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23 pages, 565 KiB  
Review
Gender Differences in the Effects of Exercise Interventions on Alzheimer’s Disease
by Yahong Dong, Lei Shi, Yixiao Ma, Tong Liu, Yingjie Sun and Qiguan Jin
Brain Sci. 2025, 15(8), 812; https://doi.org/10.3390/brainsci15080812 - 28 Jul 2025
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory loss, cognitive decline, and structural brain atrophy. Substantial sex differences have been observed in its incidence, clinical trajectory, and response to treatment. Women are disproportionately affected, exhibiting faster progression and more [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder primarily characterized by memory loss, cognitive decline, and structural brain atrophy. Substantial sex differences have been observed in its incidence, clinical trajectory, and response to treatment. Women are disproportionately affected, exhibiting faster progression and more severe cognitive impairment. Exercise has emerged as a promising non-pharmacological intervention to mitigate AD-related decline, yet growing evidence reveals that its benefits vary by sex. This review synthesizes current findings from human and animal studies, focusing on how exercise impacts AD differently in males and females. In women, exercise is more strongly associated with improvements in cognitive function, neurotrophic support, and emotional regulation. In men, benefits tend to involve structural preservation and oxidative adaptations. Underlying mechanisms include differential hormonal profiles, inflammatory responses, and neuroplastic signaling pathways. These findings underscore the need to consider sex as a biological variable in AD research. Developing sex-specific exercise strategies may enhance therapeutic outcomes and support more individualized approaches in AD prevention and care. Full article
(This article belongs to the Section Neurodegenerative Diseases)
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14 pages, 839 KiB  
Article
Biochemical Profile Variations Among Type 2 Diabetic Patients Stratified by Hemoglobin A1c Levels in a Saudi Cohort: A Retrospective Study
by Abdulrahman Alshalani, Nada AlAhmari, Hajar A. Amin, Abdullah Aljedai and Hamood AlSudais
J. Clin. Med. 2025, 14(15), 5324; https://doi.org/10.3390/jcm14155324 - 28 Jul 2025
Abstract
Background: The global increase in type 2 diabetes mellitus (T2DM) cases necessitates the need for early detection of metabolic changes. This study investigated variations in liver enzymes, renal markers, electrolytes, and lipid profiles among T2DM patients stratified by hemoglobin A1c (HbA1c) categories [...] Read more.
Background: The global increase in type 2 diabetes mellitus (T2DM) cases necessitates the need for early detection of metabolic changes. This study investigated variations in liver enzymes, renal markers, electrolytes, and lipid profiles among T2DM patients stratified by hemoglobin A1c (HbA1c) categories to support early identification and better management of diabetes-related complications. Methods: A retrospective observational study at King Khalid University Hospital (KKUH), Riyadh, included 621 adult patients diagnosed with T2DM categorized into four HbA1c groups: normal (<5.7%), prediabetes (5.7–6.4%), controlled diabetes (6.5–7.9%), and uncontrolled diabetes (≥8.0%). Biochemical parameters included the liver profile: alkaline phosphatase (ALP) and bilirubin, renal profile: creatinine, blood urea nitrogen (BUN), glucose, sodium, and chloride, and lipid profile: cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. Regression models identified predictors of ALP, cholesterol, and LDL. Results: ALP was higher in uncontrolled diabetes (89.0 U/L, Q1–Q3: 106.3–72.0) than in the prediabetes group (75.0 U/L, Q1–Q3: 96.8–62.3). Sodium and chloride were lower in uncontrolled diabetes (Na: 138.3 mmol/L, Q1–Q3: 140.3–136.4; Cl: 101.1 mmol/L, Q1–Q3: 102.9–99.4) compared to the normal group (Na: 139.5 mmol/L, Q1–Q3: 142.4–136.9; Cl: 103.5 mmol/L, Q1–Q3: 106.1–101.7). LDL was lower in uncontrolled diabetes (2.1 mmol/L, Q1–Q3: 2.8–1.7) than in the normal group (2.8 mmol/L, Q1–Q3: 3.7–2.2), while triglycerides were higher in patients with uncontrolled diabetes compared to the normal group (1.45 mmol/L, Q1–Q3: 2.02–1.11 vs. 1.26 mmol/L, Q1–Q3: 1.44–0.94). Regression models showed low explanatory power (R2 = 2.1–7.3%), with weight, age, and sex as significant predictors of select biochemical markers. Conclusions: The study observed biochemical variations across HbA1c categories in T2DM patients, likely reflecting insulin resistance. Monitoring these markers in conjunction with HbA1c can enhance early detection and improve the management of complications. Full article
(This article belongs to the Section Endocrinology & Metabolism)
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31 pages, 2753 KiB  
Article
The HCV-Dependent Inhibition of Nrf1/ARE-Mediated Gene Expression Favours Viral Morphogenesis
by Olga Szostek, Patrycja Schorsch, Daniela Bender, Mirco Glitscher and Eberhard Hildt
Viruses 2025, 17(8), 1052; https://doi.org/10.3390/v17081052 - 28 Jul 2025
Abstract
The life cycle of the hepatitis C virus (HCV) is closely linked to lipid metabolism. Recently, the stress defence transcription factor, nuclear factor erythroid 2 related factor-1 (Nrf1), has been described as a cholesterol sensor that protects the liver from excess cholesterol. Nrf1, [...] Read more.
The life cycle of the hepatitis C virus (HCV) is closely linked to lipid metabolism. Recently, the stress defence transcription factor, nuclear factor erythroid 2 related factor-1 (Nrf1), has been described as a cholesterol sensor that protects the liver from excess cholesterol. Nrf1, like its homologue Nrf2, further responds to oxidative stress by binding with small Maf proteins (sMaf) to the promotor antioxidant response element (ARE). Given these facts, investigating the crosstalk between Nrf1 and HCV was a logical next step. In HCV-replicating cells, we observed reduced levels of Nrf1. Furthermore, activation of Nrf1-dependent target genes is impaired due to sMaf sequestration in replicase complexes. This results in a shortage of sMaf proteins in the nucleus, trapping Nrf1 at the replicase complexes and further limiting its function. Weakened Nrf1 activity contributes to impaired cholesterol removal, which occurs alongside an elevated intracellular cholesterol level and inhibited LXRα promoter activation. Furthermore, inhibition of Nrf1 activity correlated with a kinome profile characteristic of steatosis and enhanced inflammation—factors contributing to HCV pathogenesis. Our results indicate that activation of Nrf1-dependent target genes is impaired in HCV-positive cells. This, in turn, favours viral morphogenesis, as evidenced by enhanced replication and increased production of viral progeny. Full article
(This article belongs to the Section Human Virology and Viral Diseases)
24 pages, 6890 KiB  
Article
Multi-Level Transcriptomic and Physiological Responses of Aconitum kusnezoffii to Different Light Intensities Reveal a Moderate-Light Adaptation Strategy
by Kefan Cao, Yingtong Mu and Xiaoming Zhang
Genes 2025, 16(8), 898; https://doi.org/10.3390/genes16080898 - 28 Jul 2025
Abstract
Objectives: Light intensity is a critical environmental factor regulating plant growth, development, and stress adaptation. However, the physiological and molecular mechanisms underlying light responses in Aconitum kusnezoffii, a valuable alpine medicinal plant, remain poorly understood. This study aimed to elucidate the adaptive [...] Read more.
Objectives: Light intensity is a critical environmental factor regulating plant growth, development, and stress adaptation. However, the physiological and molecular mechanisms underlying light responses in Aconitum kusnezoffii, a valuable alpine medicinal plant, remain poorly understood. This study aimed to elucidate the adaptive strategies of A. kusnezoffii under different light intensities through integrated physiological and transcriptomic analyses. Methods: Two-year-old A. kusnezoffii plants were exposed to three controlled light regimes (790, 620, and 450 lx). Leaf anatomical traits were assessed via histological sectioning and microscopic imaging. Antioxidant enzyme activities (CAT, POD, and SOD), membrane lipid peroxidation (MDA content), osmoregulatory substances, and carbon metabolites were quantified using standard biochemical assays. Transcriptomic profiling was conducted using Illumina RNA-seq, with differentially expressed genes (DEGs) identified through DESeq2 and functionally annotated via GO and KEGG enrichment analyses. Results: Moderate light (620 lx) promoted optimal leaf structure by enhancing palisade tissue development and epidermal thickening, while reducing membrane lipid peroxidation. Antioxidant defense capacity was elevated through higher CAT, POD, and SOD activities, alongside increased accumulation of soluble proteins, sugars, and starch. Transcriptomic analysis revealed DEGs enriched in photosynthesis, monoterpenoid biosynthesis, hormone signaling, and glutathione metabolism pathways. Key positive regulators (PHY and HY5) were upregulated, whereas negative regulators (COP1 and PIFs) were suppressed, collectively facilitating chloroplast development and photomorphogenesis. Trend analysis indicated a “down–up” gene expression pattern, with early suppression of stress-responsive genes followed by activation of photosynthetic and metabolic processes. Conclusions: A. kusnezoffii employs a coordinated, multi-level adaptation strategy under moderate light (620 lx), integrating leaf structural optimization, enhanced antioxidant defense, and dynamic transcriptomic reprogramming to maintain energy balance, redox homeostasis, and photomorphogenic flexibility. These findings provide a theoretical foundation for optimizing artificial cultivation and light management of alpine medicinal plants. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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30 pages, 2578 KiB  
Article
Real-Time Functional Stratification of Tumor Cell Lines Using a Non-Cytotoxic Phospholipoproteomic Platform: A Label-Free Ex Vivo Model
by Ramón Gutiérrez-Sandoval, Francisco Gutiérrez-Castro, Natalia Muñoz-Godoy, Ider Rivadeneira, Adolay Sobarzo, Jordan Iturra, Ignacio Muñoz, Cristián Peña-Vargas, Matías Vidal and Francisco Krakowiak
Biology 2025, 14(8), 953; https://doi.org/10.3390/biology14080953 - 28 Jul 2025
Abstract
The development of scalable, non-invasive tools to assess tumor responsiveness to structurally active immunoformulations remains a critical unmet need in solid tumor immunotherapy. Here, we introduce a real-time, ex vivo functional system to classify tumor cell lines exposed to a phospholipoproteomic platform, without [...] Read more.
The development of scalable, non-invasive tools to assess tumor responsiveness to structurally active immunoformulations remains a critical unmet need in solid tumor immunotherapy. Here, we introduce a real-time, ex vivo functional system to classify tumor cell lines exposed to a phospholipoproteomic platform, without relying on cytotoxicity, co-culture systems, or molecular profiling. Tumor cells were monitored using IncuCyte® S3 (Sartorius) real-time imaging under ex vivo neutral conditions. No dendritic cell components or immune co-cultures were used in this mode. All results are derived from direct tumor cell responses to structurally active formulations. Using eight human tumor lines, we captured proliferative behavior, cell death rates, and secretomic profiles to assign each case into stimulatory, inhibitory, or neutral categories. A structured decision-tree logic supported the classification, and a Functional Stratification Index (FSI) was computed to quantify the response magnitude. Inhibitory lines showed early divergence and high IFN-γ/IL-10 ratios; stimulatory ones exhibited a proliferative gain under balanced immune signaling. The results were reproducible across independent batches. This system enables quantitative phenotypic screening under standardized, marker-free conditions and offers an adaptable platform for functional evaluation in immuno-oncology pipelines where traditional cytotoxic endpoints are insufficient. This approach has been codified into the STIP (Structured Traceability and Immunophenotypic Platform), supporting reproducible documentation across tumor models. This platform contributes to upstream validation logic in immuno-oncology workflows and supports early-stage regulatory documentation. Full article
(This article belongs to the Section Cancer Biology)
15 pages, 239 KiB  
Article
Examining Puppetry’s Contribution to the Learning, Social and Therapeutic Support of Students with Complex Educational and Psychosocial Needs in Special School Settings: A Phenomenological Study
by Konstantinos Mastrothanasis, Angelos Gkontelos, Maria Kladaki and Eleni Papouli
Disabilities 2025, 5(3), 67; https://doi.org/10.3390/disabilities5030067 - 28 Jul 2025
Abstract
The present study focuses on investigating the contribution of puppetry as a pedagogical and psychosocial tool in special education, addressing the literature gap in the systematic documentation of the experiences of special education teachers, concerning its use in daily teaching practice. The main [...] Read more.
The present study focuses on investigating the contribution of puppetry as a pedagogical and psychosocial tool in special education, addressing the literature gap in the systematic documentation of the experiences of special education teachers, concerning its use in daily teaching practice. The main objective is to capture the way in which puppetry enhances the learning, social and therapeutic support of students with complex educational and psychosocial needs. The study employs a qualitative phenomenological approach, conducting semi-structured interviews with eleven special education teachers who integrate puppetry into their teaching. Qualitative data were analyzed using thematic analysis. The findings highlight that puppetry significantly enhances cognitive function, concentration, memory and language development, while promoting the active participation, cooperation, social inclusion and self-expression of students. In addition, the use of the puppet acts as a means of psycho-emotional empowerment, supporting positive behavior and helping students cope with stress and behavioral difficulties. Participants identified peer support, material adequacy and training as key factors for effective implementation, while conversely, a lack of resources and time is cited as a key obstacle. The integration of puppetry in everyday school life seems to ameliorate a more personalized, supportive and experiential learning environment, responding to the diverse and complex profiles of students attending special schools. Continuous training for teachers, along with strengthening the collaboration between the arts and special education, is essential for the effective use of puppetry in the classroom. Full article
15 pages, 540 KiB  
Review
Achalasia and Gut Microbiota: Is Dysbiosis an Overlooked Factor in Postoperative Surgical Outcomes?
by Agostino Fernicola, Giuseppe Palomba, Armando Calogero, Antonella Sciarra, Annachiara Cavaliere, Felice Crocetto, Caterina Sagnelli, Antonio Alvigi, Raffaele Basile, Domenica Pignatelli, Andrea Paolillo, Federico Maria D’Alessio, Giacomo Benassai, Gennaro Quarto and Michele Santangelo
Surgeries 2025, 6(3), 63; https://doi.org/10.3390/surgeries6030063 - 28 Jul 2025
Abstract
Background: Esophageal achalasia is a rare motility disorder characterized by impaired lower esophageal sphincter (LES) relaxation and food stasis. Surgical interventions, including Heller myotomy with fundoplication or peroral endoscopic myotomy (POEM), effectively alleviate symptoms but induce significant anatomical and functional alterations. In [...] Read more.
Background: Esophageal achalasia is a rare motility disorder characterized by impaired lower esophageal sphincter (LES) relaxation and food stasis. Surgical interventions, including Heller myotomy with fundoplication or peroral endoscopic myotomy (POEM), effectively alleviate symptoms but induce significant anatomical and functional alterations. In various gastrointestinal surgeries, microbiota have been implicated in modulating clinical outcomes; however, their role in achalasia surgery remains unexplored. Methods: We performed a narrative literature search of various databases to identify studies exploring potential interactions between the gastroesophageal microbiota, achalasia pathophysiology, and surgical treatment, proposing clinical implications and future research avenues. Results: Chronic esophageal stasis in achalasia promotes local dysbiosis by facilitating aberrant bacterial colonization. Surgical restoration of esophageal motility and gastroesophageal transit induces substantial shifts in the microbial ecosystem. Analogous microbiota alterations following procedures such as fundoplication, gastrectomy, and bariatric surgery underscore the significant impact of mechanical modifications on microbial composition. Comprehensive microbiota profiling in patients with achalasia may enable the identification of dysbiotic phenotypes predisposed to complications, thereby providing personalized therapeutic interventions including probiotics, prebiotics, dietary modulation, or targeted antibiotic therapy. These insights hold promise for clinical benefits, including the mitigation of inflammation and infection, monitoring of surgical efficacy through microbial biomarkers, and optimization of postoperative nutritional strategies to reestablish microbial homeostasis, ultimately enhancing patient outcomes beyond conventional treatment paradigms. Conclusions: The gastroesophageal microbiota is a compelling mediator of surgical outcomes in achalasia. Future investigations integrating microbiological and inflammatory profiling are warranted to elucidate the functional role of the gastroesophageal microbiota and assess its potential as a biomarker and therapeutic target. Full article
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18 pages, 278 KiB  
Review
Biomarkers over Time: From Visual Contrast Sensitivity to Transcriptomics in Differentiating Chronic Inflammatory Response Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
by Ming Dooley
Int. J. Mol. Sci. 2025, 26(15), 7284; https://doi.org/10.3390/ijms26157284 - 28 Jul 2025
Abstract
Chronic inflammatory response syndrome (CIRS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are debilitating multisystem illnesses that share overlapping symptoms and molecular patterns, including immune dysregulation, mitochondrial impairment, and vascular dysfunction. This review provides a chronological synthesis of biomarker development in CIRS, tracing its [...] Read more.
Chronic inflammatory response syndrome (CIRS) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) are debilitating multisystem illnesses that share overlapping symptoms and molecular patterns, including immune dysregulation, mitochondrial impairment, and vascular dysfunction. This review provides a chronological synthesis of biomarker development in CIRS, tracing its evolution from early functional tests such as visual contrast sensitivity (VCS) to advanced transcriptomic profiling. Drawing on peer-reviewed studies spanning two decades, we examine the layered integration of neuroendocrine, immunologic, metabolic, and genomic markers that collectively support a multisystem model of innate immune activation specific to environmentally acquired illness. Particular focus is given to the Gene Expression: Inflammation Explained (GENIE) platform’s use of transcriptomics to classify disease stages and distinguish CIRS from other fatiguing conditions. While ME/CFS research continues to explore overlapping pathophysiologic features, it has yet to establish a unified diagnostic model with validated biomarkers or exposure-linked mechanisms. As a result, many patients labeled with ME/CFS may, in fact, represent unrecognized CIRS cases. This review underscores the importance of structured biomarker timelines in improving differential diagnosis and guiding treatment in complex chronic illness and highlights the reproducibility of the CIRS framework in contrast to the diagnostic ambiguity surrounding ME/CFS. Full article
30 pages, 1991 KiB  
Review
Emerging Technologies for Extracting Antioxidant Compounds from Edible and Medicinal Mushrooms: An Efficient and Sustainable Approach
by Salome Mamani Parí, Erick Saldaña, Juan D. Rios-Mera, María Fernanda Quispe Angulo and Nils Leander Huaman-Castilla
Compounds 2025, 5(3), 29; https://doi.org/10.3390/compounds5030029 - 28 Jul 2025
Abstract
Edible mushrooms are well-known for their culinary and nutritional values. Additionally, they serve as a natural source of polyphenols, a group of bioactive compounds that significantly treat diseases associated with oxidative stress. The polyphenolic profile of mushrooms mainly consists of phenolic acids and [...] Read more.
Edible mushrooms are well-known for their culinary and nutritional values. Additionally, they serve as a natural source of polyphenols, a group of bioactive compounds that significantly treat diseases associated with oxidative stress. The polyphenolic profile of mushrooms mainly consists of phenolic acids and flavonoids, whose chemical properties have attracted the attention of both the food and pharmaceutical industries. Consequently, methods for extracting polyphenols from mushrooms encompass conventional techniques (maceration and Soxhlet extraction) as well as innovative or green methods (ultrasound-assisted extraction, microwave-assisted extraction, pressurized liquid extraction, supercritical fluid extraction, enzyme-assisted extraction, and pulsed electric field extraction). Nonetheless, extraction with pressurized liquids and supercritical fluids is considered the most suitable method, as they function in a gentle and selective manner, preserving the integrity of the phenolic compounds. The use of mushroom-derived phenolic compounds in food and pharmaceutical formulations continues to face challenges concerning the safety of these extracts, as they might contain unwanted substances. Future applications should incorporate purification systems to yield highly pure extracts, thereby creating safe polyphenol carriers (for food and pharmaceutical products) for consumers. Full article
(This article belongs to the Special Issue Compounds–Derived from Nature)
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18 pages, 1650 KiB  
Article
Unlocking the Fatty Acid and Antioxidant Profile of Grape Pomace: A Systematic Assessment Across Varieties and Vintages for Its Sustainable Valorization
by Teresa Abreu, Rui Ferreira, Paula C. Castilho, José S. Câmara, Juan Teixeira and Rosa Perestrelo
Molecules 2025, 30(15), 3150; https://doi.org/10.3390/molecules30153150 - 28 Jul 2025
Abstract
Grape pomace (GP), the main by-product of the wine industry, represents a valuable source of bioactive metabolites with significant potential for valorization in the context of sustainable bioresource management. This study systematically characterizes the fatty acid methyl ester (FAME) profile, total phenolic content [...] Read more.
Grape pomace (GP), the main by-product of the wine industry, represents a valuable source of bioactive metabolites with significant potential for valorization in the context of sustainable bioresource management. This study systematically characterizes the fatty acid methyl ester (FAME) profile, total phenolic content (TPC), total flavonoid content (TFC), and antioxidant activities (DPPH, ABTS, ORAC) of GP derived from seven grape varieties across three consecutive vintages (2022–2024). White GP, particularly Verdelho and Sercial, exhibited a superior lipid quality with high concentrations of methyl linoleate (up to 1997 mg/100 g DW) and methyl oleate (up to 1294 mg/100 g DW), low atherogenic (AI < 0.05) and thrombogenic indices (TI ≤ 0.13), and elevated PUFA/SFA ratios (≥8.2). In contrast, red GP, especially from Complexa and Tinta Negra, demonstrated the highest antioxidant potential, with TPC values up to 6687 mgGAE/100 g DW, TFC up to 4624 mgQE/100 g DW, and antioxidant activities reaching 5399 mgTE/100 g (DPPH) and 7219 mgTE/100 g (ABTS). Multivariate statistical analyses (PCA, PLS-DA, HCA) revealed distinct varietal and vintage-dependent clustering and identified key discriminant fatty acids, including linolenic acid (C18:3), lauric acid (C12:0), and arachidic acid (C20:0). These findings underscore the compositional diversity and functional potential of GP, reinforcing its suitability for applications in functional foods, nutraceuticals, and cosmetics, in alignment with circular economy principles. Full article
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9 pages, 420 KiB  
Article
Comparative Effectiveness of Dalerpen vs. Branded and Other Generic Tadalafil: The “Shift Study”
by Davide Arcaniolo, Carlos Miacola, Marco Bitelli, Luca Boeri, Tommaso Cai, Carlo Ceruti, Celeste Manfredi, Ilaria Ortensi, Fabrizio Palumbo, Giorgio Piubello, Chiara Polito, Nicolò Schifano and Alessandro Palmieri
Uro 2025, 5(3), 14; https://doi.org/10.3390/uro5030014 - 28 Jul 2025
Abstract
Background: Phosphodiesterase type 5 inhibitors (PDE5i), particularly tadalafil and sildenafil, are the first-line therapies for erectile dysfunction (ED). After the patent expiration of branded tadalafil in 2017, generic formulations became available. Despite equivalent efficacy, skepticism persists regarding the effectiveness and safety of generics. [...] Read more.
Background: Phosphodiesterase type 5 inhibitors (PDE5i), particularly tadalafil and sildenafil, are the first-line therapies for erectile dysfunction (ED). After the patent expiration of branded tadalafil in 2017, generic formulations became available. Despite equivalent efficacy, skepticism persists regarding the effectiveness and safety of generics. The SHIFT study aimed to evaluate the non-inferiority of a generic tadalafil (Dalerpen) compared with branded and other generic tadalafil in terms of clinical efficacy and patient satisfaction. Methods: A prospective, multicenter study was conducted involving 247 patients treated with tadalafil (either 5 mg or 20 mg) for ED. Patients switched from branded or other generic tadalafil to Dalerpen. Baseline and follow-up assessments included the International Index of Erectile Function—Erectile Function Domain (IIEF-EF) (primary endpoint), Sexual Encounter Profile (SEP-2 and SEP-3), and International Prostatic Symptom Score (IPSS). A one-month follow-up was performed. Results: A total of 247 patients were included in the final analysis. After switching to Dalerpen, significant improvements were observed in both IIEF-EF (18.8 ± 5.6 vs. 16.7 ± 5.4, p < 0.001) and IPSS scores (10.4 ± 6.7 vs. 11.2 ± 6.3, p < 0.001), though the minimal clinically important difference (MCID) was not reached. SEP-3 scores also significantly increased (3 ± 1.2 vs. 2 ± 1.1, p < 0.001). Multivariate analysis identified baseline IIEF, IPSS scores, and post-treatment IPSS as predictors of IIEF-EF improvement (p < 0.001). Switching to Dalerpen was an independent predictor of both IIEF-EF and IPSS improvement. No new adverse events were reported. Conclusions: The SHIFT study demonstrates that Dalerpen is non-inferior to branded tadalafil in terms of clinical efficacy, offering a reliable and cost-effective therapeutic option. Educating patients on bioequivalence and addressing concerns regarding generic drugs are essential to facilitate therapeutic switches. Full article
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27 pages, 1010 KiB  
Review
The Multifaceted Role of IL-35 in Periodontal Disease and Beyond: From Genetic Polymorphisms to Biomarker Potential
by Zdravka Pashova-Tasseva, Antoaneta Mlachkova, Kamen Kotsilkov and Hristina Maynalovska
Genes 2025, 16(8), 891; https://doi.org/10.3390/genes16080891 - 28 Jul 2025
Abstract
Periodontitis is a prevalent chronic inflammatory disease with complex etiopathogenesis involving microbial dysbiosis, host immune response, environmental factors, and genetic susceptibility. Among the cytokines implicated in periodontal immunoregulation, interleukin-35 (IL-35) has emerged as a novel anti-inflammatory mediator with potential diagnostic and therapeutic relevance. [...] Read more.
Periodontitis is a prevalent chronic inflammatory disease with complex etiopathogenesis involving microbial dysbiosis, host immune response, environmental factors, and genetic susceptibility. Among the cytokines implicated in periodontal immunoregulation, interleukin-35 (IL-35) has emerged as a novel anti-inflammatory mediator with potential diagnostic and therapeutic relevance. This narrative review evaluates the role of IL-35 in periodontal disease by exploring its local and systemic expression, response to non-surgical periodontal therapy (NSPT), and association with clinical disease severity. Additionally, current evidence regarding IL-35 gene polymorphisms and their potential contribution to individual susceptibility and disease progression, as well as their relevance in related systemic conditions, is assessed. A comprehensive review and synthesis of recent clinical and experimental studies were conducted, focusing on IL-35 levels in saliva, serum, and gingival crevicular fluid (GCF) among patients with healthy periodontium, gingivitis, and various stages of periodontitis, both before and after NSPT. Emphasis was placed on longitudinal studies evaluating IL-35 dynamics in correlation with periodontal parameters, as well as genetic association studies investigating IL-12A and EBI3 gene polymorphisms. IL-35 levels were generally found to be higher in healthy individuals and reduced in periodontitis patients, indicating a possible protective role in maintaining periodontal homeostasis. Following NSPT, IL-35 levels significantly increased, corresponding with clinical improvement and reduced inflammatory burden. Genetic studies revealed variable associations between IL-35 polymorphisms and susceptibility to periodontitis and related systemic conditions, although further research is needed for validation. IL-35 appears to function as a modulator of immune resolution in periodontal disease, with potential utility as a non-invasive biomarker for disease activity and therapeutic response. Its upregulation during periodontal healing supports its role in promoting tissue stabilization. The integration of cytokine profiling and genetic screening may enhance personalized risk assessment and targeted interventions in periodontal care. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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12 pages, 1515 KiB  
Article
Expression of Heat Shock Protein 90 Genes Induced by High Temperature Mediated Sensitivity of Aphis glycines Matsumura (Hemiptera: Aphididae) to Insecticides
by Xue Han, Yulong Jia, Changchun Dai, Xiaoyun Wang, Jian Liu and Zhenqi Tian
Insects 2025, 16(8), 772; https://doi.org/10.3390/insects16080772 - 28 Jul 2025
Abstract
Soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is a major pest of soybean fields. While high-temperature stress induced by global warming can initially suppress aphid populations, these pests may eventually adapt, leading to more severe infestations and crop damage. Heat shock proteins (HSPs), [...] Read more.
Soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is a major pest of soybean fields. While high-temperature stress induced by global warming can initially suppress aphid populations, these pests may eventually adapt, leading to more severe infestations and crop damage. Heat shock proteins (HSPs), which are upregulated in response to heat stress to protect aphid development, also confer tolerance to other abiotic stressors, including insecticides. To investigate the role of HSPs in insecticide resistance in A. glycines, we analyzed the expression profiles of three AgHsp90 genes (AgHsp75, AgHsp83, and AgGrp94) following exposure to high temperatures and insecticides. Functional validation was performed using RNA interference (RNAi) to silence AgHsp90 genes. Our results demonstrated that AgHsp90 genes were significantly upregulated under both heat and insecticide stress conditions. Furthermore, after feeding on dsRNA of AgHsp90 genes, mortality rates of A. glycines significantly increased when exposed to imidacloprid and lambda-cyhalothrin. This study provides evidence that AgHsp90 genes play a crucial role in mediating thermal tolerance and insecticide resistance in A. glycines. Full article
(This article belongs to the Special Issue RNAi in Insect Physiology)
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19 pages, 4707 KiB  
Article
Secondary Metabolites from Rehmannia glutinosa Protect Mitochondrial Function in LPS-Injured Endothelial Cells
by Liwen Zhong, Mengkai Lu, Huiqi Fang, Chao Li, Hua Qu and Gang Ding
Pharmaceuticals 2025, 18(8), 1125; https://doi.org/10.3390/ph18081125 - 27 Jul 2025
Abstract
Background: Rehmannia glutinosa, a traditional Chinese herb, is commonly used to treat vascular-related disorders. Sepsis-associated vascular endothelial dysfunction is closely associated with mitochondrial damage. This study investigated the protective effects of secondary metabolites from R. glutinosa against LPS-induced mitochondrial dysfunction in [...] Read more.
Background: Rehmannia glutinosa, a traditional Chinese herb, is commonly used to treat vascular-related disorders. Sepsis-associated vascular endothelial dysfunction is closely associated with mitochondrial damage. This study investigated the protective effects of secondary metabolites from R. glutinosa against LPS-induced mitochondrial dysfunction in endothelial cells, providing potential therapeutic insights into sepsis-related vascular complications. Methods: Phytochemical profiling of fresh R. glutinosa roots was conducted, and the structures of new secondary metabolites (1 and 2) were elucidated through comprehensive spectroscopic analysis and ECD calculations. UPLC-Q-TOF-MS/MS characterized phenylethanoid glycosides. Mitochondrial function was assessed by measuring the membrane potential, ROS levels, and TOM20/DRP1 expression in LPS-injured HUVECs. Results: Two novel eremophilane-type sesquiterpenes, remophilanetriols J (1) and K (2), along with five known phenylethanoid glycosides (37), were isolated from the fresh roots of R. glutinosa. UPLC-Q-TOF-MS/MS analysis revealed unique fragmentation pathways for phenylethanoid glycosides (37). In LPS-injured HUVECs, all compounds collectively restored the mitochondrial membrane potential, attenuated ROS accumulation, and modulated TOM20/DRP1 expression. In particular, remophilanetriol K (2) exhibited potent protective effects at a low concentration (1.5625 μM). Conclusions: This study identifies R. glutinosa metabolites as potential therapeutics for sepsis-associated vascular dysfunction by preserving mitochondrial homeostasis. This study provides a mechanistic basis for the traditional use of R. glutinosa and offers valuable insights into the development of novel therapeutics targeting mitochondrial dysfunction in sepsis. Full article
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27 pages, 17405 KiB  
Article
Population Pharmacokinetic Modeling of Piperacillin/Tazobactam in Healthy Adults and Exploration of Optimal Dosing Strategies
by Yun Jung Lee, Gaeun Kang, Dae Young Zang and Dong Hwan Lee
Pharmaceuticals 2025, 18(8), 1124; https://doi.org/10.3390/ph18081124 - 27 Jul 2025
Abstract
Background/Objectives: Current dosing recommendations for piperacillin/tazobactam suggest adjustments only for patients with creatinine clearance (CrCl) below 40 mL/min, potentially neglecting the variability in drug exposure among patients with a CrCl greater than 40 mL/min. This study aimed to develop a population pharmacokinetic (PK) [...] Read more.
Background/Objectives: Current dosing recommendations for piperacillin/tazobactam suggest adjustments only for patients with creatinine clearance (CrCl) below 40 mL/min, potentially neglecting the variability in drug exposure among patients with a CrCl greater than 40 mL/min. This study aimed to develop a population pharmacokinetic (PK) model for piperacillin/tazobactam and explore optimal dosage regimens tailored by renal function and pathogen susceptibility. Methods: Twelve healthy adults received a single intravenous dose of piperacillin/tazobactam (4 g/0.5 g). Population PK models were developed using nonlinear mixed-effects modeling. Monte Carlo simulations were conducted to identify optimal dosing regimens across various renal functions and MIC levels, guided by pharmacodynamic targets defined as the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (fT>MIC). Results: PK profiles of both drugs were best described by two-compartment models. Estimated glomerular filtration rate (eGFR) adjusted by body surface area and body weight were identified as significant covariates influencing drug clearance and peripheral volume of distribution. Simulations showed that the standard dosing regimen (4/0.5 g q6h with 30 min infusion) achieved a 90% probability of target attainment (PTA) for 50%fT>MIC at MIC values up to 4 mg/L in patients with normal renal function. However, this regimen often did not achieve a 90% PTA for stringent targets (100%fT>MIC, 100%fT>4MIC) or higher MICs, particularly in patients with eGFR ≥ 130 mL/min. Conclusions: These findings suggest current dosing regimens may be inadequate and highlight the potential of alternative strategies, such as extended or continuous infusion, which warrant further investigation in clinical populations to optimize therapeutic outcomes. Full article
(This article belongs to the Special Issue Therapeutic Drug Monitoring and Adverse Drug Reactions: 2nd Edition)
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