Search Results (4,202)

Background: Effective management of bone defects remains a major clinical challenge, driving continuous efforts to develop bioactive, localized delivery systems that support bone regeneration. Gold nanoparticles (AuNPs) have gained attention in regenerative medicine for their capacity to modulate cellular activity. Yet, their application in functional delivery systems for bone repair is still limited. Chitosan (CS), a naturally derived biopolymer, exhibits notable osteoinductive properties, particularly when used to modify nanoparticulate carriers. Objectives: In this study, AuNPs and chitosan-coated gold nanoparticles (CS-AuNPs) were formulated, characterized, and incorporated into gel preparations to evaluate their physicochemical properties and therapeutic potential in a rat tibial bone defect model. Methods: AuNPs were synthesized and either left uncoated or coated with CS to enhance biological activity. Both formulations were examined for particle size, zeta potential, X-ray diffraction, and Fourier-transform infrared spectroscopy (FTIR). The resulting nanoparticles were integrated into gel bases, which were assessed for gel strength, swelling index, viscosity, and pH. The in vivo study involved surgically induced bone defects in the tibias of albino rats treated with either formulation. Healing outcomes were assessed via histological analysis, quantification of newly formed bone, immunohistochemical staining, radiographic imaging, and measurement of bone-related markers using RT-qPCR. Results: The CS-AuNP gel formulation demonstrated significantly improved bone regeneration compared to the uncoated counterpart, as evidenced by histological findings, increased bone volume in radiographs, stronger immunohistochemical expression of the VEGF angiogenic protein marker, and increased genetic expression of osteogenic markers. Conclusions: Incorporating CS-AuNPs into gel formulations offers a promising approach for enhancing bone healing. The superior performance of the CS-coated system highlights its potential as a promising localized therapy for managing bone defects. Full article

Peripheral nerve injuries (PNI) present a major clinical and socioeconomic challenge due to limited regenerative capacity. Adipose-derived stem cells (ADSCs) within the stromal vascular fraction (SVF) of white adipose tissue offer a promising autologous source for regenerative support. This study evaluated the impact of mechanical processing CELT (Cell-Enriched Lipotransfer) and CELT^PLUS and electrical stimulation on the regenerative secretome of human lipoaspirates. qPCR analysis revealed that CELT^PLUS processing, which incorporates mechanical intersyringe shifting, significantly doubled the gene expression of nerve growth factor (NGF) (p = 0.015), vascular endothelial growth factor (VEGF) (p = 0.02), and brain-derived neurotrophic factor (BDNF) (p = 0.04) compared to CELT-processed lipoaspirate. Protein analysis via ELISA confirmed a time-dependent secretion of NGF and VEGF over 96 h. Furthermore, 24 h electrical stimulation (2 V) significantly enhanced NGF protein release (p < 0.001). These findings demonstrate that standardized mechanical processing effectively enriches regenerative cell populations and amplifies their neurogenic and angiogenic potential. The additional modulation of growth factor secretion via electrical stimulation highlights the potential of processed adipose tissue as a functional, autologous transplant for enhanced nerve reconstruction. Full article

Headache is a frequent and clinically relevant symptom in patients undergoing cranial radiotherapy, most often reflecting treatment-induced structural and inflammatory changes such as cerebral edema or radiation-related brain injury. Differentiating secondary headache from primary disorders, particularly migraine, is essential for appropriate management. This review aims to examine the pathophysiological mechanisms underlying headache following cranial radiotherapy, evaluate current pharmacological and complementary treatment strategies and highlight key aspects of differential diagnosis with migraine. Unlike existing literature that focuses primarily on radiological findings of radiation injury, this review adopts a symptom-driven approach, reframing headache as a critical clinical gateway for the early detection of structural complications. A structured narrative review of the literature was conducted using PubMed/MEDLINE, Scopus and Google Scholar to identify studies published between 2020 and 2025, focusing on cerebral edema, radiation-related complications, therapeutic approaches and migraine. Relevant clinical trials, systematic reviews and guidelines were included. Cerebral edema consistently emerges as the main mechanism of acute and subacute post-radiotherapy headache, whereas late-onset symptoms are most often linked to radiation necrosis. Corticosteroids remain first-line therapy, while bevacizumab has demonstrated benefit in steroid-refractory cerebral edema and radiation necrosis through inhibition of vascular endothelial growth factor (VEGF), thereby reducing vascular permeability and attenuating peritumoral edema. Its use in the context of cranial radiotherapy requires careful consideration, as the safety of concomitant administration with radiation has not been formally established, and headache itself is among its recognized adverse effects. Evidence for complementary therapies, including Boswellia serrata and plant-based compounds, remains limited. Migraine constitutes a distinct neurovascular disorder requiring careful differentiation from secondary headache in oncological patients. The review emphasizes headache as a clinically relevant indicator of underlying structural complications rather than an isolated symptom. Post-radiotherapy headache should be interpreted as a manifestation of underlying structural pathology. Accurate etiological diagnosis and individualized management are essential. Further research is needed to refine treatment strategies and clarify the role of complementary therapies. Full article

Despite reducing hernia recurrence, synthetic meshes often trigger persistent foreign body responses (FBRs). Mesh-enriched therapies (METs), incorporating autologous cellular components (MSCs, PRP, SVF), can regeneratively reprogram the host-prosthetic interactome. Following PRISMA-ScR guidelines, this scoping review involved a systematic search of PubMed, Embase, and Scopus (2000–2025). We utilized the PCC (Population, Concept, Context) framework to map evidence across systemic inflammation, local FBR, and bio-augmentation strategies. A total of sixty-five studies were synthesized and categorized into three primary thematic pillars. Regarding the Systemic Response (n = 25), the data established a predictable “foreign body signature” characterized by prominent C-reactive protein (CRP) and interleukin-6 (IL-6) spikes within the first 48 h post-implantation. For the Local Foreign Body Reaction (FBR, n = 19), human explant data extending up to 180 months revealed a perpetual, immune-mediated state driven by matrix metalloproteinase-2 (MMP-2) matrix remodeling and the development of “bridging fibrosis.” Finally, concerning Mesh-Enriched Therapy (MET) Integration (n = 21), biological enrichment successfully shifted the M1/M2 macrophage ratio toward a pro-regenerative, CD163+/CD206+ phenotype. While MET consistently enhanced vascular endothelial growth factor (VEGF)-driven angiogenesis and optimized the Collagen I/III ratio, a notable 22.2% discrepancy rate across the literature underscores the critical need for precise transforming growth factor-beta 1 (TGF-β1) dosing and release kinetics to prevent hyper-fibrosis. MET shifts hernia repair from passive mechanical reinforcement to active “biocamouflage” and integration. By modulating the Th1/Th2 rheostat, enriched therapies mitigate chronic inflammation and long-term complications. Standardized clinical trials are essential to optimize the therapeutic window for hybrid integration. Full article

Infectious wounds are plagued by persistent infection, uncontrolled inflammation, and delayed repair, while traditional therapies suffer from the poor solubility of natural drugs, low bioavailability, and bacterial drug resistance. To address these issues, this study developed a photo-responsive chitosan composite hydrogel (BBR-AS@Ce6@Matrix) cross-linked by chitosan (CS) and oxidized sodium alginate (OSA), co-loaded with Berberine–Asiaticoside cocrystal (BBR-AS) and chlorin e6-loaded chitosan nanoparticles (Ce6@CS NPs). The BBR-AS co-crystal was prepared by solvent method and verified to significantly improve the solubility and dissolution of asiaticoside. The Ce6@CS NPs were fabricated via non-solvent-assisted counterion complexation, showing high encapsulation efficiency, uniform particle size, and efficient singlet oxygen generation under irradiation. The hydrogel exhibited a three-dimensional porous network, favorable rheology, high water content, pH-dependent swelling and erosion behaviors, and significantly promoted BBR/AS release in vitro. In vitro experiments demonstrated strong antibacterial activity against Escherichia coli and Staphylococcus aureus, good cytocompatibility, and enhanced migration of L929 and Hacat cells. In a rat infectious wound model, the hydrogel combined with light irradiation markedly accelerated wound closure, promoted collagen deposition and angiogenesis, upregulated VEGF/CD31, and downregulated TNF-α/IL-6. In conclusion, BBR-AS@Ce6@Matrix integrates co-crystal solubilization, nanoparticle-facilitated release, and photodynamic synergy to achieve antibacterial, anti-inflammatory, pro-angiogenic and tissue remodeling effects, providing a promising multifunctional platform for infectious wound repair. Full article

Cancer remains one of the most frightening global health challenges, contributing substantially to morbidity and mortality across diverse populations. In recent years, naturally derived compounds have attracted considerable attention due to their potential therapeutic efficacy and fewer adverse effects. Among these, the flavokawain subclass of chalcones, comprising Flavokawains A, B, and C, obtained from various plant sources, has emerged as a promising group of bioactive phytochemicals exhibiting a broad spectrum of pharmacological activities, with notable anticancer potential. This review critically compiles and evaluates the existing preclinical evidence regarding the anticancer mechanisms of flavokawains across various cancer models. It was found that these compounds have significant potential to inhibit cancer cell proliferation, induce apoptosis, disrupt cell-cycle progression, and modulate multiple molecular pathways implicated in tumorigenesis, including phosphoinositide 3 kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), extracellular-signal regulated kinase/c-Jun N-terminal kinase/mitogen-activated protein kinase (ERK/JNK/MAPK) and so on. Importantly, flavokawains exert significant modulatory effects within the tumor microenvironment by suppressing angiogenesis through downregulation of vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1), attenuating epithelial-mesenchymal transition via restoration of E-cadherin and suppression of vimentin and Snail1, inhibiting matrix metalloproteinase (MMP)-mediated extracellular matrix remodeling, and disrupting cancer stem cell (CSC)-supportive niches. Preclinical toxicity profiles suggest a favorable safety margin, though further investigation is required to fully elucidate their therapeutic index. Due to their multifaceted mechanisms of action and selective cytotoxicity toward cancer cells, flavokawains are considered promising preclinical candidates for development as adjuncts or alternatives to conventional chemotherapeutic agents. Full article

Background/Objectives: Burn injuries in children represent a significant clinical challenge, as current standard-of-care agents such as silver sulfadiazine (SSD) present limitations, including delayed re-epithelialization. This study aimed to evaluate the therapeutic potential of Castanea sativa (sweet chestnut) flower extract—rich in polyphenols and flavonoids with documented antioxidant, anti-inflammatory, and antimicrobial properties but previously uncharacterized in burn wound healing—applied topically on second-degree burn wounds in a juvenile rat model, comparing its efficacy to SSD and their combination. Methods: Forty five-week-old female Wistar albino juvenile rats were randomly allocated into five groups (n = 8): burn control (Group C), SSD monotherapy (Group BS), vaseline vehicle/sham (Group Sham), 5% chestnut flower extract (Group BCs), and SSD combined with extract (Group BSCs). All topical treatments were applied once daily for 14 days. Healing outcomes were assessed by macroscopic wound closure analysis, systemic organ stress markers (ALT, AST, BUN), oxidative stress indices (MDA, SOD, CAT, GPx, GSH), inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10), and histopathological/immunohistochemical analyses (Ki-67, VEGF). Results: All active treatment groups demonstrated significant reductions in organ damage markers, oxidative stress burden, and pro-inflammatory cytokine levels, alongside enhanced antioxidant enzyme activity, compared to Group C (p < 0.001). Extract-treated groups exhibited more pronounced suppression of oxidative and inflammatory parameters than SSD monotherapy. The combination group (BSCs) achieved optimal wound healing outcomes, including near-complete re-epithelialization, superior collagen organization, and prominent angiogenesis, corroborated by the highest Ki-67 proliferation index and VEGF expression scores (p < 0.001). Conclusions:C. sativa flower extract significantly accelerates burn wound healing via antioxidant and anti-inflammatory mechanisms. When combined with SSD, a synergistic effect is observed that overcomes the re-epithelialization delays associated with SSD monotherapy. These findings support C. sativa flower extract as a promising candidate for further preclinical and clinical investigation in pediatric burn management, supporting the ethnopharmacological relevance of this plant in traditional wound care practices; further safety and efficacy validation is required before clinical translation. Full article

Papillary thyroid cancer (PTC) exhibits Warburg-type metabolic reprogramming with enhanced glycolysis and dependence on glucose-driven pathways. This study evaluated the effects of antihyperglycemic interventions on cytokine secretion, angiogenic signaling, metabolic activity, and proliferation in thyroid-derived cell models. Two PTC cell lines (MDA-T32 and SCC147) and a normal thyroid line (Nthy-ori) were analyzed for intracellular and extracellular cytokines, secretion efficiency (index), relative metabolic index (RMI), and marker of proliferation (Ki-67) expression following exposure to vandetanib (VDT), sodium–glucose cotransporter 2 (SGLT2), or dipeptidyl peptidase (DPP) inhibitors. Baseline analysis revealed distinct cell line-specific profiles. Compared with Nthy-ori cells, MDA-T32 cells exhibited increased vascular endothelial growth factor (VEGF) concentrations in lysates and conditioned medium (p < 0.001, q < 0.001) with enhanced VEGF secretion efficiency (p = 0.002, q = 0.008), elevated intracellular fibroblast growth factor (FGF) (p < 0.001, q < 0.001) with reduced FGF secretion index (p = 0.004, q = 0.01), and lower interleukin 8 (IL-8) concentrations accompanied by increased IL-8 secretion efficiency (p = 0.006, q = 0.02). In contrast, SCC147 cells demonstrated reduced VEGF secretion (p < 0.001, q < 0.001), decreased intracellular IL-8 (p = 0.008, q = 0.02), reduced chemokines of the growth-regulated oncogene GROβ family (GROβ) secretion (p = 0.01, q = 0.04), increased IL-8 secretion efficiency (p = 0.01, q = 0.03), and decreased GROβ secretion efficiency (p = 0.008, q = 0.02). Nthy-ori cells displayed a balanced profile. Among the investigated interventions, VDT produced the most pronounced effects. In MDA-T32 cells, VDT significantly reduced VEGF levels (p < 0.001, q < 0.001) and increased IL-8 and GROβ concentrations in conditioned medium (q < 0.05), whereas no significant effects after FDR correction were observed in SCC147 or Nthy-ori cells. SGLT2 and DPP inhibitors produced only nominal effects (p < 0.05), which did not remain significant after correction for multiple testing. VDT reduced RMI by approximately 50% in MDA-T32 cells while Ki-67 expression increased, whereas SCC147 cells remained largely unchanged. In Nthy-ori cells, SGLT2 inhibition increased RMI and decreased Ki-67 expression. These findings demonstrate marked heterogeneity among PTC cell lines and suggest that alterations in metabolic activity were not consistently accompanied by proportional changes in proliferative status under the experimental conditions used. VDT predominantly affected angiogenic and inflammatory signaling in MDA-T32 cells, whereas SGLT2 and DPP inhibition exerted limited measurable effects at clinically achievable concentrations. Full article

Background/Objectives: Faricimab is a novel bispecific antibody simultaneously inhibiting vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (Ang-2). Its efficacy in vitrectomized eyes with diabetic macular edema (DME), a setting with altered intravitreal pharmacokinetics, remains poorly characterized. We evaluated the 12-month outcomes of intravitreal faricimab (IVF) for DME in eyes vitrectomized for proliferative diabetic retinopathy (PDR). Methods: We retrospectively reviewed 12 consecutive eyes of 11 patients (mean age 59.4 ± 10.5 years) with DME after pars plana vitrectomy (PPV) for PDR who received IVF (6 mg/0.05 mL) between September 2022 and August 2024 with at least 12 months of follow-up. Best-corrected visual acuity (BCVA, logMAR) and central retinal thickness (CRT) were assessed at baseline (BL), 6 months (M6), and 12 months (M12). Results: Eight eyes were treatment-naïve and 4 had been switched from prior anti-VEGF therapy. Two eyes (16.7%) required a change in therapy: one for intraocular inflammation and one for inadequate anatomical response. In the 10 eyes that continued IVF, the mean number of injections was 4.1 ± 1.9. CRT decreased significantly from 489.5 ± 95.9 µm at BL to 328.5 ± 74.7 µm at M6 (p = 0.0065) and 307.0 ± 64.3 µm at M12 (p = 0.0023; repeated-measures ANOVA with Dunnett’s post hoc test). Mean BCVA improved from 0.33 ± 0.26 to 0.23 ± 0.21 logMAR at M12 (p = 0.0894). Conclusions: In this small retrospective study of vitrectomized eyes with DME after PPV for PDR, IVF was associated with significant anatomical improvement, while visual acuity remained stable over 12 months, with a relatively low injection burden. Faricimab may be a useful therapeutic option in this challenging population, although larger prospective studies are warranted to confirm these findings. Full article

Peripheral nerve injuries represent significant clinical challenges, often resulting in lifelong motor function loss and disability. Evidence suggests regenerating axons cannot cross nerve gaps without Schwann Cell (SC) assistance. However, FDA-approved biomaterial conduits for peripheral nerve repair lack bioactivity and structural complexity needed to facilitate SC migration. To address this, we developed a three-dimensional biomimetic in vitro model to simulate complex cellular interactions within the nerve bridge. The model features lyophilized hydrogel bioscaffolds with longitudinal channels to recapitulate the nerve microenvironment. To encourage directional SC dispersion, the top ~30% of the bioscaffold was conjugated with macrophage inflammatory protein-1α (MIP-1α). Rat SCs were seeded within no-MIP-1α- and MIP-1α-conjugated bioscaffold channels as spheroids and cultured for nine days. Histology demonstrated MIP-1α conjugation retained more SC spheroids during culture with greater cellular distributions. SC spheroid culture in MIP-1α-conjugated bioscaffold resulted in enhanced paracrine signaling characterized by increases in VEGF, ICAM-1, IL-6, and CINC-1 production, alongside downregulation of IL-1β, IL-10, and IL-13. The SC-derived pro-inflammatory and pro-angiogenic mediators did not inhibit NSC-34 motor neurite extension compared to controls. This study establishes an in vitro model that serves as both a screening platform and mechanistic tool, advancing our understanding of peripheral nerve repair. Full article

Exposure to high altitudes for hours or days is defined as acute hypobaric hypoxia (AHH) condition, which rapidly engages adjustments such as signaling pathways involving inflammation, immune modulation and oxidative stress, whose dysregulation has been described as contributing to the pathophysiology of high-altitude illnesses, due to insufficient acclimatization, such as developing acute mountain sickness (AMS). Given its traditional high-altitude use and bioactive properties, Senecio nutans (S. nutans) extract, or chachacoma (CH), has emerged as a potential therapeutic strategy to mitigate high-altitude related pathobiology. The aim of this study was to evaluate the effects of S. nutans on acclimatization, regarding the status of oxidative stress, inflammation, immune and symptoms associated with AMS in an animal model exposed to AHH. Twenty-eight female Wistar rats (≈3 months old) were randomly allocated into four experimental groups (n = 7 each): normobaric normoxia (NX), normobaric normoxia plus S. nutans administration (NX+CH), acute hypobaric hypoxia (AHH; 48 h exposure), and acute hypobaric hypoxia plus S. nutans administration (AHH+CH). S. nutans was administered subcutaneously at a dose of 80 mg/kg, one hour prior to hypoxic exposure. Outcomes included body weight, food intake, hematological parameters, lung histopathology, pulmonary mRNA expression of HIF-1α, NF-κB, TNF-α, IL-1β, IL-6, and VEGF, and lipid peroxidation in lung tissue assessed by malondialdehyde (MDA) levels. After 48 h of AHH, animals exhibited a decrease in body weight and food intake, increase in hematocrit level and total leukocytes, as well as lung injury characterized by thickening of alveolar walls and inflammatory infiltrates. In addition, AHH induced an increase in pulmonary IL-6 and IL-1β mRNA expression. In contrast, S. nutans administration partially attenuated hypoxia-induced body weight loss, mitigated the rise in hematocrit levels, and reduced lung damage, while returning total leukocyte counts to control levels. Notably, S. nutans also decreased the hypoxia-induced overexpression of IL-6 and IL-1β. Regarding lipid peroxidation, no significant differences were observed among groups. These findings suggest that S. nutans exerts a protective effect against acute hypobaric hypoxia by attenuating inflammatory responses and preserving pulmonary structure, thereby supporting its potential as a preventive strategy to mitigate early pathophysiological alterations associated with high-altitude exposure. Full article

Background and Objectives: Faricimab, the first bispecific antibody targeting VEGF-A and angiopoietin-2, has demonstrated durable efficacy in pivotal phase 3 trials for neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Real-world data on treatment-naïve patients managed with fixed-interval maintenance protocols, particularly from South-Eastern Europe, remain limited. This pilot study evaluated 24-month outcomes of intravitreal faricimab in treatment-naïve nAMD and DME, using a standardized four-injection loading phase followed by fixed every-16-week (Q16W) maintenance. Materials and Methods: This study conducted a retrospective, observational, single-center pilot cohort study of 20 consecutive treatment-naïve eyes (9 nAMD, 11 DME). All patients received four monthly loading injections followed by a fixed every-16-week (Q16W) maintenance schedule, supplemented by discretionary additional injections for residual or recurrent disease activity (215 injections total; mean 10.75 ± 0.79 per patient; range 9–12). Primary outcomes were changes in central foveal thickness (CFT) and best-corrected visual acuity (BCVA; Snellen lines with ETDRS letter equivalents) at months 4 and 24. Prespecified secondary analyses included bootstrap 95% confidence intervals, a linear mixed-effects model with a time × disease-group interaction, Bayesian credible intervals with weakly informative priors, false-discovery-rate (FDR) correction, and a minimum detectable effect-size analysis. Results: All 20 eyes completed 24-month follow-up. In nAMD, mean CFT decreased by 186.9 ± 71.9 µm (35.9%; bootstrap 95% CI 148.1–236.0; p < 0.001; d = 2.60), and BCVA improved by 3.89 ± 0.78 Snellen lines (~19 ETDRS letters; 95% CI 3.44–4.33; p < 0.001; d = 4.97). In DME, CFT decreased by 197.7 ± 65.7 µm (39.3%; 95% CI 162.5–237.3; p < 0.001; d = 3.01), and BCVA improved by 4.55 ± 1.04 lines (~23 ETDRS letters; 95% CI 4.00–5.09; p < 0.001; d = 4.39). All 20 eyes (100%) achieved ≥ 3 Snellen lines gain and ≥20% CFT reduction; 80% reached final BCVA ≥ 7 lines. A linear mixed-effects model showed a significant time effect (p < 0.001) but no time × group interaction (CFT p = 0.84; BCVA p = 0.51), indicating concordant trajectories across diseases. Bayesian analysis with weakly informative priors yielded posterior P(|d| > 0.8) ≥ 0.99 for all primary outcomes. After FDR correction, all pre-specified primary comparisons remained significant. The minimum detectable effect size with the realized sample sizes (Cohen’s d ≈ 0.66 combined, 1.07 nAMD, 0.94 DME at 80% power) was substantially below all observed effect sizes. No ocular or systemic adverse events were recorded. Conclusions: In this small, single-center, treatment-naïve pilot cohort, a fixed Q16W faricimab maintenance schedule with discretionary additional injections was associated with durable anatomical and functional improvements over 24 months in both nAMD and DME, with no adverse events recorded across 215 injections. Given the limited sample, these findings should be regarded as hypothesis-generating. The high responder rates likely reflect the cohort’s substantial baseline visual impairment (mean baseline BCVA ~20/120–20/200), which provides greater absolute capacity for measurable gain than in higher-acuity registration trial populations. These pilot data support fixed-interval faricimab as a logistically feasible candidate strategy in resource-constrained settings and should be confirmed in larger multicenter cohorts using standardized ETDRS acuity assessment. Full article

Psychological stress can affect female reproductive function through behavioral, endocrine, ovarian, and oxidative mechanisms. Antioxidant supplements have therefore attracted attention for their potential to mitigate stress-related reproductive alterations. Coenzyme Q10 (CoQ10) is a lipid-soluble quinone involved in mitochondrial energy metabolism and is widely used as a dietary supplement. However, whether CoQ10 modulates female reproductive responses to repeated psychological stress remains unclear. Although water avoidance stress (WAS) is a well-established psychogenic stress model, its effects on female reproductive outcomes are still not fully defined. In this study, we examined how repeated WAS affects female reproductive outcomes and whether CoQ10 modifies these effects. Twenty-eight regularly cycling female rats were assigned to sham control, WAS, CoQ10, or WAS + CoQ10 groups. WAS was applied for 1 h/day for 10 days, and CoQ10 was administered orally at 100 mg/kg/day. Repeated WAS did not significantly alter sexual incentive motivation parameters, reproductive hormones, corticosterone, total antioxidant capacity (T-AOC), 8-hydroxy-deoxyguanosine (8-OHdG), or mast cell count under the present experimental conditions (all p > 0.05). However, WAS reduced male-directed active investigation time (p = 0.008) and male investigation preference ratio (p = 0.024), increased absolute ovarian and adrenal gland weights (p = 0.035 and p = 0.016, respectively), reduced primordial follicle number (p = 0.030), decreased germinative epithelium thickness (p = 0.017), lowered VEGF histoscore (p = 0.033) regardless of CoQ10 treatment, and reduced corpus luteum angiogenesis in animals not receiving CoQ10 (p = 0.030). CoQ10 reduced total investigation time toward the male (p = 0.032), male investigation preference ratio (p = 0.037), 17-β estradiol (E2) (p = 0.003), testosterone (p = 0.021), and germinative epithelium thickness (p < 0.001) regardless of WAS exposure. CoQ10 also decreased kisspeptin-1 levels under non-stressed conditions (p = 0.010), while increasing corpus luteum angiogenesis under stress conditions (p = 0.003). Overall, repeated WAS produced selective behavioral and ovarian alterations rather than broad reproductive dysfunction. CoQ10 was not associated with a broadly protective or uniformly beneficial profile in this model, and its endocrine, behavioral, and ovarian effects should be interpreted with caution. Full article

Although estrogen has been identified to play crucial roles in the development of melasma, the exact mechanism of estrogen’s effect on pigmentation is incompletely elucidated. Recent studies have highlighted the pivotal role of immune cells in melasma. Interestingly, infiltrated macrophages are significantly enhanced in melasma lesions. Estrogen could facilitate M2 polarization. However, whether estrogen could stimulate melanogenesis via skewing M2 phenotype remains unknown. This study attempted to determine the significance and molecular mechanism of estrogen-induced M2 phenotype in melasma. We found that M2 infiltration was significantly increased in melasma lesions compared with perilesional skin. Arginase 1 was identified as the hub gene, and its expression was positively correlated with that of microphthalmia-associated transcription factor and tyrosinase-related protein 1 in melasma through transcriptome analysis. Moreover, β-estradiol (E2) was confirmed to promote M2 skewing while inhibiting M1 polarization via activating STAT6 signaling. Importantly, E2-induced M2 polarization robustly increased melanogenesis by increasing tyrosinase activity and expression of microphthalmia-associated transcription factor and tyrosinase in melanocytes, which were profoundly inhibited by VEGF knockdown or antagonism both in vitro and in ex vivo skin. Furthermore, VEGF was revealed to enhance melanogenesis through activating p38 MAPK and ERK1/2 signaling pathways in melanocytes. Additionally, dermal VEGF was significantly increased, and most of it colocalized with M2 macrophages in melasma lesions. Crucially, E2 administration potently reversed ovariectomy-decreased M2 skewing and subsequently promoted dermal VEGF expression and epidermal melanogenesis in the mouse tail skin, which were significantly suppressed by macrophage depletion. These findings suggest that estrogen may stimulate melanogenesis in melasma through increasing M2 skewing and VEGF expression and secretion in macrophages. Full article

Hypogonadism is increasingly recognized as an independent cardiovascular risk factor, with testosterone deficiency associated with endothelial dysfunction, increased thrombotic risk, and adverse cardiovascular outcomes. Circulating biomarkers provide valuable insights into the vascular health status of hypogonadal men and the cardiovascular effects of testosterone replacement therapy (TRT). This comprehensive review examines the molecular basis of testosterone action on the cardiovascular system and synthesizes evidence on circulating cardiovascular biomarkers in hypogonadism, including endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), platelet markers, endothelial activators, adhesion molecules, and inflammatory/oxidative stress markers. We also compare the cardiovascular safety profiles of transdermal versus intramuscular testosterone formulations. Hypogonadal men exhibit reduced circulating EPCs, elevated EMPs, increased platelet reactivity, higher levels of endothelial activators (ICAM-1, VCAM-1, E-selectin, von Willebrand factor, endothelin-1, ADMA), and increased inflammatory markers (hsCRP, IL-6, TNF-α). TRT improves most of these biomarkers through androgen receptor (AR)-dependent and AR-independent mechanisms involving PI3K/Akt/eNOS signaling, VEGF upregulation, CXCL12/CXCR4 axis modulation, and NF-κB pathway suppression. Current evidence suggests that transdermal testosterone formulations may offer advantages regarding hematological safety and more stable testosterone exposure; however, definitive evidence demonstrating superior cardiovascular outcomes compared with intramuscular formulations remains limited. Circulating cardiovascular biomarkers are significantly altered in hypogonadism and improve with TRT. Available data suggest that transdermal testosterone formulations may offer a more favorable cardiovascular safety profile than intramuscular preparations, particularly with respect to erythrocytosis and pharmacokinetic stability, although head-to-head randomized trials with hard cardiovascular endpoints are still needed. Understanding the molecular mechanisms underlying these changes is essential for optimizing TRT in hypogonadal men with cardiovascular risk factors. The cardiovascular safety advantage of transdermal formulations is currently supported primarily by pharmacokinetic and hematological evidence; direct comparative evidence from randomized trials with hard cardiovascular endpoints remains unavailable. Full article