Frontiers in bioscience (Landmark edition)最新文献

Background: Alzheimer's disease (AD) is a severe neurodegenerative disorder characterized by beta-amyloid plaques and tau neurofibrillary tangles. The diagnosis of AD is complex, with the analysis of beta-amyloid and tau in cerebrospinal fluid being a well-established diagnostic approach. However, currently no blood biomarkers have been identified or validated for clinical use. In the present study, we will identify novel plasma biomarkers for AD using our well-established organotypic mouse brain slice model connected to microcontact prints. We hypothesize that AD plasma contains factors that affect endothelial cell migration and new vessel formation.

Methods: In the present study, plasma from human patients is microcontact printed and connected to mouse brain slices. After 4 weeks in culture, laminin⁺ and lectin⁺ endothelial cells (ECs) and vessels are analyzed by immunostaining techniques. The most promising samples were processed by differential mass spectrometry.

Results: Our data show that AD plasma significantly increased the migration length of laminin⁺ and lectin⁺ ECs along the microcontact prints. Using differential mass spectrometry, we could identify three potential biomarkers: C-reactive protein, basigin, and trem-like transcript 1 protein.

Conclusion: Here we show that brain slices connected to human plasma prints allow the identification of novel human AD biomarkers with subsequent mass spectrometry. This technique represents a novel and innovative approach to translate research findings from mouse models to human applications.

Background: It is known that the transformation of liver cancer-mediated fibroblasts into cancer-related fibroblasts (CAFs) is beneficial to the development of liver cancer. However, the specific mechanism is still unclear.

Methods: Human hepatocarcinoma (HepG2) cells were treated with short hairpin RNA (shRNA) of platelet-derived growth factor-D (shPDGF-D) vector, and the exosomes secreted by the cells were separated using ultracentrifugation and identified by using nanoparticle tracking analysis, transmission electron microscope, and western blot analysis. Exosomes were co-cultured with mouse primary fibroblasts, and then the activity, proliferation, cell cycle, migration, epithelial-mesenchymal transition- (EMT-) and CAF marker-related protein expression levels of fibroblasts were determined by cell counting kit-8 (CCK-8), immunofluorescence, flow cytometry, wound healing, real-time reverse transcription-PCR, and western blotting assays, respectively. Co-cultured fibroblasts were mixed with HepG2 cells and injected subcutaneously into mice to construct animal models. The size and weight of xenograft tumor and the expression of epithelial-mesenchymal transition- (EMT-), angiogenesis- and CAFs marker-related proteins were detected.

Results: The exosomes inhibited the proliferation, migration, EMT, and induced cell cycle arrest, as well as decreased the expression of α-SMA, FAP, MMP-9, and VEGF in fibroblasts. In vivo, sh-PDGF-D inhibited tumor growth, reduced the expressions of CD31, vimentin, α-SMA, FAP, MMP9, and VEGF, and promoted the expression of E-cadherin.

Conclusions: Exosomes derived from HepG2 cells transfected with shPDGF-D prevent normal fibroblasts from transforming into CAFs, thus inhibiting angiogenesis and EMT of liver cancer.

Cluster of differentiation 44 (CD44) is a transmembrane protein expressed in normal cells but overexpressed in several types of cancer. CD44 plays a major role in tumor progression, both locally and systemically, by direct interaction with the extracellular matrix, inducing tissue remodeling, activation of different cellular pathways, such as Akt or mechanistic target of rapamycin (mTOR), and stimulation of angiogenesis. As a prognostic marker, CD44 has been identified as a major player in cancer stem cells (CSCs). CSCs with a CD44 phenotype are associated with chemoresistance, alone or in combination with other CSC markers, such as CD24 or aldehyde dehydrogenase 1 (ALDH1), and may be used for patient stratification. In the therapy setting, CD44 has been explored as a viable target, directly or indirectly. It has revealed promising potential, paving the way for its future use in the clinical setting. Immunohistochemistry effectively detects CD44 overexpression, enabling patients to be accurately selected for surgery and targeted anti-CD44 therapies. In this review, we highlight the properties of CD44, its expression in normal and tumoral tissues through immunohistochemistry and potential treatment options. We also discuss the clinical significance of this marker and its added value in therapeutic decision-making.

Background: Breast cancer (BC) is a prevalent malignancy among women, and numerous investigations have reported that platelet aggregation may play a role in BC progression. Thus, identifying new targets for BC is essential. In this regard, we focused on nucleolar protein 6 (NOL6), located on chromosome 9p13, which is implicated in tumor development.

Objective: To investigate NOL6 expression in BC, examine its role in platelet aggregation and angiogenesis, and elucidate the underlying mechanisms.

Methods: Bioinformatic analyses, immunoblotting, and quantitative real-time polymerase chain reaction (qPCR) were performed to assess NOL6 expression in BC. Cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were conducted to determine the impact of NOL6 on BC cell proliferation. Immunostaining, enzyme-linked immunosorbent assay (ELISA), and flow cytometry (FCM) assays were utilized to analyze the effects of NOL6 on platelet aggregation. Tube formation and transwell assays were performed to examine angiogenesis and invasion, immunoblot assays were used to confirm the underlying mechanisms, and tumor growth assays in mice were conducted to validate the findings in vivo.

Results: NOL6 was found to be highly expressed in BC and was associated with patient prognosis, platelet aggregation, and angiogenesis. Its knockdown inhibited BC cell proliferation and reduced platelet aggregation induced by BC cells. Additionally, NOL6 depletion impaired angiogenesis and migration of BC cells. In vivo studies confirmed that NOL6 promotes tumor growth. Mechanistically, NOL6 enhances the Twisted spiral transcription factor 1 (Twist1)/galectin-3 axis, contributing to BC progression.

Conclusions: NOL6 can promote tumor progression by facilitating platelet aggregation and angiogenesis in BC cells through the Twist1/galectin-3 axis.

Background: Bodyweight high-intensity interval training (BW-HIIT) is an effective, time-efficient exercise method that reduces cardiovascular risk factors and improves muscle endurance without requiring external equipment. High mobility group box 1 (HMGB1) is a proinflammatory protein involved in insulin resistance. Previous studies revealed that HMGB1 knockout mice show improved insulin sensitivity and hyperglycemia. This study investigates whether BW-HIIT exercise can reduce proinflammatory markers, such as HMGB1, in individuals with insulin resistance.

Methods: In total, 14 adults (2 male/12 female) aged 18 to 55 were subject to six weeks of BW-HIIT. Additionally, 10-week-old mice were subject to exercise conditioning (5 mice per group (all male)) for 4 weeks of treadmill exercise or sedentary. Human and mouse pre- and post-exercise serum/plasma samples were analyzed for lipidomics, hormonal, and cytokine multiplex assays. Cardiometabolic parameters were also performed on human subjects.

Results: Post-exercise decreased systolic blood pressure (SBP), cholesterol, triglycerides, high-density lipoprotein (HDL), and cholesterol/HDL ratio in human patients with insulin resistance. Meanwhile, hormones such as amylin, glucagon, and insulin all increased post-BW-HIIT or treadmill exercise in both human and mouse models. Moreover, circulating HMBG1 levels were reduced in insulin-resistant individuals and mice after exercise. Furthermore, treadmill exercise by the animal model increased anti-inflammatory cytokines, including interleukin (IL)-10, IL-12p40, and IL-12p70, and reduced proinflammatory cytokines: eotaxin, IL-2, and macrophage inflammatory protein (MIP)-2 or CXCL2.

Conclusions: Six weeks of BW-HIIT exercise can improve cardiometabolic health, anti-inflammatory markers, hormones, and insulin sensitivity in human and mouse models undergoing exercise. Changes in circulating HMBG1 levels following BW-HIIT exercise make HMGB1 a suitable marker for cardiometabolic disease, potentiating its role beyond an alarmin. Further studies are needed to confirm these effects and to elucidate the underlying physiological mechanisms.

Background: An appropriate animal model that can simulate the pathological process of atherosclerosis is urgently needed to improve treatment strategies. This study aimed to develop a new atherosclerosis model using ApoE^-/- mice and to characterize lipidomics, gut microbiota profiles, and phenotypic alterations in adipose tissue using this model.

Methods: After a 14- or 18-week high-fat diet (HFD), male ApoE^-/- mice were randomly divided into four groups and treated separately with or without short-term and strong co-stimulation, including ice water bath and intraperitoneal injection of lipopolysaccharide and phenylephrine. As a control group, C57BL/6 mice were fed with conventional chow. The serum lipid levels, aortic arch pathology, adipose tissue phenotypic changes, plasma lipidomics, and 16S rDNA gene sequencing of colon feces were investigated.

Results: The serum lipid levels were significantly lowered following extended HFD feeding for four weeks. However, co-stimulation increased serum interleukin (IL)-1β levels but did not affect serum lipid profiles. Co-stimulation revealed typical vulnerable atherosclerotic plaque characteristics and defective adipose hypertrophy associated with peroxisome proliferator-activated receptor γ (PPARγ) regulation in adipose tissue and a reduction in mitochondrial uncoupling protein 1 (UCP1) within brown adipose tissue. Plasma lipidomic analysis showed that sphingomyelin (SM), ceramide (Cer), and monohexosylceramide (HexCer) levels in plasma were significantly elevated by HFD feeding, whereas co-stimulation further elevated HexCer levels. Additionally, glycerophosphocholines (16:0/16:0, 18:2/20:4, 18:1/18:1) and HexCer (C12:1, C16:0), Cer (d18:1/16:0), and SM (C16:0) were the most sensitive to co-stimulation. Combined co-stimulation and HFD-fed increased the abundance of Firmicutes, the abundance of f_Erysipelotrichaceae, and the Firmicutes/Bacteroidota ratio but decreased the abundance of microflora promoting bile acid metabolism and short-chain fatty acids (SCFAs) in mouse feces. The results were consistent with the findings of epidemiologic atherosclerotic cardiovascular disease studies.

Conclusions: This study established an ApoE^-/- mouse atherosclerotic vulnerable plaque model using a multi-index evaluation method. Adipogenic disorders, dysregulation of lipid metabolism at the molecular level, and increasing harmful gut microbiota are significant risk factors for vulnerable plaques, with sphingolipid metabolism receiving the most attention.

Autophagy, a key cellular degradation and recycling pathway, is critical for maintaining cellular homeostasis and responding to metabolic and environmental stress. Evidence for age-related autophagic dysfunction and its implications in chronic age-related diseases including neurodegeneration is accumulating. However, as a complex, multi-step process, autophagy can be challenging to measure, particularly in humans and human aging- and disease-relevant models. This review describes the links between macroautophagy, aging, and chronic age-related diseases. We present three novel human cell models, peripheral blood mononuclear cells (PBMCs), primary dermal fibroblasts (PDFs), and induced neurons (iNs), which serve as essential tools for studying autophagy flux and assessing its potential as a biomarker for aging. Unlike traditional models, these cell models retain age- and disease-associated molecular signatures, enhancing their relevance for human studies. The development of robust tools and methodologies for measuring autophagy flux in human cell models holds promise for advancing our understanding of autophagy's role in aging and age-related diseases, ultimately facilitating the discovery of therapies to enhance health outcomes.

Allergic disorders rising in prevalence globally, affecting a substantial proportion of individuals in industrialized nations. The imbalance in the immune system, characterized by elevated allergen-specific T helper 2 (Th2) cells and immunoglobulin E (IgE) antibodies, is a key factor in allergy development. Allergen-specific immunotherapy (AIT) is the only treatment capable of alleviating allergic symptoms, preventing new sensitizations, and reducing asthma risk in allergic rhinitis patients. Traditional AIT, however, faces challenges such as frequent administration, adverse effects, and inconsistent patient outcomes. Nanoparticle-based approaches have emerged as a promising strategy to enhance AIT. This review explores the utilization of nanoparticles in AIT, highlighting their ability to interact with the immune system and improve therapeutic outcomes. Various types of nanoparticles, including polyesters, polysaccharide polymers, liposomes, protamine-based nanoparticles (NPs), and polyanhydrides, have been employed as adjuvants or carriers to enhance AIT's efficacy and safety. Nanoparticles offer advantages such as allergen protection, improved immune response modulation, targeted cell delivery, and reduced side effects. This review provides an overview of the current landscape of nanoparticle-based allergen immunotherapy, discussing its potential to revolutionize allergy treatment compared to traditional immunotherapy.

Inter-kingdom communication between human microbiota and mast cells (MCs), as sentinels of innate immunity, is crucial in determining health and disease. This complex signaling hub involves micro-organisms and, more importantly, their metabolic products. Gut microbiota is the host's largest symbiotic ecosystem and, under physiological conditions, it plays a vital role in mediating MCs tolerogenic priming, thus ensuring immune homeostasis across organs. Conversely, intestinal dysbiosis of various etiologies promotes MC-oriented inflammation along major body axes, including gut-skin, gut-lung, gut-liver, and gut-brain. This review of international scientific literature provides a comprehensive overview of the cross-talk under investigation. This process is a key biological event involved in disease development across clinical fields, with significant prognostic and therapeutic implications for future research.