Biomedicines

10 pages, 719 KiB

Open AccessArticle

Investigation of UCHL3 and HNMT Gene Polymorphisms in Greek Patients with Type 2 Diabetes Mellitus and Diabetic Retinopathy

by Konstantinos Flindris, Vivian Lagkada, Aikaterini Christodoulou, Maria Gazouli, Marilita Moschos, Georgios Markozannes and George Kitsos

Biomedicines 2025, 13(2), 341; https://doi.org/10.3390/biomedicines13020341 (registering DOI) - 3 Feb 2025

Abstract

Background and Objectives: Recent studies have shed light on the association between genetic factors and diabetic retinopathy (DR) onset and progression. The purpose of our study was to investigate the association between rs4885322 single-nucleotide polymorphism (SNP) of the UCHL3 gene and rs11558538 SNP [...] Read more.

Background and Objectives: Recent studies have shed light on the association between genetic factors and diabetic retinopathy (DR) onset and progression. The purpose of our study was to investigate the association between rs4885322 single-nucleotide polymorphism (SNP) of the UCHL3 gene and rs11558538 SNP of the HNMT gene with the risk of DR in Greek patients with type 2 diabetes mellitus (T2DM). Materials and Methods: In our case–control study, we included 85 T2DM patients with DR and 71 T2DM patients without DR (NDR), matched by ethnicity and gender. Demographic and clinical data of all patients were collected, and then patients went through a complete ophthalmological examination and were genotyped for rs4885322 SNP of UCHL3 gene and for the rs11558538 SNP of HNMT gene. Statistical analysis was implemented by STATA v.16.1. Results: No significant differences in demographic and clinical data were observed between the DR and the NDR group (p-value ≥ 0.05), except for the lower mean of age, longer duration of DM, more frequent use of insulin therapy, and higher levels of hemoglobin A1c (HbA1c) in the DR group. The allelic effect of rs488532 increases the risk of DR by 2.04 times, and in the dominant genetic model, the risk of DR is elevated by 123%, while both associations are statistically significant (p-value < 0.05). Moreover, the allelic effect of rs11558538 is associated with a 3.27 times increased DR risk and, in the dominant genetic model, reveals an augmented risk of DR by 231%, while both associations are also statistically significant (p-value < 0.05). Conclusions: The rs4885322 SNP of the UCHL3 gene and the rs11558538 SNP of the HNMT gene are associated with DR risk in Greek patients with T2DM. However, further studies with larger samples and different ethnicities should be implemented to clarify the exact association of these SNPs and DR onset. Full article

(This article belongs to the Special Issue Emerging Issues in Retinal Degeneration)

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16 pages, 588 KiB

Open AccessArticle

Quantifying Cognitive Function in Diabetes: Relationships Between AD8 Scores, HbA1c Levels, and Other Diabetic Comorbidities

by Hsin-Yu Chao, Ming-Chieh Lin, Tzu-Jung Fang, Man-Chia Hsu, Ching-Chao Liang and Mei-Yueh Lee

Biomedicines 2025, 13(2), 340; https://doi.org/10.3390/biomedicines13020340 (registering DOI) - 3 Feb 2025

Abstract

Background/Objectives: Dementia associated with diabetes mellitus (DM) has been well documented in the literature, but studies utilizing early screening tools to target populations with mild cognitive dysfunction remain limited. This study aimed to investigate early cognitive decline by studying the relationships between “Ascertain [...] Read more.

Background/Objectives: Dementia associated with diabetes mellitus (DM) has been well documented in the literature, but studies utilizing early screening tools to target populations with mild cognitive dysfunction remain limited. This study aimed to investigate early cognitive decline by studying the relationships between “Ascertain Dementia 8” (AD8) questionnaire scores and glycemic control, lipid profiles, estimated glomerular filtration rate (eGFR), and the complications of diabetes. Methods: This case–control, cross-sectional, observational study was conducted at a medical center and an affiliated regional hospital in southern Taiwan from 30 June 2021 to 30 June 2023. Patients diagnosed with type 2 diabetes mellitus aged ≥40 years were recruited. Their past medical history, biochemical data, and AD8 score were collected at the same time. Results: The patients with glycated hemoglobin (HbA1c) levels of ≥7% had a higher risk of cognitive impairment than those with HbA1c levels of <7% (p < 0.001). The participants whose eGFR was <60 mL/min/1.73 m² had a higher mean AD8 score compared to those with an eGFR of ≥60 mL/min/1.73 m² (p = 0.008). The patients with a medical history of peripheral artery disease and diabetic neuropathy were also associated with a higher mean AD8 score (p < 0.001 and p = 0.017, respectively). Conclusions: By employing the AD8 questionnaire as a sensitive screening tool, our study suggests that early cognitive decline is significantly associated with poorer glycemic control, a lower glomerular filtration rate, peripheral artery disease, and diabetic neuropathy. Early detection of these risk factors may facilitate timely interventions and tailored treatment strategies to treat or prevent cognitive dysfunction. Full article

(This article belongs to the Special Issue Diabetes: Pathogenesis, Therapeutics and Outcomes)

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20 pages, 4831 KiB

Open AccessArticle

Probiotic-Derived Metabolites from Lactiplantibacillus plantarum OC01 Reprogram Tumor-Associated Macrophages to an Inflammatory Anti-Tumoral Phenotype: Impact on Colorectal Cancer Cell Proliferation and Migration

by Beatrice Garavaglia, Letizia Vallino, Alessandra Ferraresi, Angela Amoruso, Marco Pane and Ciro Isidoro

Biomedicines 2025, 13(2), 339; https://doi.org/10.3390/biomedicines13020339 (registering DOI) - 3 Feb 2025

Abstract

Background: Tumor-associated macrophages (TAMs) are key players in the colorectal cancer (CRC) tumor microenvironment (TME), representing the most abundant immune cells within it. The interplay between the intestinal microbiota, macrophages, and cancer cells significantly impacts tumor progression by driving macrophage polarization. Particularly, the [...] Read more.

Background: Tumor-associated macrophages (TAMs) are key players in the colorectal cancer (CRC) tumor microenvironment (TME), representing the most abundant immune cells within it. The interplay between the intestinal microbiota, macrophages, and cancer cells significantly impacts tumor progression by driving macrophage polarization. Particularly, the polarization into the pro-tumoral M2-like TAM phenotype promotes the extracellular matrix remodeling, cancer cell proliferation, metastasis, immune suppression, and therapy resistance. Probiotic metabolites can disrupt this crosstalk, possibly reverting the TAM polarization toward a pro-inflammatory anti-tumoral phenotype, thus potentially benefiting the intestinal mucosa and opposing CRC progression. Previously, we showed that Lactiplantibacillus plantarum OC01 metabolites counter interleukin (IL)-6-induced CRC proliferation and migration. Methods: Here, we explore how probiotics affect CRC secretome and how this influences TAM polarization, which then impacts CRC malignancy. Results: The conditioning medium (CM) from CRC cells indeed promoted the polarization of macrophage toward the M2-like phenotype, whereas the CM from CRC pre-treated with L. plantarum OC01 metabolites induced a pro-inflammatory macrophage phenotype, characterized by NLRP3 inflammasome activation and reactive oxygen species (ROS) production, and by decreased expression of the M2 phenotype markers CD206 and CD163. Consistently, the expression of tumor growth factor (TGF)-β, a promoter of M2 macrophage polarization, was reduced in CRC cells treated with L. plantarum OC01. The pro-inflammatory macrophages inhibited CRC proliferation and migration. Conclusions: Overall, our study highlights the potential of metabolites from L. plantarum OC01 to reprogram the metabolism in cancer cells and thus reshape the TME by shifting TAMs toward a more inflammatory and anti-tumoral phenotype, emphasizing the promise of probiotics in advancing novel therapeutic approaches for CRC. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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14 pages, 2008 KiB

Open AccessArticle

Cytomegalovirus-Reactive IgG Correlates with Increased IL-6 and IL-1β Levels, Affecting Eating Behaviours and Tactile Sensitivity in Children with Autism

by Isti Anindya, Rini Sekartini, Ibnu Agus Ariyanto, Tjhin Wiguna, Novika Purnama Sari, Yuni Sri Rahayu and Amin Soebandrio

Biomedicines 2025, 13(2), 338; https://doi.org/10.3390/biomedicines13020338 (registering DOI) - 2 Feb 2025

Abstract

Background/Objectives: Elevated cytokine levels, including IL-6 and IL-1β, can contribute to persistent brain inflammation in children with autism and cytomegalovirus (CMV) infection, exacerbating autism-related behaviours and symptoms. This study evaluates the impact of CMV-induced cytokine increases on the eating behaviours and sensory profiles [...] Read more.

Background/Objectives: Elevated cytokine levels, including IL-6 and IL-1β, can contribute to persistent brain inflammation in children with autism and cytomegalovirus (CMV) infection, exacerbating autism-related behaviours and symptoms. This study evaluates the impact of CMV-induced cytokine increases on the eating behaviours and sensory profiles of children with autism. Methods: A cross-sectional design was employed, involving children aged two to five years (CMV-reactive IgG), with ASD (n= 98) and TD (n = 96). Serological tests using ELISA were conducted to measure IgG CMV, IL-6, and IL-1β biomarkers. Eating behaviours were evaluated using the BAMBI (Brief Autism Mealtime Behaviour Inventory), and sensory profiles were assessed using the SSP (Short Sensory Profile). Statistical analyses were performed using Spearman’s rank and chi-square tests. Results: The results show that autism significantly affects children’s eating behaviours and sensory profiles (p < 0.001), with notable differences found between the groups. Correlation analysis revealed a significant association between IgG CMV and IL-6 (p = 0.026) and IL-1β (p = 0.014) in the ASD group. Additionally, eating behaviours (food refusal and limited variety) in ASD correlated with IL-6 and IL-1β. Sensory characteristics, such as tactile sensitivity, were found to correlate with IL-6 (p = 0.027) and IL-1β (p = 0.002) in the ASD group. Conclusions: These findings suggest that CMV-infected children with autism are at increased risk of IL-6 and IL-1β dysregulation, contributing to sensory processing issues and eating behaviours. Further research is needed to enhance CMV testing protocols and better understand the virus’s role in the development of sensory and behavioural issues in children with autism. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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12 pages, 420 KiB

Open AccessArticle

Cerebrospinal Fluid Calcium Balance in Tick-Borne Encephalitis: A Preliminary Study and Future Research Directions

by Gabriela Trojan, Anna Moniuszko-Malinowska, Karolina Orywal, Ewelina Kruszewska, Barbara Mroczko, Anna Grzeszczuk and Piotr Czupryna

Biomedicines 2025, 13(2), 337; https://doi.org/10.3390/biomedicines13020337 (registering DOI) - 2 Feb 2025

Abstract

Introduction: Calcium homeostasis is essential for neurophysiological functions, with dysregulation implicated in neurodegenerative diseases. Recent studies suggest that specific viral brain infections, such as tick-borne encephalitis, can initiate neuronal loss and subsequent neurodegenerative changes. This study examines alterations in calcium levels within the [...] Read more.

Introduction: Calcium homeostasis is essential for neurophysiological functions, with dysregulation implicated in neurodegenerative diseases. Recent studies suggest that specific viral brain infections, such as tick-borne encephalitis, can initiate neuronal loss and subsequent neurodegenerative changes. This study examines alterations in calcium levels within the cerebrospinal fluid (CSF) of patients with tick-borne encephalitis (TBE). Objectives: To evaluate the concentration of calcium in the CSF of TBE patients and assess its potential as a diagnostic marker for disease severity. Materials and Methods: CSF samples were collected from 42 subjects (11 controls, 20 with TBE, 11 with other forms of meningitis). Calcium levels were measured using the Alinity c analyzer. Statistical analyses included the Shapiro–Wilk test, Mann–Whitney U test, and ROC curve analysis. Results: Calcium levels were significantly lower in TBE patients compared to controls (mean 0.85 mmol/L vs. 0.98 mmol/L). Lower calcium levels were associated with milder cases of TBE. ROC analysis (AUC 0.802, p-value 0.0053) supports the diagnostic utility of calcium concentration in differentiating TBE severity. The optimal cut-off value for calcium was >3.09 mg/dL, with a sensitivity of 84.62% and specificity of 71.43%. These findings further emphasize the potential of calcium as a diagnostic marker for TBEV. Conclusions: The observed differences in CSF calcium levels between mild and severe TBE cases highlight its potential as a diagnostic marker. Further research is warranted to elucidate calcium’s role in TBE, aiming to improve clinical management and reduce complications. We emphasize that this study is one of the first to propose calcium levels as a potential biomarker for assessing the severity of tick-borne encephalitis, offering a new perspective in the diagnostic approach to this infection. Full article

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

14 pages, 2597 KiB

Open AccessArticle

Trajectory Analysis in FBG and the Incidence of Chronic Kidney Disease: A Nationwide Population-Based Study

by Heewon Park, Ki Ryang Na, Yunkyeong Hwang, Suyeon Han, Kyungho Park, Hyerim Park, Eu Jin Lee, Young Rok Ham, Soon-Ki Ahn and Dae Eun Choi

Biomedicines 2025, 13(2), 336; https://doi.org/10.3390/biomedicines13020336 (registering DOI) - 1 Feb 2025

Abstract

Objectives: This study aimed to classify fasting blood glucose (FBG) trajectories by sex and examine their associations with the risk of chronic kidney disease (CKD). Methods: Using data from the National Health Insurance Service-National Sample Cohort in Korea, participants aged 40 years and [...] Read more.

Objectives: This study aimed to classify fasting blood glucose (FBG) trajectories by sex and examine their associations with the risk of chronic kidney disease (CKD). Methods: Using data from the National Health Insurance Service-National Sample Cohort in Korea, participants aged 40 years and above, without CKD or diabetes mellitus (DM), were followed from 2002 to 2009. Based on their FBG trajectories, participants were categorized into two classes and stratified by sex. CKD incidence rates were analyzed according to these FBG trajectories, and the impact of additional risk factors on CKD incidence was assessed. Results: A total of 91,131 participants were analyzed. Among individuals classified in Class 1, FBG levels gradually increased from 90.7 (men) and 88.7 (women) in 2002 to 96.6 (men) and 93.2 (women) in 2009. In contrast, participants classified as Class 2 exhibited a rapid increase in FBG levels, rising from 106 (men) and 106 (women) in 2002 to 144 (men) and 132 (women) in 2009. The incidence of CKD increased over time in both men and women classified as Class 2 compared to Class 1, with respective hazard ratios (HR) of 1.35 for men and 1.53 for women. Additionally, increased age, hypertension, and body mass index (BMI) were independently associated with an elevated risk of CKD. Conclusions: The Class 2 group demonstrated a significantly higher incidence of CKD compared to the Class 1 group. This finding indicates the need for the proactive management of individuals with relatively high FBG levels featuring rapid FBG increases in order to mitigate the risk of CKD development. Full article

(This article belongs to the Special Issue New Perspectives on Chronic Kidney Disease)

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34 pages, 1191 KiB

Open AccessArticle

The Interplay Between Carotid Intima-Media Thickness and Selected Serum Biomarkers in Various Stages of Chronic Kidney Disease

by Mateusz Twardawa, Piotr Formanowicz and Dorota Formanowicz

Biomedicines 2025, 13(2), 335; https://doi.org/10.3390/biomedicines13020335 (registering DOI) - 1 Feb 2025

Abstract

Background/Objectives: Chronic kidney disease (CKD), the most common cause of which is hypertension and diabetes, is a recognized risk factor for cardiovascular disease (CVD). This study investigated the association between selected serum biomarkers in the context of intima-media thickness (IMT) changes, a [...] Read more.

Background/Objectives: Chronic kidney disease (CKD), the most common cause of which is hypertension and diabetes, is a recognized risk factor for cardiovascular disease (CVD). This study investigated the association between selected serum biomarkers in the context of intima-media thickness (IMT) changes, a common predictor of subsequent cardiovascular (CV) events. Methods: A total of 251 individuals were enrolled in the study, divided into groups based on the severity of CKD, the presence of CVD, and healthy controls. For this purpose, the data from the following groups of participants were analyzed: (1) end-stage renal disease (ESRD) (n = 106), (2) pre-dialyzed (PRE) (n = 48), (3) patients at stages 1 and 2 of CKD (CKD1-2) (n = 37), (4) patients with CVD and no kidney disease (CARD) (n = 28), and (5) healthy controls (HV) (n = 31). To find markers associated with elevated IMT, the each group with CVD (ESRD, PRE and CARD) was separated into two subgroups with normal and elevated IMT and compared in the relation of the studied serum biomarkers. Results: The findings identified glucose as the only marker exclusively associated with CVD. Markers uniquely linked to CKD included urea, creatinine, eGFR, total protein, CEL, neopterin, total calcium, phosphates, iPTH, sodium, iron, ferritin, and AST. All other markers reflected a combined influence of both CKD and CVD. By comparing patients with normal and elevated IMT, distinct types of CKD–CVD interactions were observed, i.e., independent (additive effects of CKD and CVD) for MPO, ALP, MMP-9, and MMP-9/TIMP-1; combined (enhanced effect due to interactions) for AOPPs and TIMP-1; and conditional (CVD impact specific to CKD patients) for AGEs, 3-NT, magnesium, UIBC, TIBC, ALT, and TIMP-1/MMP-9. However, certain markers, i.e., CML, sRAGEs, carbamylated protein groups, protein carbamylation, hsCRP, TC, HDL-C, LDL-C, TG, IL-18, klotho, FGF-23, klotho/FGF-23 ratio, potassium, NT-proBNP, and AIP were associated with both CKD and CVD, though the exact nature of their interaction could not be determined using IMT as a distinguishing factor. Conclusions: The results showed that relations between IMT and the remaining studied factors were not trivial, and most of the analyzed parameters were altered in CKD patients, especially if compared to patients with CVD but without CKD. IMT cannot be used as a universal CVD marker. Full article

(This article belongs to the Special Issue Pathomechanisms of Disturbances Underlying Chronic Disorders—2nd Edition)

14 pages, 442 KiB

Open AccessArticle

Phenolic Content, Antioxidant Activity and In Vitro Anti-Inflammatory and Antitumor Potential of Selected Bulgarian Propolis Samples

by Yulian Tumbarski, Ivan Ivanov, Mina Todorova, Sonia Apostolova, Rumiana Tzoneva and Krastena Nikolova

Biomedicines 2025, 13(2), 334; https://doi.org/10.3390/biomedicines13020334 (registering DOI) - 1 Feb 2025

Abstract

Background/objectives: Propolis (bee glue) is a valuable bee product widely used as a natural remedy, a cosmetic ingredient, a nutritional value enhancer and a food biopreservative. The present research aims to investigate the phenolic content, antioxidant activity and in vitro anti-inflammatory and antitumor [...] Read more.

Background/objectives: Propolis (bee glue) is a valuable bee product widely used as a natural remedy, a cosmetic ingredient, a nutritional value enhancer and a food biopreservative. The present research aims to investigate the phenolic content, antioxidant activity and in vitro anti-inflammatory and antitumor potential of six propolis samples from three regions of Bulgaria (Vidin, Gabrovo and Lovech). Methods: the analysis of propolis phenolic compounds was determined by high-performance liquid chromatography (HPLC); the antioxidant activity of ethanolic propolis extracts was assessed by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and ferric-reducing antioxidant power (FRAP) assay; the in vitro anti-inflammatory activity was assessed by the inhibition of albumin denaturation method; the in vitro antitumor activity was determined in human metastatic breast cancer cell line MDA-MB-231 using 3-(4,5-Dimethyl -2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Results: The ethanolic propolis extracts exhibited the total phenolic content from 190.4 to 317.0 mg GAE/g, total flavonoid content from 53.4 to 79.3 mg QE/g and total caffeic acid derivatives content from 5.9 to 12.1 mg CAE/g. The studied propolis extracts showed significant antioxidant capacity (between 1000.3 and 1606.0 mM TE/g determined by the DPPH assay, and between 634.1 and 1134.5 mM TE/g determined by the FRAP assay). The chemical composition analysis indicated high concentrations of caffeic acid benzyl ester, chrysin, pinocembrin and pinobanksin-3-O-propionate, predominantly in three of the propolis samples originating from Gabrovo and Lovech regions. All propolis samples demonstrated promising in vitro anti-inflammatory activity, expressed as the inhibition of thermally induced albumin denaturation by 73.59% to 78.44%, which was higher than that of the conventional anti-inflammatory drugs Aspirin (58.44%) and Prednisolone Cortico (57.34%). The propolis samples exhibited high in vitro cytotoxicity against cancer cells MDA-MB-231 with IC₅₀ values ranging between 9.24 and 13.62 µg/mL as determined by MTT assay. Conclusions: Overall, we can suggest that the high phenolic content of Bulgarian propolis from respective areas contributes to its enhanced antioxidant, anti-inflammatory and antitumor activity. Taken together, our results support the beneficial properties of Bulgarian propolis, with potential application as a promising therapeutic agent. Full article

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

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14 pages, 594 KiB

Open AccessArticle

Impact of Routine and Selective Preoperative Endoscopic Retrograde Cholangiopancreatography with Stent Placement on Postoperative and Oncologic Outcomes Following Pancreaticoduodenectomy for Pancreatic Ductal Adenocarcinoma

by Pauline Aeschbacher, Anna Silvia Wenning, Shadi Katou, Haluk Morgul, Mazen Juratli, Felix Becker, Ibrahim Büdeyri, Beat Gloor, Andreas Pascher, Benjamin Struecker and Andreas Andreou

Biomedicines 2025, 13(2), 333; https://doi.org/10.3390/biomedicines13020333 (registering DOI) - 1 Feb 2025

Abstract

Background: According to current guidelines, preoperative endoscopic retrograde cholangiopancreatography (ERCP) with biliary stenting (ERCP/stenting) is often necessary in patients with obstructive jaundice due to pancreatic ductal adenocarcinoma (PDAC), including severe jaundice (bilirubin > 250 umol/l), pruritus, cholangitis, cholestatic liver dysfunction, renal failure, severe [...] Read more.

Background: According to current guidelines, preoperative endoscopic retrograde cholangiopancreatography (ERCP) with biliary stenting (ERCP/stenting) is often necessary in patients with obstructive jaundice due to pancreatic ductal adenocarcinoma (PDAC), including severe jaundice (bilirubin > 250 umol/l), pruritus, cholangitis, cholestatic liver dysfunction, renal failure, severe malnutrition, or delayed surgery for tumors requiring neoadjuvant chemotherapy. We aimed to investigate the impact of preoperative ERCP/stenting on postoperative and long-term outcomes following pancreaticoduodenectomy (PD) for PDAC. Methods: Clinicopathological data of patients who underwent partial/total PD for PDAC between 2012 and 2019 in two hepato-pancreato-biliary centers in Germany and Switzerland were assessed. We compared patients treated with preoperative ERCP/stenting with those directly undergoing surgery according to postoperative morbidity, postoperative mortality, overall survival (OS) and disease-free survival (DFS). Results: During the study period, 192 patients underwent partial/total PD for PDAC. ERCP/stenting was performed in 105 patients, and 87 patients underwent resection without prior intervention. Postoperative 90-day overall morbidity rate (71% vs. 56%, p = 0.029) and superficial surgical site infection (SSI) rate (39% vs. 17%, p < 0.001) were significantly worse following preoperative ERCP/stenting. Major postoperative morbidity rate (18% vs. 21%, p = 0.650), organ/space SSI rate (7% vs. 14%, p = 0.100), and 90-day postoperative mortality rate (4% vs. 2%, p = 0.549) did not significantly differ between the two groups. After excluding 44 patients for whom the indication for ERCP/stenting was not consistent with current guidelines, ERCP/stenting was associated with a higher superficial SSI rate (36% vs. 17%, p = 0.009) and shorter length of stay (12 vs. 16 days, p = 0.004). Median OS (ERCP/stenting: 18 months vs. no ERCP/stenting: 23 months, p = 0.490) and median DFS (ERCP/stenting: 14 months vs. no ERCP/stenting: 18 months, p = 0.645) were independent from the utilization of ERCP/stenting. Conclusions: Preoperative ERCP/stenting in patients with PDAC can be performed without increasing organ/space SSI, major perioperative morbidity, and mortality rates and without worsening oncologic outcomes. However, it is associated with higher superficial SSI rates. If ERCP/stenting is not performed routinely but according to current guidelines, it is also associated with a shorter length of hospital stay. Further refinement of the indications for preoperative ERCP/stenting may reduce superficial SSI rates. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches (3rd Edition))

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21 pages, 915 KiB

Open AccessReview

Brain-Derived Neurotrophic Factor (BDNF) as a Marker of Physical Exercise or Activity Effectiveness in Fatigue, Pain, Depression, and Sleep Disturbances: A Scoping Review

by Nada Lukkahatai, Irvin L. Ong, Chitchanok Benjasirisan and Leorey N. Saligan

Biomedicines 2025, 13(2), 332; https://doi.org/10.3390/biomedicines13020332 (registering DOI) - 31 Jan 2025

Abstract

Background/Objectives: Brain-derived neurotrophic factor (BDNF) has been investigated as a potential mechanistic marker or therapeutic target to manage symptoms such as fatigue, pain, depression, and sleep disturbances. However, the variability in BDNF response to exercise or physical activity (exercise/PA) and its clinical [...] Read more.

Background/Objectives: Brain-derived neurotrophic factor (BDNF) has been investigated as a potential mechanistic marker or therapeutic target to manage symptoms such as fatigue, pain, depression, and sleep disturbances. However, the variability in BDNF response to exercise or physical activity (exercise/PA) and its clinical relevance in symptom management remains unclear. This scoping review assesses existing studies exploring the relationships between exercise/PA, symptoms, and BDNF levels, specifically focusing on fatigue, pain, depression, and sleep disturbances in adults. Methods: Relevant studies indexed in PubMed and CINAHL were identified. Using systematic review software, two reviewers independently screened and evaluated full texts, based on the following criteria: human studies reporting BDNF levels in adults, using exercise/PA interventions, assessing symptoms (pain, fatigue, depression, and/or sleep disturbance) as outcomes, and published in English. Results: Of 950 records, 35 records met the inclusion criteria. While exercise/PA is broadly supported for managing symptoms, 74.3% (n = 26) of studies reported increased BDNF levels, and only 40% (n = 14) showed significant increases following exercise/PA. Only 14% (n = 5) of studies demonstrated a significant relationship between changes in BDNF and symptoms. No significant differences in BDNF levels and symptoms were observed between different types of exercise (e.g., aerobic vs. strength vs. flexibility/stretching) and PA. Conclusions: The current literature provides insufficient evidence to confirm BDNF as a marker for exercise/PA effectiveness on symptoms. Further clinical investigations are needed to validate its potential as a therapeutic target. Full article

(This article belongs to the Section Neurobiology and Clinical Neuroscience)

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18 pages, 4694 KiB

Open AccessArticle

Identification of Common Angiogenesis Marker Genes in Chronic Lung Diseases and Their Relationship with Immune Infiltration Based on Bioinformatics Approaches

by Lu Liu, Man Wang and Shihuan Yu

Biomedicines 2025, 13(2), 331; https://doi.org/10.3390/biomedicines13020331 (registering DOI) - 31 Jan 2025

Abstract

Objective: This study aims to explore the role of angiogenesis-related genes in chronic lung diseases (ILD and COPD) using bioinformatics methods, with the goal of identifying novel therapeutic targets to slow disease progression and prevent its deterioration into fibrosis or pulmonary artery hypertension. [...] Read more.

Objective: This study aims to explore the role of angiogenesis-related genes in chronic lung diseases (ILD and COPD) using bioinformatics methods, with the goal of identifying novel therapeutic targets to slow disease progression and prevent its deterioration into fibrosis or pulmonary artery hypertension. Methods: The research methods encompassed differential analysis, WGCNA (Weighted Gene Co-expression Network Analysis), and multiple machine learning approaches to screen for key genes. Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were utilized to assess related biological functions and pathways. Additionally, immune cell infiltration was analyzed to evaluate the immune status of the disease and the correlation between genes and immunity. Results: COPD and ILD are closely associated with pathways related to angiogenesis, immune responses, and others, with differential genes in both groups linked to inflammation-related signaling pathways. The study established a chronic lung disease-related gene set comprising 171 genes and further screened out 21 genes related to angiogenesis. Ultimately, four key genes—COL10A1, EDN1, MMP1, and RRAS—were identified through machine learning methods. These four genes are closely related to angiogenesis and immune processes, and clustering analysis based on them can reflect different disease states and variations in immune cell infiltration. Conclusions: COL10A1, EDN1, MMP1, and RRAS represent potential therapeutic targets for slowing the progression of chronic lung diseases and preventing their deterioration. Furthermore, monocytes exhibited consistent infiltration patterns across disease and control groups, as well as among different subgroups, suggesting their potential significant role in the development of chronic lung diseases. Full article

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

15 pages, 3894 KiB

Open AccessArticle

Differential Oral Microbiota and Serum Cytokine Signatures in Age-Grouped Patients with Marfan Syndrome

by Erick Ricardo Ordaz-Robles, María Elena Soto, Paulina Hernández-Ruiz, Alma Reyna Escalona-Montaño, Luis Alejandro Constantino-Jonapa, Amedeo Amedei and María Magdalena Aguirre-García

Biomedicines 2025, 13(2), 330; https://doi.org/10.3390/biomedicines13020330 (registering DOI) - 31 Jan 2025

Abstract

Introduction: Marfan syndrome (MFS) is an autosomal dominant genetic disorder, caused by a mutation in the FBN-1 gene, affecting the cardiovascular, musculoskeletal, ocular, and central nervous systems. Cardiovascular abnormalities associated with MFS lead to different pathological conditions, such as cardiac arrhythmias, coronary artery [...] Read more.

Introduction: Marfan syndrome (MFS) is an autosomal dominant genetic disorder, caused by a mutation in the FBN-1 gene, affecting the cardiovascular, musculoskeletal, ocular, and central nervous systems. Cardiovascular abnormalities associated with MFS lead to different pathological conditions, such as cardiac arrhythmias, coronary artery disease, and aortic dilatation. The latter are the primary causes of mortality in MFS patients. To date, the role of altered oral microbiota (OM) in MFS is unknown, and so the aim of our study was to determine whether there are differences in the oral microbiota of MFS patients with aortic dilatation and non-dilatation. Methods: We enrolled 36 MFS patients, who were divided into groups with aortic non-dilatation (n = 12) and with aortic dilatation (n = 24). Dental plaque samples were used for OM analysis, and serum was used for cytokine evaluation. Results: The main genera were compared between patients with aortic dilatation and non-dilatation, revealing three genera with significant differences: Actinomyces (p = 0.007) and Rothia (p = 0.002) were more abundant in those with aortic dilatation, while Fusobacterium (p = 0.044) was more abundant in non-dilatation patients. However, no significant differences in cytokine levels were observed between the presence and absence of aortic dilatation, except that the IL-1β levels were higher in non-dilatation patients (165.09 pg/mL) than in those with dilatation (117.15 pg/mL), with a significance of p = 0.057. Conclusions: This study represents the initial, tentative pilot study to understand the relationship between oral health and systemic conditions in patients with Marfan syndrome. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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25 pages, 1395 KiB

Open AccessReview

The Interplay of Nutrition, the Gut Microbiota and Immunity and Its Contribution to Human Disease

by Samantha L. Dawson, Emma Todd and Alister C. Ward

Biomedicines 2025, 13(2), 329; https://doi.org/10.3390/biomedicines13020329 - 31 Jan 2025

Abstract

Nutrition, the gut microbiota and immunity are all important factors in the maintenance of health. However, there is a growing realization of the complex interplay between these elements coalescing in a nutrition–gut microbiota–immunity axis. This regulatory axis is critical for health with disruption [...] Read more.

Nutrition, the gut microbiota and immunity are all important factors in the maintenance of health. However, there is a growing realization of the complex interplay between these elements coalescing in a nutrition–gut microbiota–immunity axis. This regulatory axis is critical for health with disruption being implicated in a broad range of diseases, including autoimmune disorders, allergies and mental health disorders. This new perspective continues to underpin a growing number of innovative therapeutic strategies targeting different elements of this axis to treat relevant diseases. This review describes the inter-relationships between nutrition, the gut microbiota and immunity. It then details several human diseases where disruption of the nutrition–gut microbiota–immunity axis has been identified and presents examples of how the various elements may be targeted therapeutically as alternate treatment strategies for these diseases. Full article

(This article belongs to the Special Issue Gut Microbiota, Diet, and Immunity: Investigating the Connections and Implications for Disease Development: 2nd Edition)

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13 pages, 2376 KiB

Open AccessArticle

HIF-1α Promotes Luteinization via NDRG1 Induction in the Human Ovary

by Akemi Nishigaki, Mitsuaki Ishida, Hiroaki Tsubokura, Yoji Hisamatsu, Yoshinobu Hirose and Hidetaka Okada

Biomedicines 2025, 13(2), 328; https://doi.org/10.3390/biomedicines13020328 - 31 Jan 2025

Abstract

Background/Objectives: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in various physiological and pathological processes of the ovary. However, the timing of HIF-1α expression and its specific biological function in the follicular development of the human ovary remain unclear. [...] Read more.

Background/Objectives: Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in various physiological and pathological processes of the ovary. However, the timing of HIF-1α expression and its specific biological function in the follicular development of the human ovary remain unclear. Therefore, in this study, we aimed to examine whether HIF-1α and its downstream gene, N-myc downstream-regulated gene 1 (NDRG1), exhibit stage-specific expression during the follicular development process in the human ovary. Methods: We used ovarian tissues from eight women with regular menstrual cycles who were not undergoing hormonal treatment. We investigated HIF-1α and NDRG1 expression and localization using immunohistochemistry. Further, we transfected human ovarian granulosa (KGN) cells with HIF-1α small interfering RNA (siRNA) to investigate the influence of HIF-1α on NDRG1 expression and progesterone synthesis. Results: The immunohistochemical analysis of human ovarian tissues revealed that HIF-1α was localized in the cytoplasm of granulosa cells (GCs) at both the primary and secondary follicular stages. Conversely, in tertiary and later developmental stages, HIF-1α was observed exclusively in the nucleus of GCs. Furthermore, while NDRG1 was not detected in primary follicles, it was present in all GCs beyond the tertiary stage. Notably, transfection of KGN cells with HIF-1α siRNA significantly decreased NDRG1 expression, at both the mRNA and protein levels, and in progesterone synthesis. Conclusion: Our results indicate that HIF-1α and NDRG1 are integral to follicular development and the early luteinization of pre-ovulatory follicles. Full article

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

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30 pages, 1566 KiB

Open AccessReview

Mitochondrial Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies

by Kai Meng, Haocheng Jia, Xiaoqing Hou, Ziming Zhu, Yuguang Lu, Yingying Feng, Jingwen Feng, Yong Xia, Rubin Tan, Fen Cui and Jinxiang Yuan

Biomedicines 2025, 13(2), 327; https://doi.org/10.3390/biomedicines13020327 - 31 Jan 2025

Abstract

Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have [...] Read more.

Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in the central nervous system (CNS) or peripheral nervous system (PNS). Examples of neurodegenerative diseases include Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role in cell signaling, immune response, and metabolic regulation. For example, mitochondrial dysfunction is closely associated with the onset and progression of a variety of diseases, including ND, cardiovascular diseases, diabetes, and cancer. The dysfunction of energy metabolism, imbalance of mitochondrial dynamics, or abnormal mitophagy can lead to the imbalance of mitochondrial homeostasis, which can induce pathological reactions such as oxidative stress, apoptosis, and inflammation, damage the nervous system, and participate in the occurrence and development of degenerative nervous system diseases such as AD, PD, and ALS. In this paper, the latest research progress of this subject is detailed. The mechanisms of oxidative stress, mitochondrial homeostasis, and mitophagy-mediated ND are reviewed from the perspectives of β-amyloid (Aβ) accumulation, dopamine neuron damage, and superoxide dismutase 1 (SOD1) mutation. Based on the mechanism research, new ideas and methods for the treatment and prevention of ND are proposed. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress)

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8 pages, 512 KiB

Open AccessEditorial

The Cell Biologist Potential of Cytomegalovirus to Solve Biogenesis and Maintenance of the Membrane Recycling System

by Pero Lučin and Hana Mahmutefendić Lučin

Biomedicines 2025, 13(2), 326; https://doi.org/10.3390/biomedicines13020326 - 31 Jan 2025

Abstract

Cytomegalovirus (CMV) is an important pathogen that extensively remodels the nucleus and cytosol of an infected cell to establish a productive infection [...] Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

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10 pages, 7354 KiB

Open AccessCase Report

X-Linked CGD Chorioretinitis in Two Young Girls

by Johnathan Abraham Bailey, Maximilian Daechul Kong, Chanakarn Piamjitchol, Baichun Hou, Abdhel Exinor, Antara Nayak, Noah Heaps, Aykut Demirkol and Stephen H. Tsang

Biomedicines 2025, 13(2), 323; https://doi.org/10.3390/biomedicines13020323 - 31 Jan 2025

Abstract

Background: Chronic granulomatous disease (CGD) is a rare genetic disorder that causes primary immunodeficiency. In addition to increasing infection susceptibility in various bodily systems, several ocular manifestations have been described in males. This condition is well described in males, due to its X-linked [...] Read more.

Background: Chronic granulomatous disease (CGD) is a rare genetic disorder that causes primary immunodeficiency. In addition to increasing infection susceptibility in various bodily systems, several ocular manifestations have been described in males. This condition is well described in males, due to its X-linked recessive inheritance. However, here we present, to our knowledge, the first cases of X-linked CGD chorioretinitis in female carriers, possibly due to skewed X-inactivation (lyonization). Methods: Comprehensive multimodal imaging, including color fundus photography, short-wavelength autofluorescence, and spectral domain optical coherence tomography (OCT), was conducted. Functional assessment was completed with full-field electroretinogram (ff-ERG). Results: This report details two sisters with X-linked CGD carrier status, both presenting chorioretinal lesions on fundoscopy. Observed features included punched-out chorioretinal lesions, perivascular atrophy, and peripheral pigment changes. Autofluorescence imaging confirmed hypoautofluorescent areas correlating with chorioretinal atrophy, and OCT revealed retinal collapse and ellipsoid zone loss in one sibling. Despite these structural changes, visual function remained stable with minimal progression over time. Subsequent serial ERGs did not show progression. Conclusions: The findings highlight that skewed X-inactivation may contribute to retinal changes in asymptomatic CGD carriers, underscoring the need for awareness of potential ocular manifestations in X-linked genetic disorders in female carriers. Full article

(This article belongs to the Special Issue Inherited Retinal Diseases: From Pathomolecular Mechanisms to Therapeutic Strategies)

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11 pages, 672 KiB

Open AccessArticle

A Case Series Focusing on Blunt Traumatic Diaphragm Injury at a Level 1 Trauma Center

by Bharti Sharma, Musili Kafaru, George Agriantonis, Aden Davis, Navin D. Bhatia, Kate Twelker, Zahra Shafaee, Jasmine Dave, Juan Mestre and Jennifer Whittington

Biomedicines 2025, 13(2), 325; https://doi.org/10.3390/biomedicines13020325 - 30 Jan 2025

Abstract

Introduction: Detection of blunt traumatic diaphragm injury (TDI) can be challenging in the absence of surgical exploration. Our objective is to study the mechanisms of injury and detection modes for patients with blunt TDI. Methods: This is a single-center, retrospective review conducted in [...] Read more.

Introduction: Detection of blunt traumatic diaphragm injury (TDI) can be challenging in the absence of surgical exploration. Our objective is to study the mechanisms of injury and detection modes for patients with blunt TDI. Methods: This is a single-center, retrospective review conducted in a level 1 trauma center from 2016 to 2023, inclusive. We identified seven patients with blunt TDI using the primary mechanisms and trauma type. Results: Out of seven patients, two were associated with motor vehicle collisions, four were pedestrians struck, and one fell down the stairs. The mean ISS was 48.4 (29–75). Of the seven patients with blunt TDI, four died in the trauma bay–two from traumatic arrest and two died spontaneously. Multiple rib fractures were one of the common injury patterns in six cases, whereas in the remaining case, blunt TDI was confirmed at laparotomy and repaired. One patient died two days after admission. Of the two patients who survived, one had a TDI identified during video-assisted thoracic surgery (VATS) for retained hemothorax, and one patient had a TDI repaired during emergent exploratory laparotomy for other injuries. In the remaining four patients, blunt TDI was confirmed based on their autopsy reports. Conclusions: Injuries in all seven cases were sustained with a high-energy injury mechanism. Multiple rib fractures were reported in six cases. Based on our findings, we recommend that clinicians maintain a high level of suspicion for blunt TDI in patients with thoracoabdominal trauma, especially in cases with rib fractures or high-impact trauma. Full article

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

15 pages, 519 KiB

Open AccessArticle

CytoSorb^® Hemadsorption in Cardiogenic Shock: A Real-World Analysis of Hemodynamics, Organ Function, and Clinical Outcomes During Mechanical Circulatory Support

by Julian Kreutz, Lukas Harbaum, Cem Benin Barutcu, Amar Sharif Rehman, Nikolaos Patsalis, Klevis Mihali, Georgios Chatzis, Maryana Choukeir, Styliani Syntila, Bernhard Schieffer and Birgit Markus

Biomedicines 2025, 13(2), 324; https://doi.org/10.3390/biomedicines13020324 - 30 Jan 2025

Abstract

Background: Cardiogenic shock (CS), characterized by inadequate tissue perfusion due to cardiac dysfunction, has a high mortality rate despite advances in treatment. Systemic inflammation and organ failure exacerbate the severity of CS. Extracorporeal hemadsorption techniques such as CytoSorb^® have been introduced to [...] Read more.

Background: Cardiogenic shock (CS), characterized by inadequate tissue perfusion due to cardiac dysfunction, has a high mortality rate despite advances in treatment. Systemic inflammation and organ failure exacerbate the severity of CS. Extracorporeal hemadsorption techniques such as CytoSorb^® have been introduced to control inflammation. However, evidence of their efficacy, particularly in patients on various mechanical circulatory support (MCS) systems, remains limited. Methods: This retrospective study analyzed data from 129 CS patients treated with CytoSorb^® at the University Hospital of Marburg between August 2019 and December 2023. Those patients receiving MCS were grouped according to MCS type: (1) Impella, (2) VA-ECMO, and (3) ECMELLA. The hemodynamic parameters of circulatory support (e.g., MCS flow rates and vasoactive inotropic score, VIS) and laboratory and ventilation parameters were assessed 24 h before start of CytoSorb^® therapy (T1) and 24 h after completion of CytoSorb^® therapy (T2). Results: Of 129 CS patients (mean age: 64.7 ± 13.1 years), 103 (79.8%) received MCS. Comparing T1 and T2, there was a significant reduction in VIS in the entire cohort (T1: 38.0, T2: 16.3; p = 0.002), with a concomitant significant reduction in the level of MCS support in all subgroups, indicating successful weaning. Analysis of laboratory parameters showed significant reductions in lactate (T1: 2.1, T2: 1.3 mmol/L; p = 0.014), myoglobin (T1: 1549.0, T2: 618.0 µg/L; p < 0.01), lactate dehydrogenase (T1: 872.0, T2: 632.0 U/L; p = 0.048), and procalcitonin (T1: 2.9, T2: 1.6 µg/L; p < 0.001). However, a significant decrease in platelets (T1: 140.0, T2: 54.0 tsd/µL; p < 0.001) and albumin (T1: 25.0, T2: 22.0 g/dL; p < 0.001) was also documented. The median SOFA score of the entire cohort was 15.0 (IQR 12.0–16.0), predicting a mortality rate of >80%, which could be reduced to 60.5% in the present study. Conclusions: During CytoSorb^® therapy in CS, a significant reduction in VIS was demonstrated, resulting in improved organ perfusion. Therefore, the results of this study underline that CytoSorb^® therapy can be considered a useful “component” in the complex management of CS, especially when combined with MCS. To refine and optimize treatment strategies in CS, prospective studies are needed to better define the role of hemadsorption. Full article

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

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