Search Results (7,907)

Background/Objectives: T cell dysfunction represents a fundamental barrier to effective cancer immunotherapy. Although immune checkpoint blockades and adoptive cell transfer have achieved clinical success, therapeutic resistance remains prevalent across cancer types. Thymopentin (TP5), a synthetic immunomodulatory pentapeptide (Arg-Lys-Asp-Val-Tyr), has demonstrated immunostimulatory properties, yet its anticancer potential remains unexplored. The aim of this study was to investigate TP5’s antitumor efficacy and underlying immunological mechanisms. Methods: We evaluated TP5’s therapeutic effects in multiple murine tumor models, including B16-F10 melanoma, MC38 colorectal carcinoma, Hepa 1-6, and LM3 hepatocellular carcinoma. Immune cell populations and functional states were characterized using flow cytometry, ELISAs, and immunofluorescence analyses. The potential of TP5 as an adjuvant for T cell-based therapies was also systematically assessed. Results: The TP5 treatment markedly suppressed tumor growth across caner models through strictly T cell-dependent mechanisms. Critically, TP5 promoted thymic rejuvenation under immunocompromised conditions, restoring the thymus–tumor immunological balance and revitalizing peripheral T cell immunity. TP5 functionally reprogrammed T cell states, preserving effector function while ameliorating exhaustion. Furthermore, TP5 demonstrated synergistic efficacy when combined with adoptive T cell therapies, enhancing both proliferation and effector functions. Conclusions: TP5 represents a promising immunomodulator that addresses fundamental limitations of current T cell therapies by simultaneously enhancing T cell function and reversing thymic involution under immunocompromised conditions. Our findings provide compelling evidence for TP5’s clinical translation in cancer treatment. Full article

Cryopreservation and transplantation of intact ovaries offer a promising approach to fertility restoration in cancer patients. However, ischemia–reperfusion injury following transplantation significantly impairs graft function. This study aimed to evaluate the protective effects of melatonin and elucidate its underlying mechanisms of action, including antioxidant and anti-inflammatory properties. Intact ovaries from 8 to 12-week-old LEWIS rats were cryopreserved and subsequently transplanted. Melatonin (25 mg/kg and 50 mg/kg) was administered daily from day 1 to day 4 postoperatively. Estrous cycle recovery and ovarian histology were examined, along with measurements of hormone concentrations, antioxidant activity, and inflammatory mediators. The oxidative stress response, particularly the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signaling pathway—including Nrf2, Kelch-like ECH-associated protein 1 (Keap1), and sMafg—was investigated to elucidate melatonin’s protective mechanisms. The roles of melatonin receptors and Nrf2 were investigated using specific receptor antagonists (Luzindole, 4P-PDOT) and an inhibitor (ML385) to confirm the involvement of the MT1/Nrf2/ARE pathway. As a result, rats treated with high-dose melatonin (50 mg/kg) exhibited accelerated estrous cycle recovery, reduced follicular loss, improved serum hormone levels, enhanced antioxidant capacity in serum and ovarian tissue, and decreased levels of inflammatory cytokines. Furthermore, melatonin exerted its antioxidant and anti-inflammatory effects through activation of the Nrf2/ARE signaling pathway via the MT1 receptor. These protective effects were abolished by the inhibition of either Nrf2 or MT1 receptor. In conclusion, these findings demonstrate that melatonin mitigates oxidative stress and inflammatory damage in intact transplanted ovaries through the MT1/Nrf2/ARE signaling axis, thereby preserving ovarian function post-transplantation. Full article

Post-fire soil and vegetation changes can intensify erosion and sediment yield by altering the factors controlling the runoff–infiltration balance. Erosion barriers (EBs) are widely used in hydrological and forest restoration to mitigate erosion, reduce sediment transport, and promote vegetation recovery. However, precise spatial assessments of their effectiveness remain scarce, requiring validation through operational methodologies. This study evaluates the impact of EB on post-fire vegetation recovery at two temporal and spatial scales: (1) Remotely Piloted Aircraft System (RPAS) imagery, acquired at high spatial resolution but limited to a single acquisition date coinciding with the field flight. These data were captured using a MicaSense RedEdge-MX multispectral camera and an RGB optical sensor (SODA), from which NDVI and vegetation height were derived through aerial photogrammetry and digital surface models (DSMs). (2) Sentinel-2 satellite imagery, offering coarser spatial resolution but enabling multi-temporal analysis, through NDVI time series spanning four consecutive years. The study was conducted in the area of the Luna Fire (northern Spain), which burned in July 2015. A paired sampling design compared upstream and downstream areas of burned wood stacks and control sites using NDVI values and vegetation height. Results showed slightly higher NDVI values (0.45) upstream of the EB (p < 0.05), while vegetation height was, on average, ~8 cm lower than in control sites (p > 0.05). Sentinel-2 analysis revealed significant differences in NDVI distributions between treatments (p < 0.05), although mean values were similar (~0.32), both showing positive trends over four years. This study offers indirect insight into the functioning and effectiveness of EB in post-fire recovery. The findings highlight the need for continued monitoring of treated areas to better understand environmental responses over time and to inform more effective land management strategies. Full article

The human microbiome is a critical factor in health and disease. While its association with breast cancer (BC) has been increasingly studied, this review provides a dedicated synthesis of the microbiota’s role in benign breast diseases (BBDs)—a common yet microbiologically overlooked spectrum of conditions. The primary aim of this work is to consolidate the current understanding of the composition, origins, and functional mechanisms of the mammary gland (MG) microbiota specifically in the context of BBD and to evaluate its potential for novel diagnostic and therapeutic targets. We detail the distinct MG microbiota, formed via exogenous (e.g., cutaneous, translocation) and endogenous (e.g., enteromammary, lymphohematogenous) pathways, and its interaction with the host through estrogen metabolism, immunomodulation, and epigenetic modifications. This narrative review reveals unique dysbiotic patterns in BBD, characterized by distinct microbial signatures, such as the enrichment of Corynebacterium kroppenstedtii in granulomatous mastitis and the presence of Staphylococcus aureus in fibroadenomas and lactational mastitis. Furthermore, specific gut microbial profiles are identified in BBD patients, including an increased abundance of genera such as Clostridium and Faecalibacterium, alongside a decrease in Collinsella and Alistipes compared to healthy controls. These specific taxa represent compelling candidates for diagnostic biomarkers. We conclude that microbial dysbiosis is a significant component of BBD pathogenesis. A paradigm shift toward multi-omics approaches and mechanistic studies is now essential to translate these associations into clinical applications. Understanding the BBD-specific microbiome holds the promise of revolutionizing patient care through microbiota-based diagnostics for differentiating benign subtypes and novel, personalized therapeutic strategies aimed at restoring microbial homeostasis. Full article

Penile prosthetic implants (PPIs) provide a definitive surgical solution for individuals requiring restoration of erectile function, most commonly due to medication-refractory erectile dysfunction (ED) or as part of gender-affirming surgical care. During the Anatomical Foundations of Clinical Practice (AFCP) course at Oakland University William Beaumont (OUWB) School of Medicine, a complete three-piece inflatable PPI was identified in a 66-year-old male donor with a medical history of congestive heart failure, hypertension, and diabetes mellitus type 2. The prosthesis included a fluid reservoir positioned in the lower abdominal cavity in the retropubic space, a scrotal pump with a release valve, and paired inflatable cylinders embedded within the penile shaft. This uncommon finding provided first-year medical students with a hands-on opportunity to examine the structure, placement, and function of a modern PPI. In addition to reinforcing foundational knowledge of ED treatment, the case highlighted the expanding clinical indications for penile implants, including their potential role in gender-affirming procedures. Integrating such real-world surgical findings into anatomical education enriches the learning experience of students and highlights the evolving scope of prosthetic urology across diverse patient populations. Full article

This narrative review addresses the complexities of managing the vertical dimension of occlusion (VDO) in restorative dentistry, focusing on predictability in prosthetic reconstructions. Altering VDO impacts biological, biomechanical, esthetic, and functional aspects, making it a controversial topic. While VDO naturally evolves throughout life, interventions require careful consideration due to potential complications. Various techniques guide VDO determination, including facial proportions, physiological methods, phonetics, and cephalometric analysis. Clinicians must understand these principles and adapt them to individual patient needs. Materials and Methods: A narrative literature review was conducted using PubMed, Scopus, Google Scholar, and the Cochrane Library, searching keywords like “vertical dimension of occlusion”, “dental”, “diagnosis”, “management” and “complications”. In addition to the literature review, two case reports with extensive prosthodontic restorations were included to illustrate the diagnostic challenges and treatment considerations in a clinical setting. Results: Increasing VDO aids restorative treatments, re-establishing morphology, and facilitating additive procedures. Minimally invasive approaches, provisional restorations, and fixed restorations with functional contours are favored. Individualized, patient-centered care is critical, recognizing unique anatomical and functional needs. This approach optimizes stomatognathic system rehabilitation while preventing adverse effects on body posture and airway dimensions. Conclusions: To ensure predictable results and minimize risks, changes in VDO should be kept to a minimum to achieve dentofacial aesthetic harmony and secure adequate space for the planned restorations The two case reports presented, with different clinical approaches, underline the importance of understanding the potential risks and benefits of VDO alteration which is crucial for achieving predictable and successful outcomes in complex restorative cases. Full article

Background: Dahuang Xiaoshi Tang (DXT), an ancient Chinese herbal remedy dating back to 220 AD, as documented initially in “Treatise on Febrile and Miscellaneous Diseases,” is used to treat damp-heat jaundice with interior sthenia syndrome. In DXT, anthraquinones and alkaloids form insoluble complexes, reducing its effectiveness. A revised herbal extract, DXT-M, was developed, and its hepatoprotective properties were demonstrated in animal models using pharmacodynamic, metabolomic, network pharmacological, and toxicological approaches. Methods: The α-naphthalene isothiocyanate was utilised to establish the acute liver injury rat model. The assays of glutamate pyruvate transaminase, glutamic oxalacetic transaminase, alkaline phosphatase, bilirubin, total bile acid, complement 3 (C3) and C4, interleukin-2 (IL-2) and IL-6, tumour necrosis factor α (TNF-α), and pathological morphology were used to evaluate the hepatoprotection of DXT in comparison to DXT-M. The ¹H-NMR-based serum and urine metabolomics were performed to identify potential biomarkers and metabolic pathways of DXT-M in treating hepatitis. The intrinsic regulatory mechanisms of DXT in liver protection, as well as the combination of network toxicology, were elucidated. Statistical analyses included RM two-way ANOVA with Geisser–Greenhouse correction and Dunnett’s post hoc test for longitudinal data, and one-way ANOVA with Dunnett’s post hoc test for group comparisons. Data were shown as mean ± SD. Results: Liver-injured animals exhibited weight loss, ruffled fur, and liver damage, accompanied by elevated liver function indicators. DXT-M effectively improved these symptoms, repaired liver damage, restored liver function, and regulated immune status by modulating complement 3. Metabonomics and other analyses indicated the CYP/GST-ROS axis is key to its hepatoprotective effects. DXT-M outperformed DXT in efficacy. Conclusions: DXT-M demonstrated significant effectiveness in restoring liver pathological damage, correcting abnormal biochemical indicators of liver function, and regulating complement factors. The pathway of CYP/GST-ROS served as the shared regulatory axis and transformation site for DXT-M’s liver protective effects. These findings suggest that DXT-M has potential as a treatment for acute liver injury, highlighting the need for further research into its underlying molecular mechanisms as well as its complete material basis. This study’s main limitation is its focus on acute models; future research should include other liver diseases and clinical observation to evaluate its full potential. Full article

Infertility remains a major global health concern, with diminished ovarian reserve (DOR), premature ovarian insufficiency (POI), polycystic ovary syndrome (PCOS), and impaired endometrial receptivity representing key contributors to poor assisted reproductive technology (ART) outcomes. Platelet-rich plasma (PRP), an autologous blood-derived concentrate enriched with growth factors and cytokines, has emerged as a promising regenerative therapy with angiogenic, anti-apoptotic, and proliferative properties. In reproductive medicine, intraovarian PRP has been evaluated for its potential to restore ovarian function in women with DOR and POI, improve oocyte competence and embryo euploidy, and promote ovulation in PCOS. Similarly, intrauterine PRP infusion or subendometrial zone injections has shown encouraging results in women with recurrent implantation failure and thin endometrium, enhancing endometrial thickness, receptivity, and implantation potential. Evidence from preclinical animal models and early clinical studies suggests multi-level mechanisms of action, including modulation of endocrine pathways, reduction in oxidative stress, activation of dormant follicles, and improvement of endometrial angiogenesis and receptivity. Despite these promising findings, results remain inconsistent due to heterogeneity in PRP preparation protocols, administration routes, timing, and study designs. Even though robust randomized controlled trials with standardized methodologies are needed to determine the efficacy and long-term reproductive outcomes of PRP in infertility treatment and anovulation in PCOS, PRP represents a novel and potentially transformative adjunct in reproductive endocrinology. Full article

The perforation of the tympanic membrane is a world-wide clinical problem resulting from trauma or infection and requiring effective regeneration methods. In recent years researchers have focused on natural polymers as promising materials for restoring the structure and function of the tympanic membrane. This review summarizes current advances in the use of natural polymers, such as silk fibroin, chitosan, hyaluronic acid, collagen, bacterial cellulose, alginates and others, for the treatment of tympanic membrane perforations. The key properties of these materials are discussed, including their biocompatibility, biodegradability, mechanical strength, and ability to support cell adhesion and proliferation. The review also covers the potential of natural polymers and their combinations in tympanic membrane regeneration and suggests the directions for future research. Full article

MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis, as well as lipid and glucose metabolism, in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome, as it restores metabolic capacity—enhancing oxidative metabolism—and reduces ectopic fat accumulation in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for the inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis while protecting dystrophic mice from muscle function decline, enhancing fatigue resistance, and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis, favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle atrophy and support its potential to restore muscle health. Full article

Under the combined effects of climate change, overexploitation, and intense grazing, temperate steppe in northern China is experiencing increasing deterioration, which is typified by a shift from structural degradation to functional disruption. Accurately tracking steppe degradation using remote sensing technology has emerged as a crucial scientific concern. Prior research failed to integrate ecosystem structure and function and lacked reference baselines, relying only on individual indicators to quantify degradation. To resolve these gaps, this study established a novel degradation evaluation index system integrating ecosystem structure and function, incorporating vegetation community distribution and proportions of degradation-indicator species to define reference states and quantify degradation severity. Analyzed spatiotemporal evolution and drivers across the temperate typical steppe (2013–2022). Key findings reveal (1) non-degraded and slightly degraded areas dominated (75.57% mean coverage), showing an overall fluctuating improvement trend; (2) minimal transitions between degradation levels, with stable conditions prevailing (59.52% unchanged area), indicating progressive degradation reversal; and (3) natural factors predominated as degradation drivers. The integrated structural–functional framework enables more sensitive detection of early degradation signals, thereby informing more effective steppe restoration management. Full article

The restoration of “Heitutan” degraded grasslands on the Qinghai-Tibetan Plateau was hindered by suboptimal grass species mixtures, leading to low vegetation productivity, impaired soil nutrient cycling, and microbial functional degradation. Based on a 22-year controlled field experiment, this study systematically elucidated the regulatory mechanisms of different artificial grass mixtures on vegetation community characteristics, soil physicochemical properties, and bacterial community structure and function. The results demonstrated that mixed-sowing treatments significantly improved soil conditions and enhanced aboveground biomass. The HC treatment (Elymus nutans Griseb. + Poa crymophila Keng ex L. Liu cv. ‘Qinghai’ + Festuca sinensis Keng ex S. L. Lu cv. ‘Qinghai’) achieved aboveground biomass of 1580.0 and 1645.0 g·m⁻², representing 66.14% and 60.91% increases, respectively, compared to the HA monoculture (E. nutans). Concurrently, this treatment increased soil organic matter content by 52.3% and 48.4%, total nitrogen by 59.4% and 69.2%, while reducing electrical conductivity by 48.99% and 51.72%, with optimal pH stabilization (7.34–7.38). These findings confirmed that optimized grass mixtures effectively enhance soil physicochemical properties and carbon–nitrogen retention. Microbiome analysis revealed that the HE treatment (E. nutans + P. crymophila + F. sinensis + Poa poophagorum Bor. + Festuca kryloviana Reverd. cv. ‘Huanhu’) exhibited superior α-diversity indices (OTU, Shannon, Ace, Chao1, Pielou) with increases of 9.36%, 4.20%, 15.0%, 1.76%, and 13.4%, respectively, over HA, accompanied by optimal community evenness (lowest Simpson index). Core bacterial phyla included Pseudomonadota (22.7–29.9%), Acidobacteriota (21.5–23.6%), and Actinomycetota (13.6–16.0%), with significant suppression of pathogenic bacteria. Co-occurrence network analysis identified specialized functional modules, with HC and HD treatments (E. nutans + P. crymophila + F. sinensis + P. poophagorum) forming a “nitrogen transformation–antibiotic secretion” network (57.3% positive connections). Structural equation modeling (SEM) revealed that mixed sowing had the strongest direct effect on bacterial diversity (β = 0.76), surpassing indirect effects via soil (β = 0.37) and vegetation (β = 0.11). Redundancy analysis (RDA) identified vegetation cover (24.7% explained variance) and soil pH (20.0%) as key drivers of bacterial community assembly. Principal component analysis (PCA) confirmed HC and HD treatments as the most effective restoration strategies. This study elucidated a tripartite “vegetation–soil–microorganism” restoration mechanism, demonstrating that intermediate-diversity mixtures (3–4 species) optimize ecosystem recovery through niche complementarity, pathogen suppression, and enhanced nutrient cycling. These findings provided a scientific basis for species selection in alpine grassland restoration. Full article

The parallel global increase in obesity and Alzheimer’s disease (AD) underscores an urgent public health challenge, with converging evidence indicating that metabolic dysfunction strongly contributes to neurodegeneration. Obesity is now recognized not only as a systemic metabolic condition but also as a modifiable risk factor for AD, acting through mechanisms such as chronic low-grade inflammation, insulin resistance, and adipose tissue dysfunction. Among the molecular mediators at this interface, adipokines have emerged as pivotal regulators linking metabolic imbalance to cognitive decline. Adipokines are hormone-like proteins secreted by adipose tissue, including adiponectin, leptin, and resistin, that regulate metabolism, inflammation and can influence brain function. Resistin, frequently elevated in obesity, promotes neuroinflammation, disrupts insulin signaling, and accelerates β-amyloid (Aβ) deposition and tau pathology. Conversely, adiponectin enhances insulin sensitivity, suppresses oxidative stress, and supports mitochondrial and endothelial function, thereby exerting neuroprotective actions. The imbalance between resistin and adiponectin may shift the central nervous system toward a pro-inflammatory and metabolically compromised state that predisposes to neurodegeneration. Beyond their mechanistic relevance, adipokines hold translational promise as biomarkers for early risk stratification and therapeutic monitoring. Importantly, natural compounds, including polyphenols, alkaloids, and terpenoids, have shown the capacity to modulate adipokine signaling, restore metabolic homeostasis, and attenuate AD-related pathology in preclinical models. This positions adipokines not only as pathogenic mediators but also as therapeutic targets at the intersection of diabetes, obesity, and dementia. By integrating mechanistic, clinical, and pharmacological evidence, this review emphasizes adipokine signaling as a novel axis for intervention and highlights natural compound-based strategies as emerging therapeutic approaches in obesity-associated AD. Beyond nutraceuticals, antidiabetic agents also modulate adipokines and AD-relevant pathways. GLP-1 receptor agonists, metformin, and thiazolidinediones tend to increase adiponectin and reduce inflammatory tone, while SGLT2 and DPP-4 inhibitors exert systemic anti-inflammatory and hemodynamic benefits with emerging but still limited cognitive evidence. Together, these drug classes offer mechanistically grounded strategies to target the adipokine–inflammation–metabolism axis in obesity-associated AD. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving the progressive degeneration of upper and lower motor neurons. While oxidative stress, RNA-binding protein (RBP) pathology, mitochondrial dysfunction, and glial–neuronal dysregulation is involved in ALS pathogenesis, current therapies provide limited benefit, underscoring the need for multi-target disease-modifying strategies. Nuclear factor erythroid 2-related factor 2 (Nrf2), classically regarded as a master regulator of redox homeostasis, has recently emerged as a central integrator of cellular stress responses relevant to ALS. Beyond its canonical antioxidant function, Nrf2 regulates critical pathways involved in mitochondrial quality control, proteostasis, nucleocytoplasmic transport, RNA surveillance, and glial reactivity. Experimental models demonstrate that astrocyte-specific Nrf2 activation enhances glutathione metabolism, suppresses neuroinflammation, promotes stress granule disassembly, and reduces RBP aggregation. In C9orf72-linked ALS, Nrf2 activation mitigates dipeptide repeat protein toxicity and restores RNA processing fidelity via modulation of nonsense-mediated decay and R-loop resolution. Recent advances in Nrf2-targeted interventions including Keap1–Nrf2 protein–protein interaction inhibitors, dual Nrf2/HSF1 activators, and cell-type-selective Adeno-associated virus 9 (AAV9) vectors show promise in preclinical ALS models. These multimodal approaches highlight Nrf2’s therapeutic versatility and potential to address the upstream convergence points of ALS pathogenesis. Taken together, positioning Nrf2 as a systems-level regulator offers a novel framework for developing precision-based therapies in ALS. Integrating Nrf2 activation with RNA- and glia-directed strategies may enable comprehensive modulation of disease progression at its molecular roots. Full article

Objective: This article evaluates the reconstructive potential and functional outcomes, as well as the risks and potential perioperative complications of using free flaps in patients with advanced-stage malignant laryngeal neoplasms who require salvage surgery and reconstruction. Additionally, it assesses the effectiveness of various flap harvesting and in-setting techniques, including the performance of microvascular anastomoses. Materials and Methods: This retrospective study included 13 male patients (age range 47–76 years) diagnosed with laryngeal neoplasms, who were referred to the Department of Otolaryngology at the University of Verona between 2017 and 2022. All patients underwent salvage total laryngectomy followed by concurrent reconstructive surgery utilizing microvascular flaps. Recovery of function (phonation) and incidence of complications were evaluated in a follow-up of at least three years. Results: Only one patient experienced necrotic failure of the microvascular free flap, probably due to post-op complications. The patient required revision on the 10th day after surgery and was reconstructed using a pedicled pectoralis major muscle flap. Two patients developed a pharyngocutaneous fistula. Other three patients had pharyngoesophageal stenosis, two experienced recurrence, and one patient passed away due to septic shock. All patients achieved satisfactory functional outcomes regarding vocalization, while complete oral intake was restored in eight patients. Conclusions: Considering the limited sample size, the findings suggest that microvascular flaps represent a feasible option for reconstructing advanced laryngeal tumors, though complication rate may still be considerable. Tailoring reconstructive approaches to individual patients may enhance surgical outcomes. Full article