Life

13 pages, 1682 KB

Open AccessArticle

Antifatigue Effects of 5-Aminolevulinic Acid Chronic Treatment on Mice

by Chinatsu Ohmori, Eiko Kumamoto, Satoka Kasai, Kotaro Okano, Urara Ota, Atsuko Kamiya, Mitsugu Yamauchi, Kiwamu Takahashi, Masahiro Ishizuka, Kazumi Yoshizawa, Daisuke Yamada and Akiyoshi Saitoh

Life 2025, 15(9), 1465; https://doi.org/10.3390/life15091465 (registering DOI) - 18 Sep 2025

Abstract

5-aminolevulinic acid (5-ALA) is a heme precursor involved in mitochondrial activation. A clinical study suggested that 5-ALA supplementation alleviates fatigue in healthy individuals who experience chronic physical tiredness. However, the detailed mechanisms are unknown. Therefore, we investigated the mechanism underlying the antifatigue effect [...] Read more.

5-aminolevulinic acid (5-ALA) is a heme precursor involved in mitochondrial activation. A clinical study suggested that 5-ALA supplementation alleviates fatigue in healthy individuals who experience chronic physical tiredness. However, the detailed mechanisms are unknown. Therefore, we investigated the mechanism underlying the antifatigue effect of 5-ALA using fatigue mouse models. C57BL/6N mice were orally administered 5-ALA hydrochloride or distilled water for 8 weeks. Fatigue mouse models were developed by housing the mice in a cage filled with water for 4 days. Fatigue was evaluated through running distance via a treadmill test. The decrease in the running distance in female mice significantly recovered after 5-ALA administration. 5-ALA administration ameliorated the decreased blood glucose levels in fatigue mouse models. These results suggest that 5-ALA improves fatigue-induced hypoglycemia by promoting the use of fatty acids. PpIX’s concentration in the FCX of the fatigue mouse models significantly increased after 5-ALA treatment. Decreased levels of 3-methoxy-4-hydroxyphenylglycol and noradrenaline (NA) turnover ratio in the FCX recovered to non-fatigue levels after 5-ALA treatment. Therefore, the antifatigue effect of 5-ALA in mice could be related to the activation of the NA neuronal systems in the FCX and the increase in energy production via glycogenesis activation from peripheral adipose tissue. Full article

(This article belongs to the Special Issue Advances in 5-Aminolevulinic Acid Applications in Medical and Healthcare)

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16 pages, 6289 KB

Open AccessArticle

The Clinical Value of the Ferning Test in Monitoring Dry Eye Syndrome in Patients with Sarcoidosis

by Călina Anda Sandu, Cosmin Victor Ganea, Vlad Constantin Donica, Anisia Iuliana Alexa, Ioana Alexandra Sandu, Madalina Ioana Bilha and Camelia Margareta Bogdănici

Life 2025, 15(9), 1464; https://doi.org/10.3390/life15091464 - 18 Sep 2025

Abstract

Background: Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas, predominantly affecting the lungs and lymph nodes. However, the disease can affect any organ, including the eye, where it most commonly manifests as uveitis and dry eye disease (DED). [...] Read more.

Background: Sarcoidosis is a systemic inflammatory disease characterized by the formation of non-caseating granulomas, predominantly affecting the lungs and lymph nodes. However, the disease can affect any organ, including the eye, where it most commonly manifests as uveitis and dry eye disease (DED). The Ferning Test (FT), a non-invasive method for tear film analysis, offers insight into tear quality. Through this study, we aimed to evaluate the ability of the FT to diagnose and differentiate DED in patients with sarcoidosis. Methods: The study included a sample of 30 patients, divided into three groups, each consisting of 10 patients: one group of patients with sarcoidosis and dry eye disease (S-DED), one group of patients with DED without other systemic pathologies, and a control group of healthy individuals. Tear film samples were collected from the right eye of each participant, without stimulation, by microcapillarity. A drop of tear was spread on a microscope slide, allowed to dry, and then examined under a microscope to analyze the crystallization pattern. Results: Microscopic analysis revealed a significant difference in the structure and morphology of crystallization, as well as in the number of formed branchings, in sarcoidosis patients compared to patients in the other two groups. This finding suggests a distinct alteration in tear film composition in patients with sarcoidosis. Conclusions: Based on these results, the FT represents a valuable and promising tool for the diagnosis of DED associated with sarcoidosis. Being a non-invasive, easy-to-perform, and inexpensive test, it can be widely implemented in any ophthalmology department, opening perspectives for the test to become an important component among the diagnostic elements of dry eye syndrome in patients with sarcoidosis. Full article

(This article belongs to the Special Issue Prognosis and Management of Dry Eye Disease)

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16 pages, 233 KB

Open AccessArticle

Diagnosis and Risk Factors in Retinopathy of Prematurity: A Five-Year Single-Center Descriptive Study

by Fatma Sumer, Mehmet Kenan Kanburoglu, Ozgur Altuntas, Fatma Erbatur Uzun, Isil Uslubas, Feyzahan Uzun and Aytac Kanar

Life 2025, 15(9), 1463; https://doi.org/10.3390/life15091463 - 18 Sep 2025

Abstract

Objective: We aimed to determine the incidence and screening outcomes of retinopathy of prematurity (ROP) in preterm infants managed at a tertiary neonatal intensive care unit (NICU) and to identify associated risk factors. Material and Methods: Medical records of 454 premature infants who [...] Read more.

Objective: We aimed to determine the incidence and screening outcomes of retinopathy of prematurity (ROP) in preterm infants managed at a tertiary neonatal intensive care unit (NICU) and to identify associated risk factors. Material and Methods: Medical records of 454 premature infants who underwent ROP screening between April 2016 and August 2021 were retrospectively analyzed. Infants with birth weight (BW) ≤ 1500 g or ≤32 weeks of gestational age and those with BW > 1500 g or GA > 32 weeks who had an unstable clinical course were included. All of them were born in the same center. Demographic characteristics, potential risk factors for ROP, ocular examination findings, and treatment requirement were recorded. Results: During the five-year study period, ROP was observed in 75 (16.6%) of a total of 454 premature infants with a mean gestational age (GA) of 30.19 ± 2.49 weeks and a mean BW of 2025.15 ± 614.46 g in the NICU. Of these patients, 67 (14.8%) had stage I disease and 8 (1.8%) had stage II disease. Advanced-stage ROP was not detected in any of the cases. The median GA of patients diagnosed with ROP was 29 weeks (22–35) and the median BW was 2100 g (500–3750), which were significantly lower than those without ROP (p < 0.001). When multivariate logistic regression analysis was evaluated with the Wald method, the accuracy rate of the model examining the combined effect of GA, intraventricular hemorrhage (IVH), respiratory distress syndrome (RDS), patent ductus arteriosus (PDA), necrotizing enterocolitis (NEC), and surfactant treatment was 85.9%. In this model, gestational age (OR: 0.712, p < 0.001), IVH (OR: 2.915, p = 0.010), RDS (OR: 2.129, p = 0.004), NEC (OR: 3.679, p < 0.001), PDA (OR: 2.434, p = 0.021), and surfactant treatment (OR: 2.271, p = 0.002) were found to be independent risk factors for ROP development. Conclusions: Small GA and low BW are the main risk factors for the development of ROP. The incidence of ROP was found to be lower than similar studies conducted in our country. While severe ROP cases have been reported in more mature infants in Turkey, our study found no treatment-requiring ROP cases, likely reflecting the higher mean GA and BW characteristics of our cohort. Full article

(This article belongs to the Special Issue Pediatric Ophthalmic Pathology—Integrating Clinical and Basic Research)

12 pages, 243 KB

Open AccessArticle

The Role of Microbiology at the 1-Month Surveillance Bronchoalveolar Lavage in the Identification of Complications in the First Year After Lung-Transplantation—A Retrospective Single-Center Experience

by Rocco Francesco Rinaldo, Antonio Curtoni, Mattia Verardo, Silvia Zaffina, Nour Shbaklo, Francesca Sidoti, Francesco Giuseppe De Rosa, Silvia Corcione, Massimo Boffini, Matteo Marro, Cristina Costa and Paolo Solidoro

Life 2025, 15(9), 1462; https://doi.org/10.3390/life15091462 - 17 Sep 2025

Abstract

Acute rejection and infections are the most frequent complications in the first year after lung transplantation, often representing relevant causes of death. There is still no consensus on the ideal strategy for preventing these events, with a still open debate on active bronchoscopic [...] Read more.

Acute rejection and infections are the most frequent complications in the first year after lung transplantation, often representing relevant causes of death. There is still no consensus on the ideal strategy for preventing these events, with a still open debate on active bronchoscopic surveillance protocols vs. clinically mandated ones. The aim of our single-center exploratory study was to evaluate retrospectively the role of microbiology at bronchoalveolar lavage (BAL) at the first month from transplantation in asymptomatic patients in relation to the development of complications up to 12 months from surgery. We collected data from 28 patients who underwent surveillance bronchoscopies according to our center protocol (transbronchial biopsies and BAL at months 1, 4, 8, 12, 18, and 24 post-transplantation) who had a 12-month follow-up. The inclusion criterion was the absence of infiltrates at 1-month post-transplantation chest CT. We excluded patients transplanted due to suppurative diseases of the lung to minimize the pre-transplantation risk factors for infection. We also assessed differences in complications according to the underlying disease. We enrolled 15 patients with interstitial lung diseases (ILDs) and 13 with chronic obstructive pulmonary disease (COPD). Of the 28 patients, 11 had a positive BAL for bacteria. Patients with a positive BAL developed a higher number of pulmonary infectious complications (odds ratio of 18.33, p-value = 0.013 at regression model), with a near significance for moderate–severe pulmonary infections (odds ratio 4.8, p-value = 0.061). We did not find a significant correlation with rejection, cytomegalovirus reactivation, or pseudomembranes. We did not find differences in the rates of complications when grouping subjects according to pre-transplantation disease. Our results suggest a possible role for BAL positivity for bacteria in asymptomatic patients at surveillance bronchoscopy in predicting the development of future infections, warranting a tailored follow-up of patients that considers this data. Larger, multicentric studies are needed to explore and confirm the utility of our findings. Full article

(This article belongs to the Section Medical Research)

24 pages, 588 KB

Open AccessReview

Chloride Homeostasis in Neuronal Disorders: Bridging Measurement to Therapy

by Daniele Arosio and Carlo Musio

Life 2025, 15(9), 1461; https://doi.org/10.3390/life15091461 - 17 Sep 2025

Abstract

Neuronal chloride (Cl⁻) homeostasis is fundamental for brain function, with disruptions increasingly recognized as pathogenic across neurological disorders. This review synthesizes evidence from preclinical models and clinical studies, integrating electrophysiological measurements, molecular analyses, imaging with genetically encoded sensors like ClopHensor, and [...] Read more.

Neuronal chloride (Cl⁻) homeostasis is fundamental for brain function, with disruptions increasingly recognized as pathogenic across neurological disorders. This review synthesizes evidence from preclinical models and clinical studies, integrating electrophysiological measurements, molecular analyses, imaging with genetically encoded sensors like ClopHensor, and behavioral assays. Key findings demonstrate that Cl⁻ dysregulation follows distinct patterns: (1) in epilepsy, KCC2 downregulation converts GABAergic inhibition to excitation, promoting seizures; (2) in Alzheimer’s disease (AD) models, pre-symptomatic KCC2 loss in hippocampus is observed, with KCC2 restoration reversing aspects of cognitive decline; (3) in autism spectrum disorders (ASD), developmental delays in GABA polarity shifts feature due to altered NKCC1/KCC2 ratios; and (4) in Huntington’s disease (HD), striatal neuron-specific Cl⁻ imbalances are linked to motor dysfunction. Methodologically, advanced tools—including subcellular Cl⁻ imaging and high-throughput drug screening—have enabled precise dissection of these mechanisms. Therapeutic strategies targeting Cl⁻ transporters (NKCC1 inhibitors like bumetanide, KCC2 enhancers like CLP290) show preclinical promise but require improved central nervous system (CNS) delivery and selectivity. These findings establish Cl⁻ homeostasis as both a biomarker and therapeutic target, necessitating precision medicine approaches to address heterogeneity in neurological disorders. Full article

(This article belongs to the Special Issue The Contribution of Neurogenetics in Disentangling the Pathophysiology of Neurodegenerative Diseases)

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14 pages, 759 KB

Open AccessArticle

The Relationship Between Preoperative Serum Ionized Calcium, Vitamin D, and Postoperative Bleeding After Major Cardiac Surgery

by Adrian Stef, Constantin Bodolea, Aurelia Georgeta Solomonean, Nadina Tintiuc, Alexandru Oprea, Oana Antal, Gabriel Cismaru and Emanuel Palade

Life 2025, 15(9), 1460; https://doi.org/10.3390/life15091460 - 17 Sep 2025

Abstract

Objective: The role of calcium in coagulation homeostasis is well established, although the relationship between calcium levels and postoperative bleeding in major cardiac surgery remains largely unexplored. Methods: This retrospective, single-center study investigated the correlations between ionized calcium levels measured at several timepoints: [...] Read more.

Objective: The role of calcium in coagulation homeostasis is well established, although the relationship between calcium levels and postoperative bleeding in major cardiac surgery remains largely unexplored. Methods: This retrospective, single-center study investigated the correlations between ionized calcium levels measured at several timepoints: preoperatively (after induction of anesthesia), immediately after cardiopulmonary bypass (CPB) weaning, on the first postoperative day measured three times at 8 h intervals, preoperative vitamin D values, and several significant bleeding outcomes. These outcomes included the volume of blood in the drainage bag (measured in milliliters on days 1 and 2), the need for surgical or medical hemostasis, the requirement for blood transfusion (red blood cells, fresh frozen plasma, or platelets), and the occurrence of extracardiac hemorrhagic complications. A multivariable logistic regression analysis was performed, with a two-sided p-value of <0.00625 considered significant after applying Bonferroni correction. Results: The study included 83 patients with a mean age of 64.9 ± 8.5 years, with 49 (59%) being male. The most common procedures were aortic valve replacement (26 patients, 31%) and coronary artery bypass grafting (26 patients, 31%). The multivariable regression analysis demonstrated a trend toward an association between low levels of preoperative calcium and increased bleeding volume immediately after CBP and on the first day after the intervention (r = 0.30; p = 0.08 for day 1 and r = 0.24; p = 0.03 for day 2). Similar trends were observed for the association between low levels of preoperative calcium, use of medical hemostasis (r = 0.30; p = 0.009), and red blood cell transfusion (r = 0.24; p = 0.03). Additionally, we observed a trend towards a positive correlation between lower serum vitamin D levels and increased postoperative blood loss on both day 1 (r = 0.32; p = 0.07) and day 2 (r = 0.29; p = 0.04). The subgroup analysis of valve procedures vs. coronary procedures showed no statistically difference between preoperative ionized calcium levels, postoperative bleeding (289 27 vs. 283 mL, p = 0.87), the need for surgical hemostasis (p = 0.5), or blood transfusion requirement (p = 0.57). Conclusions: In our study, preoperative calcium levels were consistently associated with increased bleeding after major cardiac surgery. Post-CPB ionized calcium levels did not influence bleeding outcomes. The role of calcium in coagulation homeostasis during major cardiac surgery warrants further research, ideally with more robust data, as our study’s small sample limits robust evidence. Further larger studies will conclude on the importance of calcium levels in cardiac surgery related to hemostasis and bleeding outcomes. Lower preoperative ionized calcium and vitamin D levels showed exploratory associations with increased bleeding-related outcomes following major cardiac surgery. These findings are hypothesis-generating, and larger prospective studies are needed to confirm these potential relationships and clarify their clinical implications. Full article

(This article belongs to the Special Issue Critical Issues in Intensive Care Medicine)

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24 pages, 2284 KB

Open AccessArticle

Obesity/Overweight as a Meaningful Modifier of Associations Between Gene Polymorphisms Affecting the Sex Hormone-Binding Globulin Content and Uterine Myoma

by Marina Ponomarenko, Evgeny Reshetnikov, Maria Churnosova, Inna Aristova, Maria Abramova, Vitaly Novakov, Vladimir Churnosov, Alexey Polonikov, Mikhail Churnosov and Irina Ponomarenko

Life 2025, 15(9), 1459; https://doi.org/10.3390/life15091459 - 17 Sep 2025

Abstract

The main goal of this study was to consider the role of obesity/overweight as a potential modifier of associations between gene single nucleotide polymorphisms (SNPs) affecting the sex hormone-binding globulin level (SHBG_level) and uterine myoma (UM). In the two women cohorts [...] Read more.

The main goal of this study was to consider the role of obesity/overweight as a potential modifier of associations between gene single nucleotide polymorphisms (SNPs) affecting the sex hormone-binding globulin level (SHBG_level) and uterine myoma (UM). In the two women cohorts differentiated by body mass index (BMI) (BMI ≥ 25, n = 782 [379 UM/403 control] and BMI < 25, n = 760 [190 UM/570 control]), the association of genome-wide association studies (GWAS)-correlated SHBG_level-tied nine loci with UM was studied by method logistic regression with a subsequent in-depth evaluation of the functionality of UM-causal loci and their strongly linked variants. BMI-conditioned differences in the associations of SHBG_level-tied loci with UM were revealed: in the BMI < 25 group, a variant rs17496332 (A/G) PRMT6 was UM-correlated (OR = 0.70; p_perm = 0.024), and in the BMI ≥ 25 cohort, a SNP rs3779195 (T/A) BAIAP2L1 was UM-associated (OR = 1.53; p_perm = 0.019). Both the UM-causal loci and their proxy SNPs have pronounced probable functionality in the organism as a whole, as well as in the liver (the SHBG synthesis place), adipose tissue, uterus, etc., thereby influencing significant processes for UM biology such as regulation of the gene transcription, embryogenesis/development, cell proliferation/differentiation/apoptosis, metabolism, lipid exchange, etc. In conclusion, the results of our work demonstrated, for the first time, the essential role of obesity/overweight as a meaningful modifier of associations between SHBG_level-tied polymorphisms and UM. Full article

(This article belongs to the Special Issue Gynecology Update: Modern Diagnostic Approaches and Innovative Therapies)

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17 pages, 4054 KB

Open AccessArticle

Chemogenetic Modulation of Electroacupuncture Analgesia in a Mouse Intermittent Cold Stress-Induced Fibromyalgia Model by Activating Cerebellum Cannabinoid Receptor 1 Expression and Signaling

by I-Han Hsiao, Ming-Chia Lin, Hsin-Cheng Hsu, Younbyoung Chae, Yi-Kai Su and Yi-Wen Lin

Life 2025, 15(9), 1458; https://doi.org/10.3390/life15091458 - 17 Sep 2025

Abstract

Fibromyalgia (FM) is characterized by widespread musculoskeletal pain and tenderness, cognitive dysfunction, fatigue, and insomnia. Electroacupuncture (EA) has documented efficacy against FM-associated pain, while cannabinoid receptor 1 (CB1) plays a critical role in endogenous analgesia. Herein, we examined whether pain relief initiated by [...] Read more.

Fibromyalgia (FM) is characterized by widespread musculoskeletal pain and tenderness, cognitive dysfunction, fatigue, and insomnia. Electroacupuncture (EA) has documented efficacy against FM-associated pain, while cannabinoid receptor 1 (CB1) plays a critical role in endogenous analgesia. Herein, we examined whether pain relief initiated by EA was linked with differing cerebellar CB1 levels and signaling in an intermittent cold stress (ICS) mouse model of FM. FM-like hyperalgesia and recovery were assessed by measuring mechanical and thermal nociceptive thresholds. Compared to control mice, ICS-induced FM-model mice exhibited a significantly reduced mechanical withdrawal threshold (2.3 ± 0.1 g) and shorter thermal withdrawal latency (4.0 ± 0.5 s), indicative of mechanical and thermal hyperalgesia. Both conditions were reversed by 2 Hz EA but not sham EA. Hyperalgesia was associated with reduced CB1 receptor expression and the enhanced activity of multiple nociceptive signaling pathways (PKA, PI3K, Akt, mTOR, ERK, and NF-kB) in the mouse cerebellum. The 2 Hz EA treatment reliably reversed these abnormalities, while the sham EA treatment did not. Intracerebroventricular injection of the CB1 agonist anandamide (AEA) recapitulated the effects of EA on pain thresholds, while the analgesic effects of EA were blocked by the CB1 antagonist AM251. Precise chemogenetic stimulation at the paraventricular nucleus (PVN) of the hypothalamus reliably induced FM pain. Chemogenetic inhibition at the PVN diminished FM through the CB1 pathway in the cerebellum. Our findings suggest that dysregulation of CB1 expression and aberrant hyperactivity of nociceptive signaling pathways in the cerebellum contribute to the etiology of FM and that the upregulation of CB1 signaling mediates the analgesic efficacy of EA. Full article

(This article belongs to the Section Physiology and Pathology)

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18 pages, 890 KB

Open AccessReview

Refractory Neuropathic Pain in the Head and Neck: Neuroanatomical and Clinical Significance of the Cervicotrigeminal Complex

by Marina Raguž, Marko Tarle, Koraljka Hat, Ivan Salarić, Petar Marčinković, Ivana Bičanić, Elvira Lazić Mosler, Ivica Lukšić, Tonko Marinović and Darko Chudy

Life 2025, 15(9), 1457; https://doi.org/10.3390/life15091457 - 17 Sep 2025

Abstract

Refractory neuropathic pain of the head and neck remains a major clinical challenge, particularly when mediated through the cervicotrigeminal complex (CTC), a unique anatomical hub integrating trigeminal and upper cervical nociceptive inputs. This narrative review synthesizes neuroanatomical, pathophysiological, and clinical evidence to provide [...] Read more.

Refractory neuropathic pain of the head and neck remains a major clinical challenge, particularly when mediated through the cervicotrigeminal complex (CTC), a unique anatomical hub integrating trigeminal and upper cervical nociceptive inputs. This narrative review synthesizes neuroanatomical, pathophysiological, and clinical evidence to provide a unifying framework for diagnosis and management. A structured search of PubMed, Scopus, and Web of Science identified English-language clinical and mechanistic studies addressing CTC-mediated pain, with case reports excluded unless mechanistically informative. We propose multidimensional refractoriness criteria that integrate pharmacological non-response, failed interventional strategies, and objective functional impairment. Current treatments span pharmacotherapy, peripheral interventions (nerve blocks, radiofrequency ablation), and neuromodulation at multiple network levels (occipital nerve stimulation, spinal cord stimulation, motor cortex stimulation, deep brain stimulation). Non-invasive approaches such as rTMS, tDCS, and vagus nerve stimulation are emerging but remain investigational. Advances in imaging and neurophysiological biomarkers now permit greater precision in detecting CTC dysfunction and tailoring therapy. By combining anatomical precision, mechanistic insight, and multidisciplinary strategies, this review proposes a clinically actionable definition of refractoriness and supports a stepwise, mechanism-based approach to therapy. CTC emerges as a targetable hub for diagnostic and therapeutic strategies in refractory head and neck pain. Full article

(This article belongs to the Special Issue Pain: New Insights into Mechanisms, Diagnosis, Therapy, and Management)

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18 pages, 3675 KB

Open AccessArticle

Lower ANXA3 Levels May Be Related to Major Depressive Disorder

by Mine Büşra Bozkürk, Kadir Özdel, Bilge Ozan Çiçek, Özkan Önder, Selin Yıldız and Alpaslan Öztürk

Life 2025, 15(9), 1456; https://doi.org/10.3390/life15091456 - 17 Sep 2025

Abstract

Annexin A3 (ANXA3) is a calcium-binding protein that plays a role in membrane phospholipid metabolism and inflammation, and significant alterations have been shown in some psychotic disorders. Because its association with major depressive disorder (MDD) is unclear, we aimed to compare serum ANXA3 [...] Read more.

Annexin A3 (ANXA3) is a calcium-binding protein that plays a role in membrane phospholipid metabolism and inflammation, and significant alterations have been shown in some psychotic disorders. Because its association with major depressive disorder (MDD) is unclear, we aimed to compare serum ANXA3 levels in patients with MDD and healthy controls and to investigate their relationship with depression severity. Serum ANXA3 concentrations in 90 patients diagnosed with MDD and 90 healthy controls were measured by ELISA. Depression severity was assessed using the Beck Depression Inventory (BDI). Serum ANXA3 levels were significantly lower in patients with MDD compared to controls (p < 0.001). ANXA3 showed negative correlations with neutrophil count, platelet count, neutrophil-to-lymphocyte ratio (NLR), glucose, creatinine, and ALT levels, and positive correlations with lymphocyte and red blood cell counts. We found that low ANXA3 levels, high NLR, and glucose dysregulation predicted greater depression severity. Using ROC analysis, we demonstrated that ANXA3 has high discriminatory power in distinguishing moderate to severe cases of MDD (AUC > 0.90). ANXA3 may serve as a biomarker of depression severity. Further studies are needed to clarify its clinical utility and confirm whether ANXA3 alterations represent state or trait markers of depression. Full article

(This article belongs to the Section Physiology and Pathology)

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17 pages, 3777 KB

Open AccessArticle

Predicting Seizure Risk from Routine Electroencephalographs in Medical Intensive Care Units Using the 2HELPS2B Score

by Cheng-Lun Hsiao, Wan-Ling Chang, Pei-Ya Chen, I-An Chen and Shinn-Kuang Lin

Life 2025, 15(9), 1455; https://doi.org/10.3390/life15091455 - 17 Sep 2025

Abstract

This study evaluated the utility of the 2HELPS2B score in predicting seizures from routine electroencephalographs (rEEGs). In total, 670 rEEGs obtained in a medical intensive care unit (MICU) between October 2018 and March 2023 were analyzed. More than 75% of these rEEGs were [...] Read more.

This study evaluated the utility of the 2HELPS2B score in predicting seizures from routine electroencephalographs (rEEGs). In total, 670 rEEGs obtained in a medical intensive care unit (MICU) between October 2018 and March 2023 were analyzed. More than 75% of these rEEGs were requested due to seizures and unexplained altered consciousness. Seizures occurred most frequently in patients with rEEGs characterized by brief, potentially ictal rhythmic discharges and electrographic seizures. A history of seizures was the most prevalent risk factor identified by the 2HELPS2B score. Seizures occurred in 28% of the cohort who experienced a seizure within 24 h of the rEEG and in 38% of the cohort who experienced a seizure before MICU discharge. Among the patients with suspected altered consciousness, the seizure incidence before MICU discharge (9.2%) was twice that within 24 h of the initial rEEG (4.7%). The seizure rate also increased from 12% for a 2HELPS2B score of 1 to 100% for scores ≥ 4. A score ≥ 2 was the optimal cutoff for predicting post-rEEG seizures and guiding antiseizure medication (ASM) treatment. Seizures occurred most frequently in patients whose ASMs were supplemented with new medications, and most new prescriptions for antiseizure medication were issued to patients with altered consciousness. These results demonstrate that the 2HELPS2B score can effectively predict seizures on the basis of rEEG results. Full article

(This article belongs to the Special Issue Advances in Intensive Care Medicine)

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17 pages, 2068 KB

Open AccessArticle

The Effects of FemmeBalance Supplement on Symptoms of Premenstrual Syndrome: A Four-Cycle Single-Arm Observational Study of a Novel Nutritional Supplement

by Isabel Viña and Juan R. Viña

Life 2025, 15(9), 1454; https://doi.org/10.3390/life15091454 - 17 Sep 2025

Abstract

Background: Premenstrual syndrome (PMS) affects 950 million women worldwide. However, conventional pharmacological treatments offer limited improvements. Objective: This study aimed to evaluate the effectiveness of the FemmeBalance supplement in relieving PMS symptoms. Methods: We conducted a single-group study of 38 women, aged 18–40, [...] Read more.

Background: Premenstrual syndrome (PMS) affects 950 million women worldwide. However, conventional pharmacological treatments offer limited improvements. Objective: This study aimed to evaluate the effectiveness of the FemmeBalance supplement in relieving PMS symptoms. Methods: We conducted a single-group study of 38 women, aged 18–40, with self-reported PMS symptoms. Participants received the FemmeBalance supplement (two capsules/day) for four menstrual cycles, completing the premenstrual symptoms screening tool (PSST) and study-specific questionnaires at baseline and on day 7 of each cycle. Skin changes were also assessed using dermatologist-graded facial photos. Results: By the first menstrual cycle, all PSST parameters showed significant improvement except insomnia. The greatest improvement was observed in interest in social activities, which improved by 40.13% in the fourth cycle. In addition, period heaviness was significantly decreased by the fourth cycle. Dermatologist skin grading showed improved overall skin health in 91.18% of participants. Moreover, 77.1% of the participants reported reduced PMS symptom severity, and 71.4% reported they would recommend the supplement. Conclusion: FemmeBalance was significantly effective in improving several PMS symptoms, including physical discomfort, mood disturbance, and skin health. The supplement also improved social functioning and overall menstrual health, suggesting that it could be an alternative to conventional PMS treatments. Full article

(This article belongs to the Section Pharmaceutical Science)

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13 pages, 1951 KB

Open AccessReview

Cutaneous and Lymphangitic Infection Caused by Purpureocillium lilacinum in Immunocompromised Patients: A Case Report with a Narrative Review of the Literature

by Tommaso Lupia, Cristina Sarda, Francesca Canta, Marco Casarotto, Guido Accardo, Gabriele Roccuzzo, Nicole Macagno, Federica Gelato, Rebecca Senetta, Antonio Ottobrelli, Francesco Giuseppe De Rosa, Silvia Corcione, Simone Ribero, Pietro Quaglino and Paolo Fava

Life 2025, 15(9), 1453; https://doi.org/10.3390/life15091453 - 17 Sep 2025

Abstract

Background: Purpureocillium lilacinum (P. lilacinum) is an emerging filamentous fungus known to cause opportunistic infections, particularly in immunocompromised patients. Formerly known as Paecilomyces lilacinus, this pathogen is widespread in the environment and can lead to a range of infections, from [...] Read more.

Background: Purpureocillium lilacinum (P. lilacinum) is an emerging filamentous fungus known to cause opportunistic infections, particularly in immunocompromised patients. Formerly known as Paecilomyces lilacinus, this pathogen is widespread in the environment and can lead to a range of infections, from superficial skin lesions to invasive diseases. This article presents a case of deep cutaneous hyalohyphomycosis caused by P. lilacinum in a liver transplant patient, followed by a review of the literature focusing on new antifungal agents. Methods: We reported a brief case description followed by a narrative review of the literature regarding P. lilacinum cutaneous and lymphangitic infections in immunocompromised patients. Results: We conducted a review of the literature over the past 20 years, focusing on the clinical features, diagnostic challenges, and therapeutic outcomes of cutaneous and lymphangitic P. lilacinum infections in immunocompromised hosts. Conclusions: This review highlights the critical importance of early diagnosis through the analysis of biopsy samples using standard microbiological and histological techniques, complemented by innovative molecular biology methods. We also emphasise the role of appropriate antifungal treatment, despite the absence of an established standard of care, particularly in high-risk patients. Furthermore, we review and discuss the current lack of a standardised therapeutic regimen and the potential of novel antifungal agents as promising treatment options for P. lilacinum infections. Full article

(This article belongs to the Section Physiology and Pathology)

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23 pages, 1703 KB

Open AccessSystematic Review

Effect of Different Exercise Modalities on Inflammatory Markers in Individuals with Depressive Disorder: A Systematic Review and Meta-Analysis

by Jie Song, Jinning Zhang, Xijin Wang, Jiaqi Liang and Yan Li

Life 2025, 15(9), 1452; https://doi.org/10.3390/life15091452 - 16 Sep 2025

Abstract

Background: One of the important mechanisms of depression is long-term high levels of inflammation. Exercise may help relieve depressive symptoms and is associated with anti-inflammatory effects. This research methodically assesses how various exercise modalities influence peripheral inflammatory markers in individuals with depression, so [...] Read more.

Background: One of the important mechanisms of depression is long-term high levels of inflammation. Exercise may help relieve depressive symptoms and is associated with anti-inflammatory effects. This research methodically assesses how various exercise modalities influence peripheral inflammatory markers in individuals with depression, so that more personalized and precise exercise schemes can be provided for people with depression to improve inflammation. Methods: Randomized controlled trials on depressive disorder, exercise, and inflammation published until May 2025 were screened in five databases. The Cochrane Risk of Bias tool (RoB2.0) was used to evaluate potential biases, with random effects meta-analyses gauging the impact of varying exercise regimens on peripheral inflammatory markers (CRP, IL-6 and TNF-α) involving exercise types, intensity, frequency, and length. Meta-regression analyses were employed to show the sources of heterogeneity and investigate potential moderator variables influencing CRP, IL-6, and TNF-α (PROSPERO CRD42024590612). Results: A total of 13 unique studies with 1004 participants were included. Overall, exercise training could alleviate depressive symptoms (SMD = −0.59, 95%CI: [−0.86, −0.32], I² = 61.7%, p < 0.001), and subgroup analysis showed that exercise lasting 8–12 weeks could reduce the level of TNF-α (MD = −0.74, 95%CI: [−1.30, −0.17], I² = 0, p < 0.05). Apparent discrepancies between subgroup and meta-regression findings were resolved by advanced modeling, which identified a significant non-linear relationship for TNF-α (quadratic term p = 0.003), characterized by a reduction peak at 8–12 weeks followed by a gradual increase, rather than a positive linear trend. Conclusions: Exercise could alleviate depressive symptoms in individuals with depression. However, the influence of exercise length on TNF-α levels has conflicting conclusions because of inconsistent evidence and substantial heterogeneity. Future high-quality trials with standardized biomarker measurements and better control of confounding factors are essential to determine whether the antidepressant effects of exercise are mediated by inflammation. Full article

(This article belongs to the Topic Physical Exercise Impacts on Human Physical and Psychological Health)

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21 pages, 4859 KB

Open AccessArticle

Epilithic Algae from Seven Megaliths in the Vicinity of Topolovgrad (Haskovo District, Southeast Bulgaria)

by Maya Petrova Stoyneva-Gärtner, Miroslav Ivov Androv, Blagoy Angelov Uzunov, Kristian Rosenov Ivanov and Georg Gärtner

Life 2025, 15(9), 1451; https://doi.org/10.3390/life15091451 - 16 Sep 2025

Abstract

The present work focuses on seven megaliths sampled for the first time as a continuation of our studies on the biodiversity of algae on megaliths in Bulgaria. A total of 55 species from four divisions were identified (Chlorophyta was the richest with 31 [...] Read more.

The present work focuses on seven megaliths sampled for the first time as a continuation of our studies on the biodiversity of algae on megaliths in Bulgaria. A total of 55 species from four divisions were identified (Chlorophyta was the richest with 31 species), of which 14 species are new for Bulgaria. Two species were of conservation concern, but six were potential toxin producers that could affect the health of visitors to the megaliths. Despite the general granitic character and relatively close location of the studied sites, their floristic similarity was low, with most algae (51 species) being rarely distributed (except Stichococcus bacillaris and Mychonastes homosphaera). The largest cult complex Paleokastro, furthest from populated areas, had the highest species diversity (22 species), while the lowest (8 species) was found in the highly exposed Kalinkin Kamuk, located in a village. The NMDS analysis tool showed the existence of four distinct ecological groups and that temperature and light are the most important drivers for the distribution of the epilithic algae on the investigated megaliths. Correlations with temperatures estimated to identify potential indicators or future survivors under global warming conditions were low, except for the Streptophyta. It was represented by four species of the genus Klebsormidium, which is known for its high ecological tolerance and drought resistance. Extending the studies on lithophytic algae to megaliths is important for a better knowledge of their biodiversity and ecology, but also for the protection of megaliths and for understanding the impact of climate change on these fragile monuments. Full article

(This article belongs to the Special Issue Advances in the Structure and Function of Microbial Communities)

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16 pages, 397 KB

Open AccessArticle

Inflammation, Autonomic Control, and Adiposity in Adolescents: Links to Early Cardiovascular Risk

by Vladimir Micieta, Ingrid Tonhajzerova, Nikola Ferencova and Zuzana Visnovcova

Life 2025, 15(9), 1450; https://doi.org/10.3390/life15091450 - 16 Sep 2025

Abstract

Cardiovascular diseases (CVDs) are generally associated with adulthood, although the underlying processes may begin in childhood and adolescence. Thus, detecting increased cardiovascular risk in adolescence is essential for prevention. In this cross-sectional study, we comprehensively evaluated the inter-relationships between inflammatory markers, cardiac autonomic [...] Read more.

Cardiovascular diseases (CVDs) are generally associated with adulthood, although the underlying processes may begin in childhood and adolescence. Thus, detecting increased cardiovascular risk in adolescence is essential for prevention. In this cross-sectional study, we comprehensively evaluated the inter-relationships between inflammatory markers, cardiac autonomic control indexed by heart rate variability (HRV), and adiposity measures in healthy adolescents, with sex-stratified analyses. We examined 90 adolescents (55 females; age 15.8 ± 1.5 years; BMI 21.4 ± 3.3 kg/m²). We found mixed (positive and negative) associations between inflammatory markers and HRV indices among the entire adolescent group (absolute r range: 0.266–0.395, p < 0.05 for all), while only negative associations in the male group, and only positive associations in the female group (absolute r range: 0.373–0.404, p < 0.05 for all). Furthermore, predominantly positive associations between inflammatory markers and adiposity measures were found among the adolescent group (absolute r range: 0.298–0.338, p < 0.05 for all) and female group (absolute r range: 0.342–0.485, p < 0.05 for all), while contrasting negative associations were found in the male group (absolute r range: 0.421–0.497, p < 0.05 for all). These associations, representing early pathways to cardiovascular vulnerability, seem sex-dependent, but longitudinal confirmation is required. Full article

(This article belongs to the Special Issue Cardiovascular Diseases: From Basic Research to Clinical Application—3rd Edition)

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25 pages, 865 KB

Open AccessReview

Microplastics and Nanoplastics in Health Concerning Cellular Toxicity Mechanisms, Exposure Pathways, and Global Mitigation Strategies

by Ruei-Hong Lin, Hao-Ting Chen, I-Ta Lee, Thi-Thuy-Tien Vo and Yung-Li Wang

Life 2025, 15(9), 1449; https://doi.org/10.3390/life15091449 - 16 Sep 2025

Abstract

Microplastics (MPs) and nanoplastics (NPs) have emerged as ubiquitous environmental contaminants that pose significant threats to human health, with multiple exposure pathways (e.g., ingestion and inhalation) contributing to systemic exposure. Although growing evidence highlights their biological effects, the underlying mechanisms by which these [...] Read more.

Microplastics (MPs) and nanoplastics (NPs) have emerged as ubiquitous environmental contaminants that pose significant threats to human health, with multiple exposure pathways (e.g., ingestion and inhalation) contributing to systemic exposure. Although growing evidence highlights their biological effects, the underlying mechanisms by which these particles induce cellular dysfunction remain incompletely understood. This review synthesizes current knowledge on the MPs/NPs-induced cellular toxicity mechanisms, including investigations into cellular uptake pathways, disruption of molecular signaling, oxidative stress, inflammatory responses, and genotoxic effects. MPs/NPs contamination can arise from consumer products and clinical procedures, with estimated Daily Microplastic Emission (DME)-based national totals (India) ranging from ~0.36 to 74 billion particles/day across oral-care product categories. At the cellular level, MPs and NPs trigger interconnected toxicological cascades, including impaired endocytosis, mitochondrial dysfunction, chronic inflammation, genotoxicity, endoplasmic reticulum (ER) stress, and accelerated cellular senescence. These mechanisms act in concert to compromise epithelial barrier integrity. Overall, MPs/NPs present substantial risks to health through multiple interconnected pathways. Local and systemic effects are plausible across exposed tissues which may also serve as a gateway for systemic distribution by these contaminants. These findings highlight the urgent need for coordinated global efforts, including restrictions on intentionally added MPs, improvements in product design, development of advanced removal technologies, and implementation of clinical prevention strategies. Full article

(This article belongs to the Special Issue Exploring the Mechanisms of the Effects of Microplastics and Nanomaterials on Biological Physiological Functions)

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20 pages, 3118 KB

Open AccessArticle

Exploring Ochradenus baccatus: A Novel Source of Bioactive Compounds and Phytochemical Insights for Uncharted Therapeutic Applications

by Salma Saddeek

Life 2025, 15(9), 1448; https://doi.org/10.3390/life15091448 - 16 Sep 2025

Abstract

Ochradenus baccatus (O. baccatus), a resilient medicinal plant native to arid regions, was systematically investigated for its neuroprotective potential against Alzheimer’s disease. Comprehensive phytochemical profiling of different plant parts revealed that the leaves possessed the highest levels of total phenolics (67.8 [...] Read more.

Ochradenus baccatus (O. baccatus), a resilient medicinal plant native to arid regions, was systematically investigated for its neuroprotective potential against Alzheimer’s disease. Comprehensive phytochemical profiling of different plant parts revealed that the leaves possessed the highest levels of total phenolics (67.8 mg GAE/g) and flavonoids (49.2 mg QE/g), correlating with strong antioxidant activity (DPPH IC₅₀ = 19.8 µg/mL, FRAP = 832 µmol Fe²⁺/g). HPLC and GC-MS analyses identified multiple bioactive flavonoids and fatty acids. The leaf extract demonstrated potent in vitro AChE inhibition (IC₅₀ = 32.5 µg/mL) and significantly reduced amyloid-β aggregation (by 50%). In vivo, it ameliorated cognitive deficits in scopolamine-induced mice, as evidenced by improved performance in Morris Water Maze and Y-maze tests, and restored hippocampal neuronal density (CA3: +29.7%, DG: +30%). These findings highlight the therapeutic promise of O. baccatus leaves as a rich source of multifunctional anti-Alzheimer’s phytochemicals. Full article

(This article belongs to the Special Issue Therapeutic Innovations from Plants and Their Bioactive Extracts)

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17 pages, 299 KB

Open AccessReview

Indications and Mechanisms of Action of the Main Treatment Modalities for Non-Melanoma Skin Cancer

by Marcio F. Chedid, Aline C. Tregnago, Floriano Riva, Lucas Prediger, Anisha Agarwal and Jane Mattei

Life 2025, 15(9), 1447; https://doi.org/10.3390/life15091447 - 16 Sep 2025

Abstract

Skin cancer is the most common cancer worldwide. The incidence of skin cancer has been increasing worldwide. Nearly 75% of all skin cancers are basal cell carcinomas (BCC), cutaneous squamous cell carcinoma (cSCC) represents approximately 20%, and those remaining are melanomas (4%) or [...] Read more.

Skin cancer is the most common cancer worldwide. The incidence of skin cancer has been increasing worldwide. Nearly 75% of all skin cancers are basal cell carcinomas (BCC), cutaneous squamous cell carcinoma (cSCC) represents approximately 20%, and those remaining are melanomas (4%) or other rare tumors (1%). Given the high cure rates and the ability to histologically confirm tumor clearance, surgical therapy is the gold standard for the treatment of skin cancer. Conventional surgery is the most employed technique for the removal of non-melanoma skin cancer (NMSCs). Mohs Micrographic Surgery (MMS) is the most precise surgical method for the treatment of non-melanoma skin cancer, allowing for 100% margin evaluation, being the gold-standard method for surgical treatment of non-melanoma skin cancer. Whenever it is possible to obtain wide margins (4 to 6 mm), cure rates vary from 70% to 99%. Imiquimod, a synthetic imidazoquinolinone amine, is a topical immune response modifier approved by the U.S. Food and Drug Administration (FDA) for the treatment of external anogenital warts, actinic keratosis (AK), and superficial basal cell carcinoma (sBCC). The efficacy of imiquimod is primarily attributed to its ability to modulate both innate and adaptive immune responses, as well as its direct effects on cancer cells. Imiquimod exerts its immunomodulatory effects by activating Toll-like receptors 7 and 8 (TLR7/8) on various immune cells, including dendritic cells, macrophages, and natural killer (NK) cells. Upon binding to these receptors, imiquimod triggers the MyD88-dependent signaling pathway, leading to the activation of nuclear factor kappa B (NF-κB) and interferon regulatory factors (IRFs). This cascade leads to the production of pro-inflammatory cytokines, including interferon-alpha (IFN-α), tumor necrosis factor-alpha (TNF-α), interleukin-12 (IL-12), and interleukin-6 (IL-6). These cytokines enhance local inflammation, recruit additional immune cells to the tumor site, and stimulate antigen presentation, thereby promoting an anti-tumor immune response. Radiation therapy (RTh) may be employed as a primary treatment to BCC. It may also be employed as an adjuvant treatment to surgery for SCC and aggressive subtypes of BCC. RTh triggers both direct and indirect DNA damage on cancer cells and generates reactive oxygen species (ROS) within cells. ROS trigger oxidative damage to DNA, proteins, and lipids, exacerbating the cellular stress and contributing to tumor cell death. Recently, immunotherapy emerged as a revolutionary treatment for all stages of SCC. Cemiplimab is a human programmed cell death 1 (PD-1)-blocking antibody that triggers a response to over 50% of patients with locally advanced and metastatic SCC. A randomized clinical trial (RCT) published in 2022 revealed that cemiplimab was highly effective in the neoadjuvant treatment of large SCCs. The drug promoted a significant tumor size decrease, enabling organ-sparing operations and a much better cosmetic effect. A few months ago, a RCT of cemiplimab on adjuvant therapy for locally aggressive SCC was published. Interestingly, cemiplimab was administered to patients with local or regional cutaneous squamous cell carcinoma after surgical resection and postoperative radiotherapy, at high risk for recurrence owing to nodal features, revealed that cemiplimab led to much lower risks both of locoregional recurrence and distant recurrence. Full article

(This article belongs to the Special Issue Advances in Novel Biomarkers and Emerging Immune/Targeted Therapies in Solid Tumors)

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