Search Results (32)

Mitochondria play a central role in energy metabolism and continuously adapt through dynamic processes such as fusion and fission. When the balance between these processes is disrupted, it can lead to mitochondrial dysfunction and increased oxidative stress, contributing to the development and progression of various cardiometabolic diseases (CMDs). Their role is crucial in diabetes mellitus (DM), since their dysfunction drives β-cell apoptosis, immune activation, and chronic inflammation through excessive ROS production, worsening endogenous insulin secretion. Moreover, sympathetic nervous system activation and altered dynamics, contribute to hypertension through oxidative stress, impaired mitophagy, endothelial dysfunction, and cardiomyocyte hypertrophy. Furthermore, the role of mitochondria is catalytic in endothelial dysfunction through excessive reactive oxygen species (ROS) production, disrupting the vascular tone, permeability, and apoptosis, while impairing antioxidant defense and promoting inflammatory processes. Mitochondrial oxidative stress, resulting from an imbalance between ROS/Reactive nitrogen species (RNS) imbalance, promotes atherosclerotic alterations and oxidative modification of oxidizing low-density lipoprotein (LDL). Mitochondrial DNA (mtDNA), situated in close proximity to the inner mitochondrial membrane where ROS are generated, is particularly susceptible to oxidative damage. ROS activate redox-sensitive inflammatory signaling pathways, notably the nuclear factor kappa B (NF-κB) pathway, leading to the transcriptional upregulation of proinflammatory cytokines, chemokines, and adhesion molecules. This proinflammatory milieu promotes endothelial activation and monocyte recruitment, thereby perpetuating local inflammation and enhancing atherogenesis. Additionally, mitochondrial disruptions in heart failure promote further ischemic injury and excessive oxidative stress release and impair ATP production and Ca²⁺ dysregulation, contributing to cell death, fibrosis, and decreased cardiac performance. This narrative review aims to investigate the intricate relationship between mitochondrial dysfunction and CMDs. Full article

Lipid metabolism disorders represent a significant risk factor for the pathogenesis of Alzheimer’s disease (AD). Apolipoprotein E (APOE) has been regarded as a pivotal regulator of lipid homeostasis in the central nervous system (CNS), with polymorphic alleles identified as genetic risk factors for late-onset AD. Despite advances in APOE research and the development of numerous pharmaceutical approaches targeting distinct APOE isoforms, there remain limited treatment approaches for AD that focus on lipid metabolic homeostasis. Consequently, it is necessary to reevaluate the lipid metabolic process in the CNS. Apolipoprotein A1 (APOA-I), a major component of high-density lipoprotein (HDL), plays a crucial role in reverse cholesterol transport from tissues to the liver to maintain lipid homeostasis. Over the past few decades, numerous studies have suggested a connection between reduced APOA-I levels and a higher risk of AD. APOA-I is synthesized exclusively in the liver and intestines, and there is a lack of conclusive evidence supporting its functional significance within the central nervous system, in contrast to APOE, which is produced locally by glial cells and neurons within the CNS. Moreover, APOA-I’s ability to penetrate the blood-brain barrier (BBB) is still poorly understood, which causes its significance in central lipid metabolism and AD pathophysiology to be mainly disregarded. Recent advancements in tracing methodologies have underscored the essential role of APOA-I in regulating lipid metabolism in the CNS. This review aims to elucidate the physiological functions and metabolic pathways of APOA-I, integrating its associations with AD-related pathologies, risk factors, and potential therapeutic targets. Through this discourse, we aim to provide novel insights into the intricate relationship between AD and APOA-I, paving the way for future research in this field. Full article

Background/Objectives: Dental implant success is influenced by a range of systemic and local factors. Emerging evidence suggests that metabolic markers such as lipid profiles and vitamin D levels may play a role in osseointegration and implant survival. The aim of this study was to evaluate the influence of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and vitamin D levels on the short-term survival rate of dental implants. Materials and Methods: A prospective observational study was conducted on patients receiving dental implants. Preoperative serum levels of LDL, HDL, triglycerides, and vitamin D were recorded. A total of 556 conical, platform-switching implants were placed in 166 patients, smokers and no smokers with mean age 48 years ± 4.7. Implant survival was evaluated from 14 to 21 days after placement, at 6- and at a 12-month follow-up. Spearman’s rank correlation was performed to assess potential correlations between the abovementioned systemic factors and implant loss. Results: Out of 556 implants, 13 (2.34%) were lost from 14 to 21 days after placement, a further two (0.35%) were lost after 6 months after surgery and a further eight (1.44%) were lost 12 months after placement. No significant correlation was found between HDL levels, cholesterol levels, triglyceride levels and implant loss. Spearman’s correlation analysis revealed a strong negative correlation between vitamin D levels and implant loss with no statistical significance. Conclusions: Within the limitations of this study, no statistically significant associations were found between lipid profile markers or vitamin D levels and early dental implant loss. Further large-scale and long-term studies are warranted to validate these findings and better understand the interplay between systemic biochemical markers and implant survival rate. Full article

Toll-like receptor 2 (TLR2) signaling is a pivotal component of immune system activation, and it is closely linked to the lipidation of bacterial proteins. This lipidation is guided by bacterial signal peptides (SPs), which ensure the precise targeting and membrane anchoring of these proteins. The lipidation process is essential for TLR2 recognition and the activation of robust immune responses, positioning lipidated bacterial proteins as potent immunomodulators and adjuvants for vaccines against bacterial-, viral-, and cancer-related antigens. The structural diversity and cleavage pathways of bacterial SPs are critical in determining lipidation efficiency and protein localization, influencing their immunogenic potential. Recent advances in bioinformatics have significantly improved the prediction of SP structures and cleavage sites, facilitating the rational design of recombinant lipoproteins optimized for immune activation. Moreover, the use of SP-containing lipobox motifs, as adjuvants to lipidate heterologous proteins, has expanded the potential of vaccines targeting a broad range of pathogens. However, challenges persist in expressing lipidated proteins, particularly within heterologous systems. These challenges can be addressed by optimizing expression systems, such as engineering E. coli strains for enhanced lipidation. Thus, lipoprotein signal peptides (SPs) demonstrate remarkable versatility as adjuvants in vaccine development, diagnostics, and immune therapeutics, highlighting their essential role in advancing immune-based strategies to combat diverse pathogens. Full article

Salivary biomarkers are promising molecules for diagnosing systemic diseases. Cytidine/uridine monophosphate kinase 2 (CMPK2) is associated with various systemic diseases. However, little is known about the role of the CMPK2 gene in saliva and dyslipidemia. This study investigated the relationship between serum lipid levels and Cmpk2 mRNA expression in the saliva of dyslipidemic mice. Additionally, immunofluorescence staining was employed to assess the localization of the CMPK2 protein in the submandibular gland. Two types of dyslipidemic mice were utilized: mice fed a high-fat and high-cholesterol (HFHC) diet and genetically dyslipidemic ApoE-deficient mice. The mice at 9 to 46 weeks were analyzed for serum lipid levels, Cmpk2 mRNA expression in saliva, and CMPK2 protein localization in the submandibular glands. Both dyslipidemic mice displayed elevated low-density lipoprotein cholesterol and total cholesterol in serum. ApoE-deficient mice apparently exhibited increased Cmpk2 expression in saliva. Immunofluorescence staining indicated that CMPK2 proteins were primarily localized in the serous acini, potentially associated with the secretion of Cmpk2 mRNA in saliva. These findings suggest that Cmpk2 mRNA increases and is detectable in the saliva of dyslipidemic mice, providing a viable experimental model to assess the potential use of CMPK2 as a biomarker for dyslipidemia. Full article

Background: Male factors contribute to approximately 50% of infertile couples. However, obvious causes remain unknown in many cases. This observational study aimed to investigate the associations of clinical and lifestyle parameters with sperm parameters. Methods: This study enrolled 41 men in infertile couples without obvious causes for male infertility from July 2023 to April 2024. Semen samples were evaluated for sperm number, motility, DNA fragmentation, and oxidative stress (OS) marker oxidation–reduction potential (ORP). Blood samples were analyzed for biochemical parameters, including advanced glycation end products (AGEs), and systemic OS marker diacron-reactive oxygen metabolites (d-ROMs). Skin-accumulated AGE levels were identified with an autofluorescence method. Lifestyle factors were assessed with a lifestyle questionnaire. Results: Most of the participants were under 40 years old and non-obese with normal clinical parameters. Multiple regression analyses revealed that body mass index, serum d-ROMs, and semen ORP levels were independently associated with decreased sperm number. Additionally, serum zinc and semen ORP levels were associated with sperm motility. Furthermore, serum zinc and high-density lipoprotein cholesterol levels were associated with sperm progressive motility and DNA fragmentation, respectively. The rest of the clinical and lifestyle factors, including skin-accumulated and serum AGE levels, were not correlated with any sperm parameters. Furthermore, serum d-ROM and semen ORP levels were not correlated with each other or any of the clinical and lifestyle factors. Conclusions: Our present study indicates that both systemic and local OS may be independently involved in sperm abnormality in healthy men without obvious causes for male infertility. Full article

Gliomas account for 24% of all the primary brain and Central Nervous System (CNS) tumors. These tumors are diverse in cellular origin, genetic profile, and morphology but collectively have one of the most dismal prognoses of all cancers. Work is constantly underway to discover a new effective form of glioma therapy. Photodynamic therapy (PDT) may be one of them. It involves the local or systemic application of a photosensitive compound—a photosensitizer (PS)—which accumulates in the affected tissues. Photosensitizer molecules absorb light of the appropriate wavelength, initiating the activation processes leading to the formation of reactive oxygen species and the selective destruction of inappropriate cells. Research focusing on the effective use of PDT in glioma therapy is already underway with promising results. In our work, we provide detailed insights into the molecular changes in glioma after photodynamic therapy. We describe a number of molecules that may contribute to the resistance of glioma cells to PDT, such as the adenosine triphosphate (ATP)-binding cassette efflux transporter G2, glutathione, ferrochelatase, heme oxygenase, and hypoxia-inducible factor 1. We identify molecular targets that can be used to improve the photosensitizer delivery to glioma cells, such as the epithelial growth factor receptor, neuropilin-1, low-density lipoprotein receptor, and neuropeptide Y receptors. We note that PDT can increase the expression of some molecules that reduce the effectiveness of therapy, such as Vascular endothelial growth factor (VEGF), glutamate, and nitric oxide. However, the scientific literature lacks clear data on the effects of PDT on many of the molecules described, and the available reports are often contradictory. In our work, we highlight the gaps in this knowledge and point to directions for further research that may enhance the efficacy of PDT in the treatment of glioma. Full article

Bacterial surface display platforms have been developed for applications such as vaccine delivery and peptide library screening. The type V secretion system is an attractive anchoring motif for the surface expression of foreign proteins in gram-negative bacteria. SadA belongs to subtype C of the type V secretion system derived from Salmonella spp. and promotes biofilm formation and host cell adherence. The inner membrane lipoprotein SadB is important for SadA translocation. In this study, SadA was used as an anchoring motif to expose heterologous proteins in Salmonella typhimurium using SadB. The ability of SadA to display heterologous proteins on the S. typhimurium surface in the presence of SadB was approximately three-fold higher than that in its absence of SadB. Compared to full-length SadA, truncated SadAs (SadA⁸⁷⁷ and SadA²⁶⁹) showed similar display capacities when exposing the B-cell epitopes of urease B from Helicobacter pylori (UreB158–172aa and UreB349–363aa). We grafted different protein domains, including mScarlet (red fluorescent protein), the urease B fragment (UreBm) from H. pylori SS1, and/or protective antigen domain 4 from Bacillus anthracis A16R (PAD4), onto SadA⁸⁷⁷ or SadA¹²⁹². Whole-cell dot blotting, immunofluorescence, and flow cytometric analyses confirmed the localization of Flag×3-mScarlet (~30 kDa) and Flag×3-UreBm-mScarlet (~58 kDa) to the S. typhimurium surface using truncated SadA⁸⁷⁷ or SadA¹²⁹² as an anchoring motif. However, Flag×3-UreBm-PAD4-mScarlet (~75 kDa) was displayed on S. typhimurium using SadA¹²⁹². The oral administrated pSadBA¹²⁹²-FUM/StmΔygeAΔmurI and pSadBA⁸⁷⁷-FUM/StmΔygeAΔmurI could elicit a significant mucosal and humoral immunity response. SadA could thus be used as an anchoring motif for the surface expression of large heterologous proteins as a potential strategy for attenuated bacterial vaccine development. Full article

Saudi Arabia has an alarmingly high incidence of cardiovascular disease (CVD) and its associated risk factors. To effectively assess CVD risk, it is essential to develop tailored models for diverse regions and ethnicities using local population variables. No CVD risk prediction model has been locally developed. This study aims to develop the first 10-year CVD risk prediction model for Saudi adults aged 18 to 75 years. The electronic health records of Saudi male and female patients aged 18 to 75 years, who were seen in primary care settings between 2002 and 2019, were reviewed retrospectively via the Integrated Clinical Information System (ICIS) database (from January 2002 to February 2019). The Cox regression model was used to identify the risk factors and develop the CVD risk prediction model. Overall, 451 patients were included in this study, with a mean follow-up of 12.05 years. Thirty-five (7.7%) patients developed a CVD event. The following risk factors were included: fasting blood sugar (FBS) and high-density lipoprotein cholesterol (HDL-c), heart failure, antihyperlipidemic therapy, antithrombotic therapy, and antihypertension therapy. The Bayesian information criterion (BIC) score was 314.4. This is the first prediction model developed in Saudi Arabia and the second in any Arab country after the Omani study. We assume that our CVD predication model will have the potential to be used widely after the validation study. Full article

Sulforaphane (SFN), an isothiocyanate, is one of the major dietary phytochemicals found in cruciferous vegetables. Many studies suggest that SFN can protect against cancer and cardiometabolic diseases. Despite the proposed systemic and local vascular protective mechanisms, SFN’s potential to inhibit atherogenesis by targeting macrophages remains unknown. In this study, in high fat diet fed ApoE-deficient (ApoE^−/−) mice, oral SFN treatment improved dyslipidemia and inhibited atherosclerotic plaque formation and the unstable phenotype, as demonstrated by reductions in the lesion areas in both the aortic sinus and whole aorta, percentages of necrotic cores, vascular macrophage infiltration and reactive oxygen species (ROS) generation. In THP-1-derived macrophages, preadministration SFN alleviated oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation, oxidative stress and mitochondrial injury. Moreover, a functional study revealed that peritoneal macrophages isolated from SFN-treated mice exhibited attenuated cholesterol influx and enhanced apolipoprotein A-I (apoA-I)- and high-density lipoprotein (HDL)-mediated cholesterol efflux. Mechanistic analysis revealed that SFN supplementation induced both intralesional and intraperitoneal macrophage phenotypic switching toward high expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and ATP-binding cassette subfamily A/G member 1 (ABCA1/G1) and low expression of peroxisome proliferator-activated receptor γ (PPARγ) and cluster of differentiation 36 (CD36), which was further validated by the aortic protein expression. These results suggest that the regulation of macrophages’ cholesterol transport and accumulation may be mainly responsible for SFN’s potential atheroprotective properties, and the regulatory mechanisms might involve upregulating ABCA1/G1 and downregulating CD36 via the modulation of PPARγ and Nrf2. Full article

High-grade serous ovarian carcinoma (HGSOC) is the most common and deadliest ovarian cancer subtype. Despite advances in treatment, the overall prognosis remains poor. Regardless of efforts to develop biomarkers to predict surgical outcome and recurrence risk and resistance, reproducible indicators are scarce. Exploring the complex tumor heterogeneity, serum profiling of metabolites and lipoprotein subfractions that reflect both systemic and local biological processes were utilized. Furthermore, the overall impact on the patient from the tumor and the treatment was investigated. The aim was to characterize the systemic metabolic effects of primary treatment in patients with advanced HGSOC. In total 28 metabolites and 112 lipoproteins were analyzed by nuclear magnetic resonance (NMR) spectroscopy in longitudinal serum samples (n = 112) from patients with advanced HGSOC (n = 24) from the IMPACT trial with linear mixed effect models and repeated measures ANOVA simultaneous component analysis. The serum profiling revealed treatment-induced changes in both lipoprotein subfractions and circulating metabolites. The development of a more atherogenic lipid profile throughout the treatment, which was more evident in patients with short time to recurrence, indicates an enhanced systemic inflammation and increased risk of cardiovascular disease after treatment. The findings suggest that treatment-induced changes in the metabolome reflect mechanisms behind the diversity in disease-related outcomes. Full article

The high concentration of particulate matter (PM) in broiler houses seriously endangers the biological safety of broilers and causes low growth performance, deserving more attention. This study aimed to investigate the effects of PM collected from a broiler house on the lung and systemic inflammatory responses and liver lipid anabolic process in broilers. Broilers were systemically exposed to fresh air (control) and 4 mg·m⁻³ and 8 mg·m⁻³ total suspended particles (TSP). Lung, liver, and serum were sampled after 7 (E7) and 14 (E14) days of PM exposure and 7 days after self-recovery (R 7). Corresponding kits were used to assay the inflammatory cytokines and serum biochemical indicators. The expression levels of genes related to lipid metabolism were detected by real-time polymerase chain reaction (RT-PCR) assay. The results showed a significant decrease in the average daily gain in broilers for 7 days of PM exposure (p < 0.05) and clear lung and liver inflammations in PM groups. In addition, upregulation of lung interleukin (IL)-1β and IL-8 and serum low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) occurred after 7 days of PM exposure (p < 0.05), and upregulation of lung serum tumor necrosis factor (TNF)-α and cholesterol (CHOL) occurred after 14 days of PM exposure (p < 0.05). A decrease in serum total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-px) levels was found after 14 days of PM exposure (p < 0.05), and the GSH-px level was maintained until 7 days after cessation of exposure (p < 0.05). Seven days after cessation of exposure, the expression levels of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) and fatty acid synthase (Fas) genes significantly increased (p < 0.05) and decreased (p < 0.05), respectively. These results demonstrate that exposure to PM in broiler houses can induce systemic inflammation and dyslipidemia through local pulmonary inflammation and also exert toxic effects on the liver by disturbing the expression of genes involved in the hepatic lipid anabolic process. Full article

Objective: To evaluate the feasibility of automated machine learning (AutoML) in predicting 30-day mortality in non-cholestatic cirrhosis. Methods: A total of 932 cirrhotic patients were included from the First Affiliated Hospital of Soochow University between 2014 and 2020. Participants were divided into training and validation datasets at a ratio of 8.5:1.5. Models were developed on the H₂O AutoML platform in the training dataset, and then were evaluated in the validation dataset by area under receiver operating characteristic curves (AUC). The best AutoML model was interpreted by SHapley Additive exPlanation (SHAP) Plot, Partial Dependence Plots (PDP), and Local Interpretable Model Agnostic Explanation (LIME). Results: The model, based on the extreme gradient boosting (XGBoost) algorithm, performed better (AUC 0.888) than the other AutoML models (logistic regression 0.673, gradient boost machine 0.886, random forest 0.866, deep learning 0.830, stacking 0.850), as well as the existing scorings (the model of end-stage liver disease [MELD] score 0.778, MELD-Na score 0.782, and albumin-bilirubin [ALBI] score 0.662). The most key variable in the XGBoost model was high-density lipoprotein cholesterol, followed by creatinine, white blood cell count, international normalized ratio, etc. Conclusion: The AutoML model based on the XGBoost algorithm presented better performance than the existing scoring systems for predicting 30-day mortality in patients with non-cholestatic cirrhosis. It shows the promise of AutoML in its future medical application. Full article

The localization of lipoprotein (Lol) system is responsible for the transport of lipoproteins in the outer membrane (OM) of Vibrio parahaemolyticus. LolB catalyzes the last step in the Lol system, where lipoproteins are inserted into the OM. If the function of LolB is impeded, growth of V. parahaemolyticus is inhibited, due to lack of an intact OM barrier for protection against the external environment. Additionally, it becomes progressively harder to generate antimicrobial resistance (AMR). In this study, LolB was employed as the receptor for a high-throughput virtual screening from a natural compounds database. Compounds with higher glide score were selected for an inhibition assay against V. parahaemolyticus. It was found that procyanidin, stevioside, troxerutin and rutin had both exciting binding affinity with LolB in the micromolar range and preferable antibacterial activity in a concentration-dependent manner. The inhibition rates of 100 ppm were 87.89%, 86.2%, 91.39% and 83.71%, respectively. The bacteriostatic mechanisms of the four active compounds were explored further via fluorescence spectroscopy and molecular docking, illustrating that each molecule formed a stable complex with LolB via hydrogen bonds and pi–pi stacking interactions. Additionally, the critical sites for interaction with V. parahaemolyticus LolB, Tyr108 and Gln68, were also illustrated. This paper demonstrates the inhibition of LolB, thus, leading to antibacterial activity, and identifies LolB as a promising drug target for the first time. These compounds could be the basis for potential antibacterial agents against V. parahaemolyticus. Full article

Background: Local eradication of periodontal infection could potentially have a much broader impact on the diabetic condition by also contributing to the modification of the lipid profile, which is directly compromised in the alteration of endothelium-dependent vasodilation. The aim of this trial was to assess the benefits of intensive periodontal treatment (IPT) on the lipid profile and endothelial function of diabetic patients. Methods: This was a 6-month, randomized controlled trial involving diabetic patients with generalized periodontitis. The study group comprised 290 individuals who were randomly assigned to receive Intensive Periodontal Treatment (IPT, Intervention Group) or conventional adult prophylaxis (Control Periodontal Treatment, CPT, Control Group). Outcomes encompassed lipid profile involving serum total cholesterol, serum triglyceride, low-density lipoprotein cholesterol, high-density lipo-protein cholesterol, and flow-mediated vasodilation (FMD) as an index of endothelium-dependent vasodilation (primary outcomes); periodontal indices and high-sensitive C-reactive protein were evaluated at baseline, 3 and 6 months after periodontal treatment. Results: An increase in endothelium-dependent flow-mediated dilatation (FMD) was observed in the Intensive Periodontal Treatment group in comparison with Control (p < 0.001), but results are not statistically different. There were no differences in lipid profile in individuals of both groups. Conclusions: An intensive periodontal treatment might improve endothelial function, suggesting a direct beneficial effect on the vasculature, possibly mediated by systemic inflammatory reduction. However, no statistically significant differences between groups were observed, and no benefits were proved on lipid profile. Full article