Histopathological analysis following ISO standards revealed that GG-HA-HNY had the lowest ISO score, indicating minimal reactivity and inflammation, which corroborated the cytocompatibility. Conclusions: Combining these insights with previous findings enhances our understanding of wound regeneration dynamics and contributes to refining therapeutic strategies for chronic wounds. The formulations were designed to balance therapeutic efficacy with cost-effectiveness, leveraging low-cost raw materials and straightforward production methods. Full article

(This article belongs to the Topic Current Challenges and Advances in Skin Repair and Regeneration)

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31 pages, 658 KiB

Open AccessReview

Telomere Dynamics in Post-Traumatic Stress Disorder: A Critical Synthesis

by Ravi Philip Rajkumar

Biomedicines 2025, 13(2), 507; https://doi.org/10.3390/biomedicines13020507 - 18 Feb 2025

Abstract

Post-traumatic stress disorder (PTSD), a mental disorder caused by exposure to traumatic stress, affects 5–10% of the world’s population. There is some evidence that PTSD is associated with accelerated cellular aging, leading to an increased risk of medical and neurodegenerative comorbidities. Alterations in [...] Read more.

Post-traumatic stress disorder (PTSD), a mental disorder caused by exposure to traumatic stress, affects 5–10% of the world’s population. There is some evidence that PTSD is associated with accelerated cellular aging, leading to an increased risk of medical and neurodegenerative comorbidities. Alterations in telomere length (TL) and telomerase enzyme activity have been proposed as biomarkers of this process. This hypothesis was seemingly confirmed in preliminary research, but more recent studies have yielded mixed results. The current narrative review was conducted to provide a critical synthesis of existing research on telomere length and telomerase in PTSD. Data from 26 clinical studies suggest that TL in PTSD is highly variable and may be influenced by methodological, demographic, trauma-related, and psychosocial factors. There is no evidence for altered telomerase activity in PTSD. In contrast, animal research suggests that exposure to traumatic stress does lead to TL shortening. Overall, it is likely that TL is not, by itself, a reliable biomarker of cellular aging in PTSD. Other markers of cellular senescence, such as epigenetic changes, may prove to be more specific in measuring this process in patients with PTSD. Full article

(This article belongs to the Special Issue The Role of Telomere and Telomerase in Human Disease)

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35 pages, 864 KiB

Open AccessReview

The Role of Cytokines in Perioperative Neurocognitive Disorders: A Review in the Context of Anesthetic Care

by Hyun Jung Koh and Jin Joo

Biomedicines 2025, 13(2), 506; https://doi.org/10.3390/biomedicines13020506 - 18 Feb 2025

Abstract

Perioperative neurocognitive disorders (PNDs), including postoperative delirium, delayed neurocognitive recovery, and long-term postoperative neurocognitive disorders, present significant challenges for older patients undergoing surgery. Inflammation is a protective mechanism triggered in response to external pathogens or cellular damage. Historically, the central nervous system (CNS) [...] Read more.

Perioperative neurocognitive disorders (PNDs), including postoperative delirium, delayed neurocognitive recovery, and long-term postoperative neurocognitive disorders, present significant challenges for older patients undergoing surgery. Inflammation is a protective mechanism triggered in response to external pathogens or cellular damage. Historically, the central nervous system (CNS) was considered immunoprivileged due to the presence of the blood–brain barrier (BBB), which serves as a physical barrier preventing systemic inflammatory changes from influencing the CNS. However, aseptic surgical trauma is now recognized to induce localized inflammation at the surgical site, further exacerbated by the release of peripheral pro-inflammatory cytokines, which can compromise BBB integrity. This breakdown of the BBB facilitates the activation of microglia, initiating a cascade of neuroinflammatory responses that may contribute to the onset of PNDs. This review explores the mechanisms underlying neuroinflammation, with a particular focus on the pivotal role of cytokines in the pathogenesis of PNDs. Full article

(This article belongs to the Special Issue The Role of Cytokines in Health and Disease: 2nd Edition)

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9 pages, 1695 KiB

Open AccessArticle

Advancing Breast Cancer Diagnosis: Optimization of Raman Spectroscopy for Urine-Based Early Detection

by David Andras, Ramona G. Cozan, Delia E. Muresan, Vlad Moisoiu, George Crisan, Vasile Bintintan, George C. Dindelegan, Nicolae Leopold and Stefania D. Iancu

Biomedicines 2025, 13(2), 505; https://doi.org/10.3390/biomedicines13020505 - 18 Feb 2025

Abstract

Background: Surface-enhanced Raman spectroscopy (SERS) analysis of urine is a promising liquid biopsy technique for cancer detection. However, its clinical translation is hindered by two major challenges that impact classification efficacy. First, the SERS signal of urine is confounded by fluctuations induced [...] Read more.

Background: Surface-enhanced Raman spectroscopy (SERS) analysis of urine is a promising liquid biopsy technique for cancer detection. However, its clinical translation is hindered by two major challenges that impact classification efficacy. First, the SERS signal of urine is confounded by fluctuations induced by physiological differences in urine composition such as pH and dilution. Second, the molecular origin of the SERS signal of urine is incompletely understood, limiting the interpretability of machine learning classifiers in terms of specific biochemical markers. Methods: In this pilot study, we analyzed urine samples from breast cancer patients (n = 18) and control subjects (n = 10) at three pH levels (5, 7, and 9). Additionally, we analyzed simulated urine mixtures consisting of uric acid, hypoxanthine, xanthine, and creatinine in physiological concentrations to explain the variation in the SERS spectra at different pH values. Results: Urine at pH 9 yielded the most detailed spectral features. The SERS spectral pattern under alkaline pH reflected greater contributions from hypoxanthine, uric acid, and creatinine, while xanthine contributions diminished due to competitive interactions at the SERS substrate surface. Normalizing SERS signals to the creatinine band at 1420 cm⁻¹ effectively mitigated the confounding effects of urine dilution. Conclusions: Optimizing the pH to 9 and normalizing to creatinine significantly enhances the interpretability and accuracy of SERS-based urine analysis for cancer detection. These findings offer important theoretical and practical advancements for the development of SERS-based liquid biopsy tools for cancer detection. Full article

(This article belongs to the Special Issue Breast Cancer: New Diagnostic and Therapeutic Approaches)

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9 pages, 502 KiB

Open AccessBrief Report

Midkine Serum Levels in Inflammatory and Non-Inflammatory Dilated Cardiomyopathy

by Ulrich Grabmaier, Bartolo Ferraro, Kristin Lehnert, Astrid Petersmann, Stephan B. Felix and Ludwig T. Weckbach

Biomedicines 2025, 13(2), 504; https://doi.org/10.3390/biomedicines13020504 - 18 Feb 2025

Abstract

Objectives: This retrospective study examines midkine, an inflammatory cytokine, as a potential serological biomarker to distinguish dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi). Identifying such a biomarker is crucial for effective treatment of these two entities. Methods: The study included [...] Read more.

Objectives: This retrospective study examines midkine, an inflammatory cytokine, as a potential serological biomarker to distinguish dilated cardiomyopathy (DCM) and inflammatory dilated cardiomyopathy (DCMi). Identifying such a biomarker is crucial for effective treatment of these two entities. Methods: The study included 54 patients with heart failure, reduced left ventricular systolic function, and suspected cardiac inflammation. Endomyocardial biopsies were obtained from all 54 patients to differentiate between DCM and DCMi. Blood sera were collected from these patients the same day the endomyocardial biopsy was performed and compared with those of 13 age-matched healthy individuals for different measurements such as midkine and NT-proBNP. Patients were followed up to a median of 194 days after the baseline visit. Results: Endomyocardial biopsies from patients with DCMi were associated with more infiltrating immune cells such as CD68⁺ macrophages and CD3⁺ T cells and a more frequent presence of a viral genome than those from patients with DCM. Both groups showed similar improvements in LV function and dimensions over time. MK serum levels were significantly higher in DCM/ DCMi patients than in healthy individuals but did not differ significantly between DCM and DCMi. MK levels did not significantly correlate with NYHA class, NT-proBNP, LVEDD, or LVEF, except for a weak correlation with LVEF at follow-up. Conclusions: Midkine serum levels were significantly higher in patients with a DCM phenotype and severely reduced systolic function. However, these levels could not distinguish between DCM and DCMi and showed no correlation with baseline or follow-up parameters. Therefore, midkine cannot be used as a biomarker to distinguish between DCM and DCMi. Full article

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

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14 pages, 692 KiB

Open AccessSystematic Review

Fibromyalgia, Depression, and Autoimmune Disorders: An Interconnected Web of Inflammation

by Stefania Sedda, Maria Piera L. Cadoni, Serenella Medici, Elena Aiello, Gian Luca Erre, Alessandra Matilde Nivoli, Ciriaco Carru and Donatella Coradduzza

Biomedicines 2025, 13(2), 503; https://doi.org/10.3390/biomedicines13020503 - 18 Feb 2025

Abstract

Background: Fibromyalgia, depression, and autoimmune diseases represent a triad of interconnected conditions characterized by overlapping biological pathways, including chronic inflammation, immune dysregulation, and neurochemical imbalances. Understanding their shared mechanisms offers opportunities for innovative therapeutic approaches. Objective: This systematic review explores the common inflammatory- [...] Read more.

Background: Fibromyalgia, depression, and autoimmune diseases represent a triad of interconnected conditions characterized by overlapping biological pathways, including chronic inflammation, immune dysregulation, and neurochemical imbalances. Understanding their shared mechanisms offers opportunities for innovative therapeutic approaches. Objective: This systematic review explores the common inflammatory- and immune-related pathways among these conditions, emphasizing their implications for biomarker development and novel therapeutic strategies. Methods: Following PRISMA guidelines, a comprehensive literature search was conducted in databases including PubMed, Scopus, Web of Science, and the Cochrane Library. Studies examining the relationship between fibromyalgia, depression, and autoimmune diseases with a focus on immune responses, inflammatory biomarkers, and therapeutic interventions were included. The quality of the selected studies was assessed using the Cochrane Risk of Bias tool. Results: From the 255 identified studies, 12 met the inclusion criteria. Evidence supports the role of pro-inflammatory cytokines (e.g., IL-6, TNF-α) and neurochemical dysregulation (e.g., serotonin, dopamine) as key factors in the pathophysiology of these conditions. Pilot studies highlight the potential of immune-modulating therapies, including low-dose IL-2 and anti-inflammatory agents such as N-acetylcysteine and minocycline, in alleviating both physical and psychological symptoms. Emerging biomarkers, including cytokine profiles and platelet serotonin activity, show promise for personalized treatment approaches. Conclusions: The shared inflammatory pathways linking fibromyalgia, depression, and autoimmune diseases underscore the need for integrated therapeutic strategies. Although pilot studies provide preliminary insights, validation through large-scale, multicenter trials is essential. Future research should focus on standardizing methodologies and leveraging biomarker-driven precision medicine to improve outcomes for patients with these complex, multifactorial conditions. Full article

(This article belongs to the Special Issue Molecular Research of Neurodegenerative and Psychiatric Diseases, 2nd Edition)

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6 pages, 180 KiB

Open AccessEditorial

Obesity: A Global Health Challenge Demanding Urgent Action

by Zaida Abad-Jiménez and Teresa Vezza

Biomedicines 2025, 13(2), 502; https://doi.org/10.3390/biomedicines13020502 - 18 Feb 2025

Abstract

Obesity has become one of the most critical health crises of the modern era, affecting millions of individuals worldwide [...] Full article

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

19 pages, 2857 KiB

Open AccessArticle

Dupilumab in the Treatment of Severe Uncontrolled Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and Comorbid Asthma—A Multidisciplinary Monocentric Real-Life Study

by Gian Luca Fadda, Chiara Rustichelli, Simone Soccal, Simone Moglio, Alessandro Serrone, Francesca Bertolini, Vitina Carriero, Stefano Pizzimenti, Stefano Levra, Giovanni Cavallo, Fabio Luigi Massimo Ricciardolo and Giuseppe Guida

Biomedicines 2025, 13(2), 501; https://doi.org/10.3390/biomedicines13020501 - 17 Feb 2025

Abstract

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma are mutually correlated with Type-2 inflammation. Dupilumab is effective in uncontrolled and relapsing CRSwNP. However, the precise characterization of Type-2 inflammation and the impact of previous surgery on clinical outcomes need clarification. Methods: [...] Read more.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) and asthma are mutually correlated with Type-2 inflammation. Dupilumab is effective in uncontrolled and relapsing CRSwNP. However, the precise characterization of Type-2 inflammation and the impact of previous surgery on clinical outcomes need clarification. Methods: We present a prospective observational study on a 38 CRSwNP-patient cohort, whose Type-2 endotype was confirmed after a multidisciplinary approach shared among ENTs, pneumologists and allergologists. Patients were treated with dupilumab and evaluated at 15 days and 1-3-6-12-18-24-30 months, focusing on clinical (VAS, nasal polyp score—NPS), radiological (Lund-Mackay) and quality of life (SNOT-22) parameters, as well olfactory function, asthma control, variation of Type-2 markers and number and extent (ACCESS score) of previous surgeries. Results: We confirmed the efficacy of dupilumab in total and sub-items VAS, NPS, SNOT-22 and sniffing score, as well as Lund–Mackay score improvements, observable and significant after 2 weeks of treatment (p < 0.0001) and long-lasting over 30 months. Good to excellent response criteria to biologic treatment at 6 months was observed in 30/32 patients. Comorbid asthma reached rapid control (p < 0.0001) and exhaled nitric oxide normalization was achieved. One single “not adequate” surgery showed a trend to milder improvement, as well as a higher ACCESS score to better olfactory outcome. Conclusions: The accurate selection of uncontrolled relapsing CRSwNP in terms of Type-2 endotyping by multidisciplinary approach can maximize dupilumab efficacy. The number and extent of previous surgeries may differentiate the response, although this effect is difficult to catch in real life. “Adequate” ESS surgery before dupilumab may drive mostly effective disease control. Full article

(This article belongs to the Special Issue Recent Advances in Chronic Rhinosinusitis and Asthma)

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23 pages, 3687 KiB

Open AccessArticle

Assessing the Clinical Relevance of Soluble PD-1 and PD-L1: A Multi-Cohort Study Across Diverse Tumor Types and Prognostic Implications

by Nikolay E. Kushlinskii, Olga V. Kovaleva, Alexei N. Gratchev, Alexander A. Alferov, Yurii B. Kuzmin, Nikolai Y. Sokolov, Dmitry A. Tsekatunov, Irina B. Ryzhavskaya, Igor N. Kuznetsov, Dmitry N. Kushlinskii, Zaman Z. Mamedli and Ivan S. Stilidi

Biomedicines 2025, 13(2), 500; https://doi.org/10.3390/biomedicines13020500 - 17 Feb 2025

Abstract

Background/Objectives: Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have revolutionized cancer immunotherapy, however the clinical relevance of their soluble forms (sPD-1 and sPD-L1) remains less studied. Soluble PD-1 and PD-L1 have been implicated in tumor progression, prognosis, and treatment response across various malignancies. [...] Read more.

Background/Objectives: Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have revolutionized cancer immunotherapy, however the clinical relevance of their soluble forms (sPD-1 and sPD-L1) remains less studied. Soluble PD-1 and PD-L1 have been implicated in tumor progression, prognosis, and treatment response across various malignancies. This study aims to provide a comprehensive analysis of sPD-1 and sPD-L1 levels in serum across diverse tumor types, including rare malignancies, and to evaluate their associations with clinicopathological characteristics and prognostic significance. Methods: In this study we analyzed sPD-1 and sPD-L1 levels in serum samples from 675 cancer patients representing a range of malignancies, including ovarian cancer, breast cancer, gastric cancer, colorectal cancer, renal cell carcinoma, and bone tumors. sPD-1 and sPD-L1 concentrations were measured using ELISA. Statistical analyses were performed to evaluate associations between soluble marker concentrations and clinicopathological factors, including tumor stage, size, histological subtype, and survival outcomes. Results: Elevated sPD-L1 levels were observed in several tumor types, including ovarian cancer, renal cell carcinoma, and gastric cancer, where they were associated with features of advanced disease, such as tumor size, stage, and metastases. In contrast, sPD-1 levels showed limited associations, with significant findings solely in gastric cancer and bone tumors, where levels correlated with histological subtype and differentiation. Prognostic analyses identified sPD-L1 as a marker of poor survival outcomes in ovarian cancer and bone tumors, while sPD-1 displayed no consistent prognostic significance. Conclusions: This study identifies the potential of sPD-L1 as a biomarker for tumor progression and prognosis across multiple malignancies. In contrast, sPD-1 showed limited clinical relevance, suggesting the importance of further investigation. These findings contribute to our understanding of soluble immune checkpoint proteins and their integration into personalized oncology strategies. Full article

(This article belongs to the Section Cancer Biology and Oncology)

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Biomedicines, Volume 13, Issue 2 (February 2025) – 282 articles

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