Search Results (1,469)

Background: Aging is a complex biological process characterized by the accumulation of molecular and cellular damage over time, often driven by oxidative stress. This oxidative stress is particularly detrimental to the testes, where it causes degeneration, reduced testosterone levels, and compromised fertility. D-galactose (D-gal) is commonly used to model aging as it induces oxidative stress, mimicking age-related cellular and molecular damage. Testicular aging is of significant concern due to its implications for reproductive health and hormonal balance. This research examines the protection by thymoquinone (TQ) or thymoquinone-loaded chitosan nanoparticles (NCPs) against D-galactose (D-gal)-induced aging in rat testes, focusing on biochemical, histological, and molecular changes. Aging, which is driven largely by oxidative stress, leads to significant testicular degeneration, reducing fertility. D-gal is widely used to model aging due to its ability to induce oxidative stress and mimic age-related damage. TQ, a bioactive ingredient of Nigella sativa, has earned a reputation for its anti-inflammatory, anti-apoptotic, and antioxidant characteristics, but its therapeutic application is limited by its poor bioavailability. Methods: Thymoquinone was loaded into chitosan nanoparticles (NCPs) to enhance its efficacy, and this was hypothesized to improve its stability and bioavailability. Four groups of male Wistar rats participated in the study: one for the control, one for D-gal, one for D-gal + TQ, and the last one for D-gal + NCP. Results: The results exhibited that D-gal substantially increased oxidative injury, reduced testosterone levels, and caused testicular damage. Treatment with TQ and NCPs significantly reduced oxidative stress, improved antioxidant enzyme levels, and restored testosterone levels, with NCPs showing a stronger protective effect than TQ alone. A histological analysis confirmed that NCPs better preserved testicular structure and function. Additionally, the NCP treatment upregulated the expression of key genes of oxidative stress resistance, mitochondrial function, and reproductive health, including SIRT1, FOXO3a, and TERT. Conclusions: The findings suggest that NCPs offer enhanced protection against aging-related testicular damage compared with TQ alone, which is likely due to the improved bioavailability and stability provided by the nanoparticle delivery system. This research emphasizes the potential of NCPs as a more effective therapeutic strategy for mitigating oxidative stress and age-related reproductive dysfunction. Future research should further explore the mechanisms underlying these protective effects. Full article

Diabetic wound healing presents significant challenges due to impaired angiogenesis, chronic inflammation, and cellular dysfunction. Building on previous research, this study further explores the potential of a plant-derived glucosyloxybenzyl 2-isobutylmalates (B-CGT) hydrogel in promoting diabetic wound healing. Network pharmacology and molecular docking analyses suggest that B-CGT may regulate key mechanisms, such as apoptosis, inflammation, and matrix remodeling, through core targets including SIRT1, CASP8, and MMP8. In vivo studies further demonstrated that B-CGT hydrogel significantly accelerated wound closure in diabetic mice, enhanced angiogenesis, promoted collagen deposition, and achieved immune balance by modulating macrophage polarization, thereby shifting the inflammatory environment toward a repair state. Moreover, B-CGT hydrogel significantly improved the wound microenvironment by upregulating VEGF expression and exerting antioxidant effects. By combining theoretical predictions with experimental validation, this study elucidates the multi-target synergistic regulatory mechanisms of B-CGT hydrogel. These findings provide new research directions for addressing immune imbalance and angiogenesis defects in diabetic wound healing and lay a scientific foundation for the optimization and application of chronic wound treatment strategies. Full article

Background and aims: Ginsenoside compound K (CK), a saponin metabolite of ginseng, exerts anticancer effects; however, its molecular mechanisms of action in lung cancer remain unclear. We investigated the involvement of silent information regulator 6 (SIRT6) and poly (ADP-ribose) polymerase 1 (PARP-1) in the anticancer effects of CK in lung cancer. Methods and Results: CK induced PARP-1 activation-mediated parthanatos via sequestosome-1/p62-mediated SIRT6 degradation and inhibited the proliferation of H460 cells. Although CK reduced procaspase-8 levels, no significant apoptotic cleavage of procaspase-3 or PARP-1 was observed. Furthermore, CK upregulated p27, p21, phospho-p53, and gamma-H2AX levels. CK increased LC3-II levels in a p62-independent manner, but p62 was upregulated by autophagy inhibition, indicating that p62 is involved in CK-induced autophagy. CK-treated cells showed typical features of parthanatos, including PARP-1 hyperactivation, intracellular redistribution of poly ADP-ribose and pro-apoptotic factors, and chromatin fragmentation. SIRT6 was degraded in a CK concentration- and time-dependent manner. SIRT6 protein was upregulated by PARP-1 inhibition, nicotinamide adenine dinucleotide (NAD)+ supplementation, antioxidants, and p62 knockdown, but was decreased by autophagy blockade. PARP-1 activation was negatively correlated with SIRT6 levels, indicating that SIRT6 and PARP-1 activation play complementary roles in CK-induced growth inhibition. Immunofluorescence staining, fractionation studies, and immunoprecipitation were used to confirm the colocalization and interaction between p62 and SIRT6. Conclusions: PARP-1 activation is promoted by p62-mediated SIRT6 degradation, which plays an important role in CK-induced growth inhibition. Therefore, SIRT6 is a potential biomarker for the chemopreventive effect of CK in lung cancer cells, but further studies on SIRT6 are needed for the clinical application of CK. Full article

Diabetic patients experience hyperglycemia, which can affect multiple organs, including brain function, leading to disabling neurological complications. Hyperglycemia plays a key role in promoting neuroinflammation, the most common complication in diabetic individuals, through the activation of microglia. Attenuating hyperglycemia-related neuroinflammation in microglia may reduce diabetes-associated neurological comorbidities. Natural remedies containing phenolic compounds have shown efficacy in mitigating microglia-mediated neuroinflammation. The aim of this study was to investigate the potential of a Melissa officinalis L. (MO) phytocomplex, obtained from plant cell cultures and enriched in its main polyphenolic constituent, rosmarinic acid (RA), in attenuating hyperglycemia-induced neuroinflammation in microglia. A time-course morphological analysis of BV2 microglial cells exposed to high glucose (HG) levels showed a shift towards a proinflammatory phenotype, peaking after 48 h, which was reversed by pretreatment with MO. Biochemical assays revealed increased expression of the microglial marker CD11b (187%), activation of the NF-κB pathway (179%), expression of iNOS (225%), enhanced phosphorylation of ERK1/2 (180%), and increased expression of the proinflammatory cytokine IL-6 (173%). Pretreatment with MO prevented the aberrant expression of these proinflammatory mediators and restored SIRT1 levels. Exposure of neuronal SH-SY5Y cells to the conditioned medium from HG-exposed microglia significantly reduced cell viability. MO counteracted this effect, exhibiting neuroprotective activity. RA showed efficacy comparable to that of MO. In conclusion, MO and RA attenuated microglia-mediated oxidative imbalance and neuroinflammation under HG exposure by inhibiting the morphological shift toward a proinflammatory phenotype induced by HG and abrogating the subsequent activation of the downstream ERK1/2–NF-κB–iNOS pathway. Full article

Obesity results from a disproportionate accumulation of fat and has become a global health concern. The increase in adipose tissue is responsible for several systemic and testicular changes including hormone levels (leptin, adiponectin, testosterone, estrogen), inflammatory cytokines (increase in TNF-α and IL-6 and decrease in IL-10), and redox state (increase in reactive oxygen species and reduction in antioxidant enzymes). This results in poor sperm quality and compromised fertility in men with obesity. Lifestyle modifications, particularly diet transition to caloric restriction and physical exercise, are reported to reverse these negative effects. Nevertheless, precise mechanisms mediating these benefits, including how they modulate testicular oxidative stress, inflammation, and metabolism, remain to be fully elucidated. The main pathway described by which these lifestyle interventions reverse obesity-induced oxidative damage is the Nrf2-SIRT1 axis, which modulates the overexpression of antioxidant defenses. Of note, some of the detrimental effects of obesity on the testis are inherited by the descendants of individuals with obesity, and while caloric restriction reverses some of these effects, no significant work has been carried out regarding physical exercise. This review discusses the consequences of obesity-induced testicular oxidative stress on adult and pediatric populations, emphasizing the therapeutic potential of lifestyle to mitigate these detrimental effects. Full article

Enterovirus 68 (EV-D68) is a non-enveloped virus with a positive-sense single-stranded RNA genome that causes respiratory diseases and acute flaccid myelitis, posing significant threats to human health. However, an effective vaccine remains undeveloped. SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent enzyme, plays a key role in cellular metabolism, but its interaction with NAD+ during viral infections is not well understood. In this study, through a metabolomics analysis, we demonstrate that EV-D68 infection influences cellular metabolism. Additionally, we show that NAD+ inhibits EV-D68 infection both in vivo and in vitro. EV-D68 reduces cellular NAD+ levels by regulating the expression of enzymes involved in NAD+ consumption and synthesis. Moreover, the infection increases the expression of sirtuin 1 (SIRT1), which inhibits EV-D68 replication in turn. Mechanistically, SIRT1 suppresses EV-D68 5′UTR-mediated translation, and the antiviral effect of SIRT1 on EV-D68 replication is enhanced by NAD+. Collectively, our findings highlight the critical role of NAD+ metabolism in EV-D68 infection and reveal the antiviral potential of SIRT1, providing valuable insights for the development of antiviral strategies. Full article

Mitochondria play a central role in cell biological processes, functioning not only as producers of ATP but also as regulators of Ca²⁺ signaling. Mitochondrial calcium uptake occurs primarily through the mitochondrial calcium uniporter channel (mtCU), with the mitochondrial calcium uptake subunits 1, 2, and 3 (MICU1, MICU2, and MICU3) serving as the main regulatory components. Dysregulated mitochondrial calcium uptake is a hallmark of cellular degeneration. Sirtuin 1 (SIRT1), a key regulator of cellular metabolism, plays a critical role in aging and various neurodegenerative conditions. By blocking SIRT1 using EX527 or shSIRT1, we observed mitochondrial structural fragmentation as well as intensified and prolonged mitochondrial calcium overload. Our study revealed a direct interaction between SIRT1 and MICU1. Notably, SIRT1 inhibition resulted in reduced MICU1 expression, hence led to mitochondrial calcium overload, illustrating the unconventional role of SIRT1 in governing mitochondrial function. Full article

Background: Cellular senescence is a biological process with a dual role in organismal health. While transient senescence supports tissue repair and acts as a tumor-suppressive mechanism, the chronic accumulation of senescent cells contributes to aging and the progression of age-related diseases. Senotherapeutics, including senolytics, which selectively eliminate senescent cells, and senomorphics, which modulate the senescence-associated secretory phenotype (SASP), have emerged as promising strategies for managing age-related pathologies. Among these, polyphenols, a diverse group of plant-derived bioactive compounds, have gained attention for their potential to modulate cellular senescence. Methods: This review synthesizes evidence from in vitro, in vivo, and clinical studies on the senolytic and senomorphic activities of bioactive polyphenols, including resveratrol, kaempferol, apigenin, and fisetin. The analysis focuses on their molecular mechanisms of action and their impact on fundamental aging-related pathways. Results: Polyphenols exhibit therapeutic versatility by activating SIRT1, inhibiting NF-κB, and modulating autophagy. These compounds demonstrate a dual role, promoting the survival of healthy cells while inducing apoptosis in senescent cells. Preclinical evidence indicates their capacity to reduce SASP-associated inflammation, restore tissue homeostasis, and attenuate cellular senescence in various models of aging. Conclusions: Polyphenols represent a promising class of senotherapeutics for mitigating age-related diseases and promoting healthy lifespan extension. Further research should focus on clinical validation and the long-term effects of these compounds, paving the way for their development as therapeutic agents in geriatric medicine. Full article

Understanding hormonal and molecular changes during the transition from preterm to near-term gestation is essential for investigating how pregnancy complications impact fetal heart development and contribute to long-term cardiovascular risks for offspring. This study examines these cardiac changes in fetal sheep, focusing on the changes between 116 days (preterm) and 140 days (near term) of gestation (dG, term = 150) using Western blotting, LC-MS/MS, and histological techniques. We observed a strong correlation between cortisol and T₃ (Triiodothyronine) in heart tissue in near-term fetuses, highlighting the role of glucocorticoid signalling in fetal heart maturation. Protein expression patterns in the heart revealed a decrease in multiple glucocorticoid receptor isoforms (GRα-A, GR-P, GR-A, GRα-D2, and GRα-D3), alongside a decrease in IGF-1R (a marker of cardiac proliferative capacity) and p-FOXO1(Thr24) but an increase in PCNA (a marker of DNA replication), indicating a shift towards cardiomyocyte maturation from preterm to near term. The increased expression of proteins regulating mitochondrial biogenesis and OXPHOS complex 4 reflects the known transition from glycolysis to oxidative phosphorylation, essential for meeting the energy demands of the postnatal heart. We also found altered glucose transporter expression, with increased pIRS-1(ser789) and GLUT-4 but decreased GLUT-1 expression, suggesting improved insulin responsiveness as the heart approaches term. Notably, the reduced protein abundance of SIRT-1 and SERCA2, along with increased phosphorylation of cardiac Troponin I(Ser23/24), indicates adaptations for more energy-efficient contraction in the near-term heart. In conclusion, these findings show the complex interplay of hormonal, metabolic, and growth changes that regulate fetal heart development, providing new insights into heart development that are crucial for understanding pathological conditions at birth and throughout life. Full article

Winemaking by-products, such as grape pomace and grape seed oil, provide sustainable and eco-friendly resources for cosmetics and are rich in bioactive compounds like phenolic bioactives, proteins, and lipids (i.e., unsaturated fatty acids, bioactive polar lipids, and carotenoids). These compounds, extracted using advanced techniques such as ultrasound, microwave, and enzyme-assisted methods, exhibit antioxidant, antimicrobial, anti-aging, and anti-inflammatory properties. In vitro and in vivo studies on keratinocytes and fibroblasts demonstrate their efficacy in enhancing skin hydration, elasticity, and UV protection while reducing oxidative stress and inflammation through pathways like SIRT1 and HSP47. Encapsulation techniques further improve their stability and bioavailability. The aim of this review is to investigate in detail the advanced techniques for the extraction of bioactive compounds from winemaking by-products and to evaluate their effectiveness in the isolation of phenolic compounds, proteins, and lipids. At the same time, it focuses on the application of the extracted compounds in the cosmetics industry, highlighting their contribution to products with antioxidant, anti-aging, antimicrobial, and anti-inflammatory properties. Finally, special emphasis is given to encapsulation techniques to improve their stability and bioavailability, with the aim of developing innovative and sustainable cosmetic products. Full article

This study compares dosimetric approaches for lung dosimetry in ¹⁶⁶ radioembolization (Ho-TARE) with direct Monte Carlo (MC) simulations on a voxelized anthropomorphic phantom derived from a real patient’s CT scan, preserving the patient’s lung density distribution. Lung dosimetry was assessed for five lung shunt (LS) scenarios with conventional methods: the mono-compartmental organ-level approach (MIRD), voxel S-value convolution for soft tissue (kST, ICRU soft tissue with 1.04 g/cm³) and lung tissue (kLT, ICRU lung tissue with 0.296 g/cm³), local density rescaling (kST_L and kLT_L, respectively, for soft tissue and lung tissue), or global rescaling for a lung mean density of 0.221 g/cm³ (kLT₂₂₁). Significant underestimations in the mean absorbed dose (AD) were observed, with relative differences with respect to the reference (MC) of −64% for MIRD, −93% for kST, −56% for kST_L, −76% for kLT, −68% for kLT₂₂₁, and −60% for kLT_L. Given the high heterogeneity of lung tissue, standard dosimetric approaches cannot accurately estimate the AD. Additionally, MC results for ¹⁶⁶Ho showed notable spatial absorbed dose inhomogeneity, highlighting the need for tailored lung dosimetry in Ho-TARE accounting for the patient-specific lung density distribution. MC-based dosimetry thus proves to be essential for safe and effective radioembolization treatment planning in the presence of LS. Full article

Autophagy and mitophagy are critical cellular processes that maintain homeostasis by removing damaged organelles and promoting cellular survival under stress conditions. In the context of diabetic kidney disease, these mechanisms play essential roles in mitigating cellular damage. This review provides an in-depth analysis of the recent literature on the relationship between autophagy, mitophagy, and diabetic kidney disease, highlighting the current state of knowledge, existing research gaps, and potential areas for future investigations. Diabetic nephropathy (DN) is traditionally defined as a specific form of kidney disease caused by long-standing diabetes, characterized by the classic histological lesions in the kidney, including mesangial expansion, glomerular basement membrane thickening, nodular glomerulosclerosis (Kimmelstiel–Wilson nodules), and podocyte injury. Clinical markers for DN are albuminuria and the gradual decline in glomerular filtration rate (GFR). Diabetic kidney disease (DKD) is a broader and more inclusive term, for all forms of chronic kidney disease (CKD) in individuals with diabetes, regardless of the underlying pathology. This includes patients who may have diabetes-associated kidney damage without the typical histological findings of diabetic nephropathy. It also accounts for patients with other coexisting kidney diseases (e.g., hypertensive nephrosclerosis, ischemic nephropathy, tubulointerstitial nephropathies), even in the absence of albuminuria, such as a reduction in GFR. Full article

Over-accumulation of reactive oxygen species (ROS) causes hepatocyte dysfunction and apoptosis that might lead to the progression of liver damage. Sirtuin-3 (SIRT3), the main NAD+-dependent deacetylase located in mitochondria, has a critical role in regulation of mitochondrial function and ROS production as well as in the mitochondrial antioxidant mechanism. This study explores the roles of astragaloside IV (AST-IV) and formononetin (FMR) in connection with SIRT3 for potential antioxidative effects. It was shown that the condition of combined pre- and post-treatment with AST-IV or FMR at all concentrations statistically increased and rescued cell proliferation. ROS levels were not affected by pre-or post-treatment individually with AST-IV or pre-treatment with FMR; however, post-treatment with FMR resulted in significant increases in ROS in all groups. Significant decreases in ROS levels were seen when pre- and post-treatment with AST-IV were combined at 5 and 10 μM, or FMR at 5 and 20 μM. In the condition of combined pre- and post-treatment with 10 μM AST-IV, there was a significant increase in SOD activity, and the transcriptional levels of Sod2, Cat, and GPX1 in all treatment groups, which is indicative of reactive oxygen species detoxification. Furthermore, AST-IV and FMR activated PGC-1α and AMPK as well as SIRT3 expression in AML12 hepatocytes exposed to t-BHP-induced oxidative stress, especially at high concentrations of FMR. This study presents a novel mechanism whereby AST-IV and FMR yield an antioxidant effect through induction of SIRT3 protein expression and activation of an antioxidant mechanism as well as mitochondrial biogenesis and mitochondrial content and potential. The findings suggest these agents can be used as SIRT3 modulators in treating oxidative-injury hepatocytes. Full article

High-fat diet (HFD)-induced obesity represents a significant challenge to male reproductive health, affecting approximately 13% of the global adult population. This comprehensive review synthesizes current evidence regarding mulberry (Morus alba L.) fruit extract’s therapeutic potential for HFD-induced male reproductive dysfunction. Through comprehensive analysis of the peer-reviewed literature from multiple databases (PubMed, Web of Science, Scopus, and Google Scholar; 2005–2024), we evaluated mulberry extract’s effects on testicular morphology, spermatogenesis, sperm parameters, and the underlying molecular mechanisms. Mechanistic studies reveal that standardized mulberry extract mediates protective effects through multiple pathways: enhanced antioxidant enzyme activities (SOD: +45%, Catalase: +38%, GPx: +35%), reduced inflammatory markers (TNF-α: −64%, IL-6: −58%), and modulated NF-κB signaling (−42.3%). These effects are facilitated by mulberry’s rich phytochemical profile, particularly anthocyanins (2.92–5.35 mg/g dry weight) and polyphenols (4.23–6.38 mg/g). The extract demonstrates particular efficacy in preserving seminiferous tubule integrity and maintaining blood-testis barrier function, with treated groups maintaining up to 85% of normal tubular architecture compared to HFD controls. Key molecular mechanisms include AMPK/SIRT1 pathway activation (2.3-fold increase), enhanced mitochondrial function (67% increase in mtDNA copy number), and epigenetic regulation of metabolic pathways. Temporal analysis indicates optimal therapeutic effects after 28 days of treatment, with initial improvements observable within 14 days. While current evidence is promising, limitations include predominant reliance on rodent models and lack of standardized extraction protocols. Future research priorities include well-designed human clinical trials, standardization of preparation methods, and investigation of potential synergistic effects with other therapeutic agents. This comprehensive review indicates that mulberry extract is a promising therapeutic candidate for obesity-related male infertility, warranting further clinical investigation. Full article

Background/Objectives: Whole body vibration (WBV) is a valuable tool to mitigate physiological adaptations related to age and inactivity. Although significant benefits have been found at the musculoskeletal level, including increased bone mass and reduced muscle atrophy, the underlying biological mechanisms remain largely unknown. Therefore, our study aimed to evaluate the effects of vibratory training on bone tissue in murine models of different age groups by investigating the structural and distribution changes in some crucial biomarkers involved in musculoskeletal homeostasis. Methods: Specifically, 4-, 12-, and 24-month-old mice were trained with a WBV protocol characterized by three series of 2 min and 30 s, interspersed with a recovery period of the same duration, on a 3-weekly frequency for 3 months. At the end of the training, histological and morphometric analyses were conducted, in association with immunohistochemical analysis to investigate changes in the distribution of fibronectin type III domain-containing protein 5 (FNDC5), NADPH oxidase 4 (NOX4), and sirtuin 1 (SIRT1). Results: Our preliminary results showed that WBV improves musculoskeletal health by preserving bone architecture and promoting up-regulation of FNDC5 and SIRT1 and down-regulation of NOX4. Conclusions: Our study confirms vibratory training as a viable alternative to counter musculoskeletal decline in elderly and/or sedentary subjects. Further investigations should be conducted to deepen knowledge in this field and explore the role of other molecular mediators in physiological adaptations to vibration. Full article