Search Results (146)

Background: Cerebral aneurysm (CA) is a focal or diffuse pathological dilation of the cerebral arterial wall that arises due to various etiological factors. It represents a serious vascular condition, particularly affecting the elderly, and carries a high risk of rupture and neurological morbidity. Clonidine (CL), an α2-adrenergic receptor agonist, has been reported to suppress aneurysm progression; however, its underlying molecular mechanisms, especially in relation to cerebral endothelial dysfunction, remain unclear. This study aimed to investigate the potential of CL to mitigate CA development by modulating apoptosis, inflammation, and oxidative stress in an Angiotensin II (Ang II)-induced endothelial injury model. Methods: Human brain microvascular endothelial cells (HBMECs) were used to establish an in vitro model of endothelial dysfunction by treating cells with 1 µM Ang II for 48 h. CL was administered 2 h prior to Ang II exposure at concentrations of 0.1, 1, and 10 µM. Cell viability was assessed using the MTT assay. Oxidative stress markers, including reactive oxygen species (ROS) and Nitric Oxide (NO), were measured using 2′,7′–dichlorofluorescin diacetate (DCFDA). Gene expression levels of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP-2 and MMP-9), high mobility group box 1 (HMGB1), and nuclear factor kappa B (NF-κB) were quantified using RT-qPCR. Levels of proinflammatory cytokines; tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and interferon-gamma (IFN-γ); were measured using commercial ELISA kits. Results: Ang II significantly increased ROS production and reduced NO levels, accompanied by heightened proinflammatory cytokine release and endothelial dysfunction. MTT assay revealed a marked decrease in cell viability following Ang II treatment (34.18%), whereas CL preserved cell viability in a concentration-dependent manner: 44.24% at 0.1 µM, 66.56% at 1 µM, and 81.74% at 10 µM. CL treatment also significantly attenuated ROS generation and inflammatory cytokine levels (p < 0.05). Furthermore, the expression of VEGF, HMGB1, NF-κB, MMP-2, and MMP-9 was significantly downregulated in response to CL. Conclusions: CL exerts a protective effect on endothelial cells by reducing oxidative stress and suppressing proinflammatory signaling pathways in Ang II-induced injury. These results support the potential of CL to mitigate endothelial injury in vitro, though further in vivo studies are required to confirm its translational relevance. Full article

Background: This study aimed to investigate endocan (ESM-1) levels in periodontitis patients before and after non-surgical periodontal treatment by analyzing the relationship between vascular endothelial growth factor A (VEGF-A) and tumor necrosis factor-alpha (TNF-α) in gingival crevicular fluid (GCF). Methods: This study included 26 periodontally healthy people as controls (Group 1) and 27 patients with Stage III-Grade B periodontitis (Group 2). Demographic and periodontal variables were assessed. GCF samples were collected from every subject both before and 6 weeks following non-surgical periodontal therapy (NSPT). Using an enzyme-linked immunosorbent test, biomarker levels were determined. Results: The periodontitis patients showed higher ESM-1 levels than the controls, although the difference was not significant (p > 0.005). The ESM-1 levels decreased significantly after treatment (p = 0.001). The VEGF-A levels did not differ significantly between the periodontitis patients and controls (p > 0.005) and decreased non-significantly following treatment (p > 0.005). The TNF-α levels were significantly higher in the periodontitis patients than the controls (p = 0.000) and decreased significantly after treatment (p = 0.000). A significant correlation was found between TNF-α and both probing depth (PD) and interproximal clinical attachment level (iCAL) in the control group (p < 0.05). In the periodontitis group, the VEGF levels were significantly correlated with the gingival index (GI) (p < 0.05). Significant correlations were identified between ESM-1 and VEGF-A and ESM-1 and TNF-α, as well as VEGF-A and TNF-α, in both the control group and following treatment (p < 0.05). Conclusions: ESM-1 and TNF-α levels decreased with non-surgical periodontal treatment in GCF. Within the limits of the study, the findings suggest that ESM-1 levels in periodontal tissues may be an indicator of periodontal disease. Full article

Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy, with the treatment for transplant-ineligible localized disease traditionally relying on locoregional therapies, such as surgical resection, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE). Systemic therapy has historically been reserved for advanced, unresectable HCC. However, lenvatinib, an oral multikinase inhibitor, has recently gained traction as part of a multimodal approach for localized HCC in combination with locoregional treatments. An upfront TACE or TARE can induce tumor hypoxia, leading to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis and progression. The rationale for combining lenvatinib with a locoregional therapy is to enhance tumor shrinkage while preserving liver function before a definitive intervention. Clinical trials, such as TACTICS and LAUNCH, have demonstrated improved outcomes with this approach. Additionally, retrospective studies, including those incorporating immune checkpoint inhibitors, have reported further benefits. This review explores the combination of lenvatinib with various locoregional modalities, including TARE, microwave ablation (MWA), and radiofrequency ablation (RFA), highlighting their indications and clinical outcomes. Furthermore, we discuss the ongoing and upcoming clinical trials investigating the integration of systemic agents with locoregional therapies for intermediate-stage HCC, including EMERALD-1, EMERALD-3, LEAP-012, and CheckMate 74W. Full article

Background and Objectives: The purpose of this study was to evaluate potential protective effects of suramin on inflammation, oxidative stress, and histopathological damage a rat model of acute colitis created with acetic acid. Materials and Methods: Wistar albino (male) rats were randomly assigned to three groups: control (n = 10), colitis + saline (n = 10), and colitis + suramin (n = 10). Rectal instillation of 4% acetic acid was used to induce acute colitis. Suramin (10 mg/kg/day) or saline was administered intraperitoneally for 15 days. Plasma concentrations of pentraxin 3 (PTX3), tumor necrosis factor-alpha (TNF-α), neutrophil extracellular traps (NETs), and malondialdehyde (MDA) were determined using enzyme-linked immunosorbent assay (ELISA) and spectrophotometric methods. In addition, vascular endothelial growth factor (VEGF) and TNF-α levels in colonic tissue were also measured. Histopathological evaluations were conducted using hematoxylin and eosin staining. Results: Significant increases in plasma and tissue inflammatory markers, oxidative stress parameters, and histopathological scores were observed when compared to control group; values were higher in colitis group. Suramin treatment significantly reduced plasma PTX3, TNF-α, NETs, and MDA levels, and colonic TNF-α and VEGF concentrations compared to the untreated colitis group. Histological analysis showed reduced epithelial injury and leukocyte presence in rats receiving suramin. Conclusions: Our findings demonstrate that suramin significantly attenuates inflammatory and oxidative damage in an experimental model of acute colitis. These results suggest that suramin may possess therapeutic potential in intestinal inflammation; however, this effect requires further support through advanced experimental and clinical studies. Full article

Fabry disease (FD) is a lysosomal disorder due to alpha-galactosidase-A enzyme deficiency, accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) which lead to proinflammatory effects. Males develop progressive hypertrophic cardiomyopathy (HCM) followed by fibrosis; females develop nonconcentric hypertrophy and/or early fibrosis. The inflammatory response to Gb3/lyso-Gb-3 accumulation is one of the suggested pathogenic mechanisms in FD cardiomyopathy when the secretion of inflammatory and transforming growth factors with infiltration of lymphocytes and macrophages into tissue promotes cardiofibrosis. This study aims to evaluate inflammation-driving cytokines and cardio-hypertrophic remodeling biomarkers contributing to sex-specific HCM progression. Biomarkers were studied in 20 healthy subjects and 45 FD patients. IL-2, IL-10, TNF-α, and IFN-γ were elevated in all patients, while IL-1α, MCP-1, and TNFR2 showed sex-specific differences. The increased cytokines were associated with the NF-kB pathway in FD males with HCM, revealing a correlation between MCP-1, IFN-γ, VEGF, GM-CSF, IL-10, and IL-2. In female patients, the impaired TNFα/TNFR2/TGFβ cluster with correlations to MCP-1, VEGF, GM-CSF, and IL-1α was observed. The activation of cytokines and the NF-kB pathway indicates significant inflammation during HCM remodeling in FD males. The TNFα/TNFR2/TGFβ signaling cluster may explain early fibrosis in females with FD cardiomyopathy. Sex-specific inflammatory responses in FD influence the severity and progression of HCM. Full article

Pancreatic islet transplantation (PIT) is a promising treatment for type 1 diabetes (T1D) but faces challenges pre- and post-transplantation. Co-transplantation with mesenchymal stromal cells (MSCs), known for their regenerative properties, has shown potential in improving PIT outcomes. This study examined the secretome of islets cultured alone compared to the secretomes of islets co-cultured with adipose-derived stromal cells (ASCs), a subtype of MSCs, under transplantation-relevant stressors: normoxia, cytokines, high glucose, hypoxia, and combined hypoxia and high glucose. Islet co-culture with ASCs significantly altered the proteome, affecting pathways related to energy metabolism, angiogenesis, extracellular matrix organization, and immune modulation. Key signaling molecules (e.g., VEGF, PDGF, bFGF, Collagen I alpha 1, IL-1α, and IL-10) were differentially regulated depending on culture conditions and ASC presence. Functional assays demonstrated that the co-culture secretome could enhance angiogenesis, collagen deposition, and immune modulation, depending on the stress conditions. These findings highlight possible mechanisms through which ASCs may support islet survival and function, offering insights into overcoming PIT challenges. Moreover, this work contributes to identifying biomarkers of the post-transplantation microenvironment, advancing therapeutic strategies for T1D and regenerative medicine. Full article

Background and aims: Enhanced cell proliferation is crucial for reducing production time and cost in cell therapy, and human platelet lysate (HPL) is often used to boost cell proliferation due to its favorable safety profile. Understanding the roles of different HPL components and their effects on cell culture can lead to more informed choices in medium formulation, which in turn can influence cell behavior and outcomes. Therefore, this study aimed to investigate the effects of two types of HPL, i.e., heparin-supplemented HPL (He-HPL) and fibrinogen-depleted HPL without heparin (Fd-HPL), on human osteoblasts. Materials and Methods: He-HPL and Fd-HPL were prepared from expired platelet concentrates. The presence of growth factors, i.e., brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF), and cytokines, i.e., interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), in HPL was evaluated. Human fetal osteoblast (hFOB) cells were cultured in Dulbecco’s Modified Eagle Medium supplemented with either He-HPL or Fd-HPL. The cell morphology, viability, calcium deposition, and expression of osteogenic genes were assessed. Results: Comparable levels of BDNF (p > 0.05), VEGF (p > 0.05), and IL-6 (p > 0.05) were detected in both types of HPL, whereas He-HPL exhibited significantly higher levels of TNF-α (p < 0.05). However, there were no notable differences in cell morphology, viability, population doubling time, or total cell yield between the two HPL types. Similarly, no differences were observed in the mineralization of cells treated with He-HPL compared to Fd-HPL. Nonetheless, hFOB cells cultured with He-HPL demonstrated significantly higher expression of osteogenic markers Runx2 and ALP (p < 0.05) compared to those cultured with Fd-HPL. Conclusions: He-HPL and Fd-HPL demonstrate comparable performance in promoting osteoblast proliferation and mineralization, making both usable for bone tissue engineering. However, He-HPL might have a slight edge as it enhances osteogenic gene expression. Full article

Particulate matter (PM) negatively impacts brain health, while exercise training can mitigate these effects and promote brain health. However, the effect of the interaction between PM exposure and exercise on brain health remains insufficiently explored. This study investigated the effects of PM exposure and exercise training on neuroplasticity-related growth factors and blood–brain barrier (BBB) integrity. Forty male C57BL/6 mice were randomly assigned to four groups as follows: control (CON, n = 10), PM exposure (PM, n = 10), exercise training (EX, n = 10), and PM exposure with exercise training (PMEX, n = 10). PM exposure and exercise training interventions were conducted over 8 weeks. The PM group showed significantly elevated levels of malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), S100 calcium-binding protein β (S100β), and neuron-specific enolase (NSE) (p < 0.05) and reduced levels of superoxide dismutase (SOD), insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) (p < 0.05) compared to the CON and EX groups. Conversely, the EX group demonstrated significantly reduced MDA, IL-6, TNF-α, S100β, and NSE levels (p < 0.05) and enhanced SOD, IGF-1, BDNF, and VEGF levels (p < 0.05) compared to the PM group. However, the PMEX group exhibited attenuated benefits, showing higher MDA, IL-6, TNF-α, S100β, and NSE levels (p < 0.05) and lower SOD and IGF-1 levels (p < 0.05) compared to the EX group. These findings suggest that PM exposure induces oxidative stress, inflammation, and BBB disruption while downregulating neuroplasticity-related growth factors. Exercise training mitigates these adverse effects by enhancing antioxidant activity, reducing inflammation, upregulating neuroplasticity-related growth factors, and preserving BBB integrity. However, the protective effects of exercise may be partially diminished under conditions of PM exposure. Full article

Over the past few years, biomaterial-based periodontal tissue engineering has gained popularity. An ideal biomaterial for treating periodontal defects is expected to stimulate periodontal-derived cells, allowing them to contribute most efficiently to tissue reconstruction. The present study focuses on evaluating the in vitro behavior of human periodontal ligament-derived stromal cells (hPDL-MSCs) when cultured on gelatin/Polycaprolactone prototype (GPP) and volume-stable collagen matrix (VSCM). Cells were cultured onto the GPP, VSCM, or tissue culture plate (TCP) for 3, 7, and 14 days. Cell morphology, adhesion, proliferation/viability, the gene expression of Collagen type I, alpha1 (COL1A1), Vascular endothelial growth factor A (VEGF-A), Periostin (POSTN), Cementum protein 1 (CEMP1), Cementum attachment protein (CAP), Interleukin 8 (IL-8) and Osteocalcin (OCN), and the levels of VEGF-A and IL-8 proteins were investigated. hPDL-MSCs attached to both biomaterials exhibited a different morphology compared to TCP. GPP exhibited stronger capabilities in enhancing cell viability and metabolic activity compared to VSCM. In most cases, the expression of all investigated genes, except POSTN, was stimulated by both materials, with GPP having a superior effect on COL1A1 and VEGF-A, and VSCM on OCN. The IL-8 protein production was slightly higher in cells grown on VSCM. GPP also exhibited the ability to absorb VEGF-A protein. The gene expression of POSTN was promoted by GPP and slightly suppressed by VSCM. In summary, our findings indicate that GPP electrospun nanofibers effectively promote the functional performance of PDLSCs in periodontal regeneration, particularly in the periodontal ligament and cementum compartment. Full article

Breast cancer is a heterogeneous disease characterized by a wide range of biomarker expressions, resulting in varied progression, behavior, and prognosis. While traditional biopsy-based molecular classification is the gold standard, it is invasive and limited in capturing tumor heterogeneity, especially in deep or metastatic lesions. Molecular imaging, particularly positron emission tomography (PET) imaging, offering a non-invasive alternative, potentially plays a crucial role in the classification and management of breast cancer by providing detailed information about tumor location, heterogeneity, and progression. This narrative review, which focuses on both clinical patients and preclinical studies, explores the latest advancements in PET imaging for breast cancer, emphasizing the development of new tracers targeting hormone receptors such as the estrogen alpha receptor, progesterone receptor, androgen receptor, estrogen beta receptor, as well as the ErbB family of receptors, VEGF/VEGFR, PARP1, PD-L1, and markers for indirectly assessing Ki-67. These innovative radiopharmaceuticals have the potential to guide personalized treatment approaches based on the unique tumor profiles of individual patients. Additionally, they may improve the assessment of treatment efficacy, ultimately leading to better outcomes for those diagnosed with breast cancer. Full article

Diabetic sensorimotor neuropathy (DSPN) is strongly associated with the extent of cellular oxidative stress and endothelial dysfunction in type 2 diabetes (T2DM). Alpha-lipoic acid (ALA) attenuates the progression of DSPN through its antioxidant and vasculoprotective effects. Kallistatin has antioxidant and anti-inflammatory properties. We aimed to evaluate changes in kallistatin levels and markers of endothelial dysfunction in patients with T2DM and DSPN following six months of treatment with 600 mg/day of ALA. A total of 54 patients with T2DM and DSPN and 24 control patients with T2DM but without neuropathy participated in this study. The serum concentrations of kallistatin, ICAM-1, VCAM-1, oxLDL, VEGF, ADMA, and TNF-alpha were measured by an ELISA. Peripheral sensory neuropathy was assessed with neuropathy symptom questionnaires and determination of the current perception threshold. After ALA treatment, the level of kallistatin significantly decreased, as well as the levels of TNF-alpha and ADMA. Changes in kallistatin levels were positively correlated with changes in oxLDL. The improvement in DSPN symptoms following ALA treatment showed a positive correlation with changes in kallistatin, VEGF, oxLDL, and ADMA levels. Based on our results, kallistatin could represent a potential new biomarker for assessing therapeutic response during ALA treatment in patients with DSPN. Full article

Sepsis is a potentially catastrophic organ dysfunction arising from an infection-induced immunologic reaction leading to severe inflammation, progression of septic shock, and damage to body organs. Sepsis is marked by noticeable hepatotoxicity caused by activating oxidative stress, inflammation, and apoptotic mechanisms. Through Cecal Ligation and Puncture (CLP) in rats, our study is the first to investigate the potential preventive effect of the antihypertensive medicine “Nebivolol” on sepsis-induced hepatotoxicity at a molecular level. Six groups of sixty albino Wistar rats (male) were randomly assigned. Biochemical and oxidative stress markers of liver function were measured. Additionally, apoptosis- and inflammatory-related gene and protein expressions were examined. Finally, the liver tissues were examined for histological assessments. The hepatic architecture was considerably altered by CLP, which also resulted in marked elevations of blood aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total and direct bilirubin levels, and hepatic malondialdehyde (MDA). In contrast, it decreased serum albumin level, hepatic superoxide dismutase (SOD) activity, and glutathione (GSH) level. It also significantly elevated all hepatic inflammatory mediators (Interlukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), and Interlukin-1 beta (IL-1β)) and alleviated Interlukin-10 (IL-10). It magnified the expression of p-AKT/t-AKT, p-JNK1/2/t-JNK1/2, and p-p38/t-p38 proteins, raised Matrix Metalloproteinase 2/9 (MMP 2/9) and nuclear factor-kappa B (NF-κB) gene transcriptions, and lessened Vascular Endothelial Growth Factor (VEGF) gene expression. In contrast, Nebivolol administration dramatically mitigated all biochemical and histological changes obtained by CLP. The present finding demonstrated that Nebivolol succeeded, for the first time, in improving the hepatic injury obtained from CLP-evoked sepsis through modulating oxidative stress, inflammatory mediators, and apoptotic pathways through targeting the crosstalk between protein kinase B (AKT), NF-κB, and mitogen-activated protein kinase (MAPK), making Nebivolol a hopeful treatment for hepatic injury. Full article

Background/Objectives: Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly and is characterized by a multifactorial etiology. Emerging evidence points to the potential involvement of the gut–retina axis in AMD pathogenesis, prompting exploration into novel therapeutic strategies. This study aims to investigate the effects of some micronutrients (such as lutein and zeaxanthin) and saffron (as a supplement)—known for their anti-inflammatory properties—on ophthalmological and microbial parameters in neovascular AMD (nAMD) patients. Methods: Thirty naive nAMD patients were randomized to receive daily micronutrient supplementation alongside anti-VEGF (vascular endothelial growth factor) therapy, or anti-VEGF treatment alone, over a 6-month period, with comparisons made to a healthy control (HC) group (N = 15). Ophthalmological assessments, biochemical measurements, and stool samples were obtained before and after treatment. Gut microbiota (GM) characterization was performed using 16S rRNA sequencing, while short-chain fatty acids (SCFAs), medium-chain fatty acids (MCFAs), and long-chain fatty acids (LCFAs) were analyzed with a gas chromatography–mass spectrometry protocol. Results: Compared to HC, nAMD patients exhibited reduced GM alpha diversity, altered taxonomic composition, and decreased total SCFA levels, in addition to elevated levels of proinflammatory octanoic and nonanoic acids. Micronutrient supplementation was associated with improved visual acuity relative to the group treated with anti-VEGF alone, along with a decrease in the total amount of MCFAs, which are metabolites known to have adverse ocular effects. Conclusions: In conclusion, despite certain limitations—such as the limited sample size and the low taxonomic resolution of 16S rRNA sequencing—this study highlights compositional and functional imbalances in the GM of nAMD patients and demonstrates that micronutrient supplementation may help restore the gut–retina axis. These findings suggest the therapeutic potential of micronutrients in enhancing ocular outcomes for nAMD patients, underscoring the complex interaction between GM and ocular health. Full article

Harnessing the body’s intrinsic resources for wound healing is becoming a rapidly advancing field in regenerative medicine research. This study investigates the effects of the topical application of a novel porcine Hypoxia Preconditioned Serum Hydrogel (HPS-H) on wound healing using a minipig model over a 21-day period. Porcine HPS exhibited up to 2.8× elevated levels of key angiogenic growth factors (VEGF-A, PDGF-BB, and bFGF) and demonstrated a superior angiogenic effect in a tube formation assay with human umbilical endothelial cells (HUVECs) in comparison to porcine normal serum (NS). Incorporating HPS into a hydrogel carrier matrix (HPS-H) facilitated the sustained release of growth factors for up to 5 days. In the in vivo experiment, wounds treated with HPS-H were compared to those treated with normal serum hydrogel (NS-H), hydrogel only (H), and no treatment (NT). At day 10 post-wounding, the HPS-H group was observed to promote up to 1.7× faster wound closure as a result of accelerated epithelialization and wound contraction. Hyperspectral imaging revealed up to 12.9% higher superficial tissue oxygenation and deep perfusion in HPS-H-treated wounds at day 10. The immunohistochemical staining of wound biopsies detected increased formation of blood vessels (CD31), lymphatic vessels (LYVE-1), and myofibroblasts (alpha-SMA) in the HPS-H group. These findings suggest that the topical application of HPS-H can significantly accelerate dermal wound healing in an autologous porcine model. Full article

Spontaneous chronic corneal epithelial defects (SCCEDs) are characterized by nonadherent corneal epithelium leading to poor attachment to the corneal stroma. The objective of this study was to characterize corneal outcomes concurrently with the quantification of tumor necrosis factor-alpha (TNF-α) and vascular endothelial growth factor-A (VEGF-A) in tear fluid after the subconjunctival injection of canine adipose-derived mesenchymal stem cells (cAD-MSCs) in canine SCCEDs. Ten eyes with SCCEDs, which were nonresponsive to two rounds of diamond burr debridement, were included in this study. All eyes received a single subconjunctival injection of 1 × 10⁶ cAD-MSCs. Ophthalmic examinations were performed before treatment and on day 7, 14, and 21 after treatment. Tear samples were collected for the quantification of TNF-α and VEGF-A concentrations by a canine multiplex immunoassay. Nine out of ten eyes revealed complete healing by day 21. The mean healing time was 10.89 ± 1.7 days. All eyes showed a decreased degree of ocular discomfort, in accordance with the degree of corneal characteristics. The concentrations of VEGF-A significantly reduced from pre-treatment (4334.91 ± 1275.92 pg/mL) to day 21 post-treatment (3064.61 ± 1028.66 pg/mL). No significant difference in TNF-α concentration was observed before/after treatment. In conclusion, the single use of a subconjunctival injection of cAD-MSCs could be used as an alternative treatment for canine SCCEDs. Full article