Life

20 pages, 966 KB

Open AccessReview

Unraveling the Genome Diversity of Leishmania Parasites Using Next-Generation DNA Sequencing Strategies

by Alejandro Llanes, Carlos M. Restrepo and Ricardo Lleonart

Life 2025, 15(10), 1590; https://doi.org/10.3390/life15101590 (registering DOI) - 11 Oct 2025

Parasites of the Leishmania genus are globally distributed and cause various clinical presentations in animals and humans, collectively known as leishmaniasis. The genomes of Leishmania and other trypanosomatids exhibit remarkable plasticity, shaped by several distinctive genetic features. Although these features can hinder the [...] Read more.

Parasites of the Leishmania genus are globally distributed and cause various clinical presentations in animals and humans, collectively known as leishmaniasis. The genomes of Leishmania and other trypanosomatids exhibit remarkable plasticity, shaped by several distinctive genetic features. Although these features can hinder the application of next-generation DNA sequencing (NGS) technologies, NGS data have been successfully used to characterize the whole-genome diversity of circulating Leishmania strains. The results complement and are broadly aligned with previous findings obtained with more traditional methods, offering greater resolution when working with geographically closer strains. In this review, we summarize advances over the past two decades in characterizing the genome diversity of Leishmania parasites using NGS strategies. We also discuss the application of these strategies to elucidate other aspects relevant to the epidemiology of these parasites, including their population structure and mode of reproduction. The vast majority of the studies to date have focused on species within the L. donovani/infantum complex or the L. (Viannia) subgenus, highlighting the need to incorporate other relevant underrepresented species and regions from both the Old and New World. Full article

(This article belongs to the Special Issue New Insights Into Leishmaniasis and Chagas Disease: Focus on Diagnosis and Genetic Characterization of Parasites: 2nd Edition)

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17 pages, 1369 KB

Open AccessArticle

Heme Oxygenase-1 Expression as a Prognostic Marker in Early-Stage HCC Undergoing Resection or Liver Transplantation

by Ramona Cadar, Alin Mihai Vasilescu, Ana Maria Trofin, Alexandru Grigorie Nastase, Mihai Zabara, Cristina Muzica, Corina Lupascu Ursulescu, Mihai Danciu, Andrei Pascu, Iulian Buzincu, Delia Ciobanu, Ianole Victor and Cristian Dumitru Lupascu

Life 2025, 15(10), 1589; https://doi.org/10.3390/life15101589 (registering DOI) - 11 Oct 2025

Abstract

Background: Hepatocellular carcinoma (HCC) is a prevalent malignancy with high mortality, often arising in the context of chronic liver diseases. Heme oxygenase-1 (HO-1), an inducible enzyme involved in heme degradation, has been implicated in both hepatoprotection and tumor progression. This study evaluates the [...] Read more.

Background: Hepatocellular carcinoma (HCC) is a prevalent malignancy with high mortality, often arising in the context of chronic liver diseases. Heme oxygenase-1 (HO-1), an inducible enzyme involved in heme degradation, has been implicated in both hepatoprotection and tumor progression. This study evaluates the expression of HO-1 in HCC and its association with clinicopathological features and patient survival. Materials and Methods: We retrospectively analyzed 58 HCC cases diagnosed between 2018 and 2023 at “Sf. Spiridon” Emergency County Hospital, Iasi. HO-1 expression was assessed immunohistochemically and quantified using a semi-quantitative immunoreactivity score (IRS). Statistical correlations between HO-1 expression and clinical, pathological, and survival parameters were evaluated using univariate analysis, ROC curves, and Kaplan–Meier survival models. Results: High HO-1 expression (IRS > 1) was significantly associated with hepatitis C virus etiology (p = 0.004, V = 0.381), vascular invasion (p = 0.019, V = 0.309) and perioperative anticoagulant therapy (p = 0.007, V = 0.352). However, HO-1 expression did not correlate with overall survival (OS). In contrast, solid growth pattern (p = 0.030) and serum α-fetoprotein levels of 10–99 ng/mL (p = 0.022) were negatively associated with OS. Conclusions: HO-1 expression in HCC was found to be associated with vascular invasion, but not with overall survival. While this may indicate a potential link to certain aggressive tumor features, the overall role of HO-1 in HCC biology remains unclear. These findings suggest that HO-1 should be considered an exploratory rather than definitive prognostic marker, and further research is warranted to clarify its function and potential utility, including investigation of its detectability in biological fluids for non-invasive monitoring. Full article

(This article belongs to the Special Issue Gastrointestinal Diseases: Innovations in Diagnostics, Therapeutics, and Prognosis)

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16 pages, 1271 KB

Open AccessReview

Hidden Impacts of Peritoneal Dialysis on the Endocrine System

by Hiromichi Ueno, Yoichi Ueta, Jun-ichiro Koga, Takashi Maruyama, Tetsu Miyamoto and Masaharu Kataoka

Life 2025, 15(10), 1588; https://doi.org/10.3390/life15101588 (registering DOI) - 11 Oct 2025

Abstract

Peritoneal dialysis (PD) is a widely used renal replacement therapy in which hyperosmolar solutions are instilled into the abdominal cavity to facilitate the removal of excess water, electrolytes, and metabolic waste products. During PD treatment, homeostasis is maintained through adaptive responses of the [...] Read more.

Peritoneal dialysis (PD) is a widely used renal replacement therapy in which hyperosmolar solutions are instilled into the abdominal cavity to facilitate the removal of excess water, electrolytes, and metabolic waste products. During PD treatment, homeostasis is maintained through adaptive responses of the neuroendocrine system to high glucose exposure, changes in circulating blood volume, and shifts in electrolyte balance. Clinical observations and limited experimental studies suggest that these neurohormonal dynamics may influence both the complications and therapeutic efficacy of PD. However, systematic investigations remain scarce, largely because hormonal and neural responses are highly dynamic, involve complex interactions, and are substantially influenced by individual patient characteristics. In this review, we synthesize current clinical and experimental evidence linking PD-related complications with hidden hormone dynamics, with particular emphasis on hypothalamic hormones such as arginine vasopressin. We also discuss how the biocompatibility of PD solutions—traditionally assessed by their effects on peritoneal mesothelial cells—could be reconsidered when neuroendocrine aspects are taken into account. We propose that integrating both clinical insights and emerging basic research will provide a more comprehensive understanding of neuroendocrine regulation in PD and may contribute to the development of novel therapeutic strategies. Full article

(This article belongs to the Section Medical Research)

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16 pages, 965 KB

Open AccessArticle

Protective Effect of Exogenous Adenosine Triphosphate Against Ocular Toxicity of Linezolid in Rats

by Cenap Mahmut Esenulku, Ibrahim Cicek, Ahmet Mehmet Somuncu, Bulent Yavuzer, Esra Tuba Sezgin, Tugba Bal Tastan, Nurinisa Yücel, Ezgi Karatas and Halis Suleyman

Life 2025, 15(10), 1587; https://doi.org/10.3390/life15101587 (registering DOI) - 11 Oct 2025

Abstract

Linezolid, a synthetic antimicrobial agent, may induce oxidative damage in ocular tissues, particularly in the optic nerve. Adenosine triphosphate (ATP) is involved in the production of antioxidants that scavenge and neutralize reactive oxygen species. This study aims to evaluate the potential protective effect [...] Read more.

Linezolid, a synthetic antimicrobial agent, may induce oxidative damage in ocular tissues, particularly in the optic nerve. Adenosine triphosphate (ATP) is involved in the production of antioxidants that scavenge and neutralize reactive oxygen species. This study aims to evaluate the potential protective effect of exogenous ATP against linezolid-induced ocular damage in rats, in comparison with methylprednisolone. Wistar-type rats were divided into five groups as follows: healthy (HG), ATP-only (ATPG), linezolid-only (LZDG), ATP + linezolid (ATLDG), and methylprednisolone + linezolid groups (MPLDG). Oxidative stress markers, antioxidant biomarkers, and proinflammatory cytokines were analyzed in isolated ocular tissues. Optic nerve tissue was also evaluated histopathologically. Linezolid administration increased the oxidative stress marker MDA and the proinflammatory cytokine TNF-α, while decreasing antioxidant parameters such as tGSH, SOD and CAT in rat ocular tissues, compared to the healthy group. However, it did not significantly alter serum troponin I levels. Histopathological analysis revealed that linezolid induced oxidative damage and inflammation in optic nerve tissue, with marked glial alterations. ATP administration reduced linezolid-induced oxidative stress in ocular tissue, as indicated by decreased MDA levels. It also enhanced antioxidant defenses by increasing tGSH, SOD, and CAT levels. In addition, ATP lowered proinflammatory cytokine levels, thereby alleviating inflammation. These effects collectively contributed to the restoration of biochemical parameters toward normal levels. In addition, ATP mitigated linezolid-induced optic nerve damage and glial alterations. The critical role of ATP in reducing oxidative stress, restoring antioxidant balance, and suppressing inflammation may represent a promising therapeutic approach for linezolid-induced ocular toxicity. Full article

(This article belongs to the Topic Oxidative Stress and Inflammation, 3rd Edition)

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12 pages, 1161 KB

Open AccessArticle

Metabolic Dysfunction-Associated Steatotic Liver Disease in a Patient with Phelan–McDermid Syndrome

by Luigi Boccuto, Giuseppe Guido Maria Scarlata, Bridgette A. Moffitt, Sara M. Sarasua, Katy Phelan, Curtis Rogers and Ludovico Abenavoli

Life 2025, 15(10), 1586; https://doi.org/10.3390/life15101586 (registering DOI) - 11 Oct 2025

Abstract

Background: Phelan–McDermid syndrome (PMS), caused by SHANK3 variants or 22q13.3 deletions, often includes systemic features such as gastrointestinal and hepatic abnormalities. This study highlights the overlap between PMS and metabolic-associated steatotic liver disease (MASLD), focusing on PNPLA3 variants and underscoring the need for [...] Read more.

Background: Phelan–McDermid syndrome (PMS), caused by SHANK3 variants or 22q13.3 deletions, often includes systemic features such as gastrointestinal and hepatic abnormalities. This study highlights the overlap between PMS and metabolic-associated steatotic liver disease (MASLD), focusing on PNPLA3 variants and underscoring the need for structured metabolic monitoring. Methods: We describe a 25-year-old male with PMS due to a 22q13.33 microdeletion involving SHANK3. He exhibited developmental delay, seizures, and hypotonia. Genetic testing revealed homozygosity for the PNPLA3 p.I148M variant. Clinical, anthropometric, biochemical, imaging, and metabolic investigations were performed, including liver ultrasound and metabolic profiling of lymphoblastoid cell lines. Results: Ultrasound revealed moderate hepatic steatosis consistent with MASLD. After ursodeoxycholic acid treatment and a Mediterranean-style diet, steatosis improved to mild. Metabolic profiling demonstrated increased nicotinamide adenine dinucleotide generation under metabolic stimuli, suggesting altered energy homeostasis. Conclusions: We highlight the contribution of PNPLA3 to MASLD in PMS and support systematic hepatic monitoring. Genotype–phenotype associations in PMS may provide insights relevant to MASLD research and clinical management. Full article

(This article belongs to the Special Issue Gastrointestinal Health: Clinical Research and Therapeutic Innovations)

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30 pages, 3728 KB

Open AccessSystematic Review

Gut Microbiota and Obsessive–Compulsive Disorder: A Systematic Review of Mechanistic Links, Evidence from Human and Preclinical Studies, and Therapeutic Prospects

by Shayan Eghdami, Mahdieh Saeidi, Sasidhar Gunturu, Mahsa Boroon and Mohammadreza Shalbafan

Life 2025, 15(10), 1585; https://doi.org/10.3390/life15101585 - 10 Oct 2025

Abstract

Obsessive–compulsive disorder (OCD) is a multifactorial condition, and interest in gut–brain interactions is increasing. We conducted a systematic two-step review, registered in PROSPERO (CRD420251083936). Step 1 mapped core OCD biology to gut-relevant pathways, including neuroimmune activation, epithelial barrier function, microbial metabolites, and stress [...] Read more.

Obsessive–compulsive disorder (OCD) is a multifactorial condition, and interest in gut–brain interactions is increasing. We conducted a systematic two-step review, registered in PROSPERO (CRD420251083936). Step 1 mapped core OCD biology to gut-relevant pathways, including neuroimmune activation, epithelial barrier function, microbial metabolites, and stress circuitry, to clarify plausible mechanisms. Step 2 synthesized evidence from human and preclinical studies that measured or manipulated microbiota. Searches across PubMed, EMBASE, Web of Science, PsycINFO, and Cochrane (September 2025) yielded 357 biological and 20 microbiota-focused studies. Risk of bias was assessed using the Joanna Briggs Institute checklist for human studies and SYRCLE’s tool for animal studies. Although taxonomic findings in human cohorts were heterogeneous, functional patterns converged: reduced short-chain fatty acid capacity, enrichment of pro-inflammatory pathways, and host markers of barrier disruption and inflammation correlating with OCD severity. Transferring patient microbiota to mice induced OCD-like behaviors with neuroinflammatory changes, partly rescued by metabolites or barrier-supporting strains. Mendelian randomization suggested possible causal contributions at higher taxonomic levels. Diet, especially fiber intake, and psychotropic exposure were major sources of heterogeneity. Evidence supports the microbiota as a modifiable co-factor in a subset of OCD, motivating diet-controlled, stratified clinical trials with composite host–microbe endpoints. Full article

(This article belongs to the Special Issue Microbiome–Gut–Brain Connections: New Windows into Health and Disease)

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22 pages, 2323 KB

Open AccessArticle

Effects of Asparagus Powder Supplementation on Glycemic Control, Lipid Profile, and Oxidative Stress in Overweight and Obese Adults: An Exploratory Randomized Controlled Trial

by Jittima Mongraykang, Tadsawiya Padkao, Orachorn Boonla, Yothin Teethaisong, Thapanee Roengrit, Sukrisd Koowattanatianchai and Piyapong Prasertsri

Life 2025, 15(10), 1584; https://doi.org/10.3390/life15101584 (registering DOI) - 10 Oct 2025

Abstract

This study investigated the effects of asparagus powder supplementation on blood glucose regulation, insulin, lipid profile, and oxidative stress in overweight and obese individuals. Forty-four adults aged 18–59 years participated in a 12-week randomized controlled trial and were randomly assigned to receive either [...] Read more.

This study investigated the effects of asparagus powder supplementation on blood glucose regulation, insulin, lipid profile, and oxidative stress in overweight and obese individuals. Forty-four adults aged 18–59 years participated in a 12-week randomized controlled trial and were randomly assigned to receive either asparagus powder (40 mg/kg/day) or a placebo (maltodextrin, 40 mg/kg/day). Assessments included an oral glucose tolerance test (OGTT), fasting blood glucose (FBG), insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and β-cell function (HOMA-B), lipid profile, and oxidative stress markers (malondialdehyde [MDA], protein carbonyl, and superoxide dismutase [SOD]). In the asparagus group, OGTT at 30 min and low-density lipoprotein cholesterol (LDL-C) significantly decreased, while SOD activity significantly increased (all p < 0.05). In contrast, the placebo group showed significant increases in OGTT at 30 min, insulin, HOMA-IR, HOMA-B, triglycerides (TG), the TG/high-density lipoprotein cholesterol (HDL-C) ratio, and the total cholesterol (TC)/HDL-C ratio (all p < 0.05). Between-group comparisons indicated that FBG, area under the BG curve at 30–120 min, TG, TG/HDL-C, and MDA levels were significantly lower in the asparagus group than in the placebo group (all p < 0.05), whereas OGTT, LDL-C, SOD activity, insulin, HOMA-IR, HOMA-B, and TC/HDL-C did not differ significantly. Other indices, including TC, HDL-C, and protein carbonyl, showed no significant within- or between-group differences. In conclusion, 12 weeks of asparagus powder supplementation partially improved glycemic control, lipid profile, and oxidative stress in overweight and obese individuals. These findings suggest a potential role of asparagus as a complementary nutritional strategy to reduce the risk of diabetes and cardiovascular disease in this population. Full article

(This article belongs to the Special Issue Therapeutic Potential of Natural Products in Chronic Diseases)

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24 pages, 1384 KB

Open AccessReview

Breast Cancer Treatments: Drugs Targeting the PI3K/AKT/mTOR Pathway, TNBC Therapy and Future Directions: A Review

by Klaudia Dynarowicz, Dorota Bartusik-Aebisher, Katarzyna Koszarska, Aleksandra Kotlińska and David Aebisher

Life 2025, 15(10), 1583; https://doi.org/10.3390/life15101583 - 10 Oct 2025

Abstract

Breast cancer affects women at an increasingly younger age, with genetic predispositions and other factors contributing to its second-highest cancer mortality rate. The diversity of pharmacological treatment stems from its heterogeneity, which favors a more precise approach to each subtype. Despite the extensive [...] Read more.

Breast cancer affects women at an increasingly younger age, with genetic predispositions and other factors contributing to its second-highest cancer mortality rate. The diversity of pharmacological treatment stems from its heterogeneity, which favors a more precise approach to each subtype. Despite the extensive advances in medicine in recent decades, the problem of treating cancer patients remains significant. The problem with modern therapeutic methods is low effectiveness, emerging side effects, difficulty in eliminating all cancer cells, and the quite common use of monotherapy and the associated drug resistance, which may lead to disease progression. The aim of this review is to present the latest therapeutic strategies (combination therapies) used in the treatment of breast cancer. PubMed databases and clinical data from ClinicalTrials.gov were used for this purpose. The review included characteristics of the latest clinical trials from the last year (2024–2025), which present currently recruiting studies of breast cancer treatment with immunotherapy. The review also presented characteristics of clinical trials from the last 5 years (2020–2025) using nanoparticles as an adjunct to breast cancer treatment. Articles published between 2016 and August 2025 (excluding articles that describe the first use of a given drug) were included in the review. The review analyzed drugs targeting molecular targets, including intracellular pathways responsible for cell cycle regulation, as well as new directions such as nanotechnology in treatment breast cancer. Full article

(This article belongs to the Special Issue New Insights into Breast Cancer: Current Controversies and Future Perspectives)

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22 pages, 924 KB

Open AccessReview

Innate Immune Signaling in Gliomas: Regulatory Mechanisms and Targeting Potential in Tumor Progression

by Edmund Jung, Sara Al Jadidi and Christina Piperi

Life 2025, 15(10), 1582; https://doi.org/10.3390/life15101582 - 10 Oct 2025

Abstract

Gliomas present as highly heterogeneous and aggressive central nervous system (CNS) tumors with challenging diagnosis and management. Traditional and current therapies are lacking efficacy in overcoming the complex and dynamic behavior of gliomas and the local tumor microenvironment. Emerging research highlights the significant [...] Read more.

Gliomas present as highly heterogeneous and aggressive central nervous system (CNS) tumors with challenging diagnosis and management. Traditional and current therapies are lacking efficacy in overcoming the complex and dynamic behavior of gliomas and the local tumor microenvironment. Emerging research highlights the significant role of innate immune receptors including Toll-like, NOD-like and RIG-like receptors, as well as cGAS-STING receptors, scavenger and C-type lectin receptors in glioma development and progression. These receptors can both impact immune modulation as well as facilitate tumor growth through interactions with tumor-associated macrophages, myeloid-derived suppressor cells and cytokine networks, contributing to immune evasion in the tumor microenvironment. Herein, we discuss the main signaling pathways induced through innate immune receptors in gliomas along with their functional properties in glioma pathology while exploring current applications to treatment. Utilizing innate immune receptors as therapeutic targets holds great promise, especially when used along with traditional chemotherapy and radiation schemes, strengthening immune responses. Future studies focusing on the deeper understanding of innate immune receptors signaling and complexity are highly required to enable novel immunoregulatory treatment schemes for gliomas. Full article

(This article belongs to the Section Medical Research)

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25 pages, 2321 KB

Open AccessReview

The Role of Renalase in Cardiovascular Disease: A Comprehensive Review of Its Molecular Biology, Genetic Associations, and Clinical Significance

by Siarhei A. Dabravolski, Andrey V. Omelchenko, Elizaveta R. Korchagina, Olga N. Maltseva, Vsevolod V. Pavshintsev and Tatiana I. Kovyanova

Life 2025, 15(10), 1581; https://doi.org/10.3390/life15101581 - 10 Oct 2025

Abstract

Renalase, a flavin adenine dinucleotide (FAD)-dependent enzyme/hormone, has emerged as a molecule of significant interest in cardiovascular medicine since its discovery nearly two decades ago. Initially proposed as a catecholamine-degrading enzyme crucial for blood pressure regulation, its functional repertoire has expanded to include [...] Read more.

Renalase, a flavin adenine dinucleotide (FAD)-dependent enzyme/hormone, has emerged as a molecule of significant interest in cardiovascular medicine since its discovery nearly two decades ago. Initially proposed as a catecholamine-degrading enzyme crucial for blood pressure regulation, its functional repertoire has expanded to include potential α-NAD(P)H oxidase/anomerase activity and roles as a signalling cytokine. This review synthesises the current understanding of renalase, encompassing its fundamental biology, intricate gene regulation by transcriptional factors, microRNAs, and physiological stimuli, and its implications in cardiovascular health and disease. A central focus is the critical appraisal of circulating renalase as a clinical biomarker. We critically evaluate findings from preclinical animal and cellular models related to atherosclerosis, heart failure, and blood pressure control. Furthermore, this review examines the extensive literature on RNLS gene polymorphisms and their associations with human cardiovascular phenotypes, alongside the complex and often context-dependent data regarding circulating renalase levels as a potential clinical biomarker in conditions such as hypertension, coronary artery disease, atrial fibrillation, and heart failure. While renalase shows context-specific promise, its multifaceted biology and the current methodological disparities limit its immediate clinical application. This review concludes by outlining a clear path forward, emphasising the need for standardised research and mechanistic studies to unlock the true diagnostic and therapeutic potential of renalase in CVD. Full article

(This article belongs to the Section Physiology and Pathology)

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28 pages, 358 KB

Open AccessReview

Vitamin D as an Immune Modulator in Systemic Lupus Erythematosus: A Narrative Review

by Oana Raluca Predescu, Florentin Ananu Vreju, Stefan Cristian Dinescu, Cristina Elena Bita, Anca Emanuela Musetescu, Alesandra Florescu and Paulina Lucia Ciurea

Life 2025, 15(10), 1580; https://doi.org/10.3390/life15101580 - 10 Oct 2025

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease in which environmental factors modulate genetically determined immune dysregulation. Vitamin D has emerged as a plausible modifier of disease expression because its active metabolite signals through the vitamin D receptor on innate and adaptive [...] Read more.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease in which environmental factors modulate genetically determined immune dysregulation. Vitamin D has emerged as a plausible modifier of disease expression because its active metabolite signals through the vitamin D receptor on innate and adaptive immune cells and influences antigen presentation, cytokine balance, and lymphocyte differentiation. This narrative review synthesizes current evidence on vitamin D status and supplementation in SLE with attention to organ-specific domains. Observational studies consistently report high rates of hypovitaminosis D in SLE and associations with less favorable clinical profiles, including higher global and renal disease activity, adverse cardiometabolic features, greater infection vulnerability, and neuropsychiatric manifestations. Preclinical models demonstrate neuroprotective and barrier-stabilizing actions of vitamin D analogs, supporting biological plausibility. Interventional trials indicate that supplementation safely corrects deficiency and shows signals of benefit for selected outcomes (e.g., modest activity reductions or fatigue in specific contexts), although effects on interferon signatures, complement, and autoantibodies are heterogeneous and often limited. Overall, current evidence supports optimization of vitamin D status as a low-risk adjunct in comprehensive SLE care while highlighting the need for adequately powered, organ-focused randomized trials using standardized measurements and prespecified endpoints to define causality, therapeutic targets, and long-term safety. Full article

(This article belongs to the Section Medical Research)

21 pages, 574 KB

Open AccessReview

Continuous Glucose Monitoring in People at High Risk of Diabetes and Dysglycaemia: Transforming Early Risk Detection and Personalised Care

by Alexandros L. Liarakos, Grigorios Panagiotou, Maria Chondronikola and Emma G. Wilmot

Life 2025, 15(10), 1579; https://doi.org/10.3390/life15101579 - 10 Oct 2025

Abstract

Continuous glucose monitoring (CGM)-based interventions have been predominantly conducted in people with established diabetes. Recently, there has been an increasing interest in using CGM for clinical and research purposes in people without diabetes. In this review, we describe the current evidence regarding the [...] Read more.

Continuous glucose monitoring (CGM)-based interventions have been predominantly conducted in people with established diabetes. Recently, there has been an increasing interest in using CGM for clinical and research purposes in people without diabetes. In this review, we describe the current evidence regarding the use of CGM in people at high risk of diabetes. To date, there is no strong evidence to support the global implementation of CGM in individuals who are at risk of developing diabetes. However, there are promising results highlighting the benefits of CGM in specific populations such as people living with obesity, prediabetes, gestational diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, other endocrinopathies, and genetic syndromes. Also, CGM has shown promising potential in people with positive islet autoantibodies and pre-symptomatic type 1 diabetes, those treated with medications that induce hyperglycaemia or diabetes, and individuals receiving solid organ transplantation who are at risk of post-transplant diabetes mellitus. However, larger studies are needed to confirm these preliminary results. CGM-derived data are not currently validated for the diagnosis of diabetes. There is no CGM-derived definition of normoglycaemia in people without diabetes. Looking to the future, CGM metrics, in tandem with physical activity, dietary intake, and clinical parameters, and eventually bioinformatics, may inform personalised risk scores for precision prevention of individuals at risk. We conclude that further research is needed to clarify the indications, drawbacks, and feasibility of CGM use in people at high risk of diabetes to identify those groups who could benefit most from this technology. Full article

(This article belongs to the Special Issue Personalized Prevention and Treatment in Endocrinology, Diabetes and Metabolic Diseases)

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15 pages, 3801 KB

Open AccessArticle

Mechanisms of Substrate Recognition by the Multispecific Protein Lysine Methyltransferase SETD6

by Gizem T. Ulu, Sara Weirich, Jana Kehl, Thyagarajan T. Chandrasekaran, Franziska Dorscht, Dan Levy and Albert Jeltsch

Life 2025, 15(10), 1578; https://doi.org/10.3390/life15101578 - 10 Oct 2025

Abstract

The SETD6 protein lysine methyltransferase monomethylates specific lysine residues in a diverse set of substrates which contain the target lysine residue in a highly variable amino acid sequence context. To investigate the mechanism underlying this multispecificity, we analyzed SETD6 substrate recognition using AlphaFold [...] Read more.

The SETD6 protein lysine methyltransferase monomethylates specific lysine residues in a diverse set of substrates which contain the target lysine residue in a highly variable amino acid sequence context. To investigate the mechanism underlying this multispecificity, we analyzed SETD6 substrate recognition using AlphaFold 3 docking and peptide SPOT array methylation experiments. Structural modeling of the SETD6–E2F1 complex suggested that substrate binding alone is insufficient to restrict SETD6 activity to only one lysine residue, pointing to additional sequence readout at the target site. Methylation of mutational scanning peptide SPOT arrays derived from four different SETD6 substrates (E2F1 K117, H2A.Z K7, RELA K310, and H4 K12) revealed sequence preferences of SETD6 at positions −1, +2, and +3 relative to the target lysine. Notably, glycine or large aliphatic residues were favored at −1, isoleucine/valine at +2, and lysine at +3. These preferences, however, were sequence context dependent and variably exploited among different substrates, indicating conformational variability of the enzyme–substrate interface. Mutation of SETD6 residue L260, which forms a contact with the +2 site in the available SETD6-RELA structure, further demonstrated substrate-specific differences in recognition at the +2/+3 sites. Together, these findings reveal a versatile mode of peptide recognition in which the readout of each substrate position depends on the overall substrate peptide sequence. These findings can explain the multispecificity of SETD6 and similar mechanisms may underlie substrate selection in other protein methyltransferases. Full article

(This article belongs to the Special Issue Structure, Activity, and Function of Protein Methyltransferases: 2nd Edition)

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15 pages, 3004 KB

Open AccessArticle

Computational–Experimental Identification of Palindromic Motifs Bound by Bacterial XRE Family Transcriptional Regulators

by Linjia Wang, Shitong Zhong, Liangyan Wang, Huizhi Lu and Yuejin Hua

Life 2025, 15(10), 1577; https://doi.org/10.3390/life15101577 - 10 Oct 2025

Abstract

Bacteria employ transcriptional regulators, such as those belonging to the Xenobiotic Response Element (XRE) family, to regulate metabolic processes. These regulators often exhibit autoregulatory properties and function as dimers to recognize palindromic DNA motifs. However, the binding motifs of the XRE family transcriptional [...] Read more.

Bacteria employ transcriptional regulators, such as those belonging to the Xenobiotic Response Element (XRE) family, to regulate metabolic processes. These regulators often exhibit autoregulatory properties and function as dimers to recognize palindromic DNA motifs. However, the binding motifs of the XRE family transcriptional regulators in bacteria have not yet been well characterized on a large scale. To identify potential XRE transcriptional regulator recognition motifs efficiently, we developed a computational approach combining structural alignment, sequence scanning, and motif clustering. We first identified the potential motifs of XRE regulators using computational methods. Using the helix–turn–helix (HTH) domain of XRE family regulators as a template, we collected 27,732 proteins containing the domain from bacterial databases. By extracting upstream sequences of these proteins and employing bioinformatics tools like MEME and motifStack to search potential motifs, 5622 motifs were identified and subsequently clustered into 223 clusters. These clusters can be classified into 7 main types based on the base conservation patterns observed in motifs. Interaction models between representative proteins and their corresponding motifs were predicted using AlphaFold. Subsequently, we conducted experimental validation via electrophoretic mobility shift assays (EMSAs) and confirmed the feasibility of our approach, as nine out of ten tested interactions showed clear protein–DNA binding. However, due to limitations in experimental conditions, the remaining predicted motifs have not yet undergone experimental validation. Since conserved sequences and well-predicted structures cannot replace real-world scenarios, there are limitations to relying solely on computational predictions, and experimental validation remains necessary. In summary, our study establishes a reliable framework for identifying XRE family transcriptional regulator recognition motifs and provides valuable insights into bacterial regulation. Full article

(This article belongs to the Section Genetics and Genomics)

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19 pages, 527 KB

Open AccessArticle

AI-Powered Early Detection of Sepsis in Emergency Medicine

by Sergey Aityan, Rolando Herrero, Abdolreza Mosaddegh, Haitham Tayyar, Ebunoluwa Adebesin, Sai Pranavi Jeedigunta, Hangyeol Kim, Manuel Mersini, Rita Lazzaro, Nicola Iacovazzo and Ciro Gargiulo Isacco

Life 2025, 15(10), 1576; https://doi.org/10.3390/life15101576 - 10 Oct 2025

Abstract

Sepsis remains a critical medical emergency caused by a dysregulated immune response to infection, with timely detection and intervention being essential for improving survival rates. Traditional methods often rely on clinician intuition and structured scoring systems, which may be time-intensive and prone to [...] Read more.

Sepsis remains a critical medical emergency caused by a dysregulated immune response to infection, with timely detection and intervention being essential for improving survival rates. Traditional methods often rely on clinician intuition and structured scoring systems, which may be time-intensive and prone to variability. To address these limitations, Machine Learning (ML) offers a powerful alternative, bringing precision and efficiency to sepsis detection. This study investigates both white-box and complex black-box ML models applied to patient data collected across the continuum of care, including monitoring at the urgent care, en route in ambulances, and diagnostics conducted within hospital emergency department settings themselves. White-box models, such as logistic regression and decision trees, are valued for their interpretability, allowing healthcare providers to understand and trust the reasoning behind predictions. Meanwhile, black-box models like deep neural networks and support vector machines deliver superior accuracy but pose challenges in clinical transparency. This trade-off between explainability and performance is explored in detail, supported by experimental results aimed at identifying the most effective computational strategies for early sepsis recognition across diverse healthcare environments. Full article

(This article belongs to the Special Issue Artificial Intelligence and Computational Models in Understanding Human Diseases)

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39 pages, 2235 KB

Open AccessReview

Cross-Priming and Cross-Tolerance After Intramuscular mRNA Vaccination for Viral Infections: Feasibility and Implications

by Siguna Mueller

Life 2025, 15(10), 1575; https://doi.org/10.3390/life15101575 - 9 Oct 2025

Abstract

The induction of robust CD8 T cell immunity after intramuscular (i.m.) mRNA vaccination has remained a challenge. Due to the limited presence of professional antigen-presenting cells (APCs) in muscle tissue, this route of administration tends to result in the transfection of muscle cells [...] Read more.

The induction of robust CD8 T cell immunity after intramuscular (i.m.) mRNA vaccination has remained a challenge. Due to the limited presence of professional antigen-presenting cells (APCs) in muscle tissue, this route of administration tends to result in the transfection of muscle cells at the injection site with insufficient T cell activation capacity. The attraction of migratory APCs and related processes that lead to the acquisition of antigenic material from transfected non-APCs arises as a potential alternative to facilitate activation of CD8 T cells in the draining lymph nodes. This indirect pathway, known as antigen cross-presentation, has remained underappreciated for mRNA vaccines. This review provides a comprehensive analysis of this process. Due to the paucity of information available in this context, it also extrapolates from insights for antigen cross-presentation more generally and for traditional vaccines. Arguments are provided as to why this natural process in the context of pro-drugs, such as mRNA vaccines, may engender both specific and nonspecific responses and, in certain situations, evoke cross-tolerance rather than immunity. This widely unaccounted T cell activation process may, therefore, explain several key mysteries surrounding i.m. RNA vaccination, including its impact on heterologous infections. But it also raises numerous open questions that are clearly described. Full article

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23 pages, 1303 KB

Open AccessReview

Advancing the Diagnosis and Treatment of Early Chronic Pancreatitis Through Innovation in Imaging and Biomarker Profiling—A Narrative Review

by Alexandru-Ionut Coseru, Diana Elena Floria, Constantin Simiras, Radu Alexandru Vulpoi, Vadim Rosca, Roxana Nemteanu, Oana Petrea, Irina Ciortescu, Oana-Bogdana Barboi, Gheorghe G. Balan, Catalin Sfarti, Georgiana-Emanuela Gîlca-Blanariu, Catalina Mihai, Liliana Gheorghe, Alina Plesa and Vasile-Liviu Drug

Life 2025, 15(10), 1574; https://doi.org/10.3390/life15101574 - 9 Oct 2025

Abstract

Early chronic pancreatitis (ECP) represents a potentially reversible stage in the natural history of chronic pancreatic disease. Timely diagnosis of ECP offers a possibility for intervention, yet its diagnosis remains challenging due to nonspecific symptoms, lack of standardized criteria, and the limited diagnostic [...] Read more.

Early chronic pancreatitis (ECP) represents a potentially reversible stage in the natural history of chronic pancreatic disease. Timely diagnosis of ECP offers a possibility for intervention, yet its diagnosis remains challenging due to nonspecific symptoms, lack of standardized criteria, and the limited diagnostic sensitivity of conventional tools. This review aims to synthesize recent advancements in the understanding, detection, and management of ECP, with a focus on innovation in imaging techniques and biomarker profiling. The goal is to facilitate earlier diagnosis and more effective patient stratification. We reviewed the literature from the past five years, including original studies, meta-analyses, and expert consensus statements, to address the current evidence across genetic, inflammatory, imaging, and biochemical domains relevant to ECP. Endoscopic ultrasound and advanced magnetic resonance techniques offer high sensitivity in detecting early parenchymal changes, although inter-observer variability and lack of standardization persist. Biomarker discovery has focused on inflammatory (IL-6, sCD163), fibrotic (TGF-β1, TIMP-1), and oxidative markers, as well as novel candidates like microRNAs. Genetic predisposition (PRSS1, SPINK1, CTRC, CPA1, CLDN2) significantly influences disease onset and progression and could enable selection of high-risk individuals. Therefore, diagnosing ECP should involve a multidisciplinary precision-based approach integrating clinical, radiologic, molecular, serologic, and genetic data for individualized risk stratification. Full article

(This article belongs to the Section Medical Research)

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10 pages, 2893 KB

Open AccessTechnical Note

Cement-Augmented Screw Fixation for Unreconstructible Acetabular Posterior Wall Fractures: A Technical Note

by Jihyo Hwang, Ho won Lee, Yonghyun Yoon and King Hei Stanley Lam

Life 2025, 15(10), 1573; https://doi.org/10.3390/life15101573 - 9 Oct 2025

Abstract

The management of severely comminuted acetabular posterior wall fractures in young, active patients presents a significant surgical challenge. When anatomical open reduction and internal fixation (ORIF) is not feasible, primary total hip arthroplasty (THA) is often considered but is a suboptimal solution due [...] Read more.

The management of severely comminuted acetabular posterior wall fractures in young, active patients presents a significant surgical challenge. When anatomical open reduction and internal fixation (ORIF) is not feasible, primary total hip arthroplasty (THA) is often considered but is a suboptimal solution due to concerns over long-term implant survivorship and the inevitability of revision surgery. This single-patient technical note presents a novel joint-preserving technique for managing unreconstructible acetabular posterior wall fractures using with cement-augmented screw fixation via the Kocher–Langenbeck approach. A 28-year-old male sustained a left posterior hip dislocation with a comminuted acetabular posterior wall fracture involving >30% of the articular surface, alongside a tibial shaft fracture, following a high-energy motorcycle collision. Intraoperative assessment confirmed the posterior wall was unreconstructible, with six non-viable osteochondral fragments. A joint-preserving salvage procedure was performed. After debridement, a stable metallic framework was created using three screws anchored in the posterior column. Polymethylmethacrylate (PMMA) bone cement was then applied over this framework in its doughy phase, meticulously contoured to reconstruct the articular surface. The hip was reduced, and the tibia was fixed with an intramedullary nail. The patient was mobilized with weight-bearing as tolerated on postoperative day 3. At the 21-month follow-up, the patient reported no pain during daily activities and only mild discomfort during deep squatting. Radiographic and CT evaluations demonstrated a stable hip joint, concentric reduction, well-maintained joint space, and no evidence of implant loosening or osteolysis. Level of Evidence: V (Technical Note/single-patient Case report). For unreconstructible, comminuted fractures of the non-weight-bearing portion of the acetabular posterior wall in young patients, cement-augmented screw fixation offers a viable joint-preserving alternative to primary THA. This technique provides immediate stability, facilitates early mobilization, and preserves bone stock. While long-term outcomes require further study, this case demonstrates excellent functional and radiographic results at 21 months, presenting a promising new option for managing these complex injuries. Full article

(This article belongs to the Special Issue Advanced Strategies in Fracture Treatments)

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34 pages, 1463 KB

Open AccessReview

Brain Structures, Circuits, and Networks Involved in Immune Regulation, Periodontal Health, and Disease

by Torbjørn Jarle Breivik, Per Gjermo, Per Kristian Opstad, Robert Murison, Stephan von Hörsten and Inge Fristad

Life 2025, 15(10), 1572; https://doi.org/10.3390/life15101572 - 9 Oct 2025

Abstract

The interaction between microorganisms in the dental microfilm (plaque) at the gingival margin, the immune system, and the brain is vital for gingival health. The brain constantly receives information regarding microbial composition and inflammation status through afferent nerves and the bloodstream. It modulates [...] Read more.

The interaction between microorganisms in the dental microfilm (plaque) at the gingival margin, the immune system, and the brain is vital for gingival health. The brain constantly receives information regarding microbial composition and inflammation status through afferent nerves and the bloodstream. It modulates immune responses via efferent nerves and hormonal systems to maintain homeostasis. This relationship determines whether the gingiva remains healthy or develops into gingivitis (non-destructive inflammation) or periodontitis (a destructive condition), collectively referred to as periodontal disease. Factors associated with severe periodontitis heighten the responsiveness of this homeostatic system, diminishing the adaptive immune system’s defence against symbiotic microorganisms with pathogenic properties, known as pathobionts. This leads to excessive innate immune system activation, effectively preventing infection but damaging the periodontium. Consequently, investigating the microbiota–brain axis is vital for understanding its impact on periodontal health and disease. Herein, we examine recent advancements in how the defence against pathobionts is organised within the brain, and how it regulates and adapts the pro-inflammatory and anti-inflammatory immune balance, controlling microbiota composition. It also discussed how pathobionts and emotional stress can trigger neurodegenerative diseases, and how inadequate coping strategies for managing daily stress and shift work can disrupt brain circuits linked to immune regulation, weakening the adaptive immune response against pathobionts. Full article

(This article belongs to the Special Issue Microbiome–Gut–Brain Connections: New Windows into Health and Disease)

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