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PubMed1997

Potential to alter the content and composition of milk fat through nutrition.

Nutritional manipulation of the rumen ecosystem provides a strategy to alter the content and composition of milk fat. Dietary fat supplements affect the content and composition of milk fat. The magnitude of changes is influenced by the degree of protection; as protection increases, the deleterious effects fatty acids on microbial activity decreases, and biohydrogenation of C18 unsaturated fatty acids is reduced. In addition, change is influenced by the transfer of dietary fat into milk, which is related to fatty acid composition, degree of ruminal metabolism, and efficiency of digestion. A cascade of metabolic events involving specific nutrients (e.g., trans fatty acids and cyclopropene acids) occurs that regulates the activity of key enzymes in pathways of endogenous fat synthesis within the mammary gland. When cattle are fed oilseeds (e.g., canola and cotton) with > 75% protection from biohydrogenation, the proportion of saturated to unsaturated fatty acids is changed, and the fat content of milk is increased. Human consumption of dairy products containing elevated proportions of C18 mono- and polyunsaturated fatty acids reduces the content of cholesterol in plasma low density lipoproteins. These fat-modified dairy products are more susceptible to autoxidation, which can be controlled by including vitamin E in the diet of lactating cow. These products also have much less solid fat, which improves spreadability of butter. By protecting different oilseeds from ruminal metabolism, demands for energy can be satisfied while producing milk fat that can be designed for consumer and manufacturing requirements.

Animal Nutritional Physiological Phenomena↗
PubMed2003

Igf-I influence on breast cancer cell survival.

The insulin-like growth factor system has been implicated in the proliferative control of breast cancer cells. In addition to this function, IGF action can also protect cells from programmed cell death. Substantial knowledge has been gained about death effector molecules and their regulation in breast cancer. IGF receptor can influence several key cell death pathways. In this review, we will focus on the intracellular mechanisms activated by IGF-I that influence cell survival.

Journal Article↗
PubMed2025

High-Frequency Irreversible Electroporation Alters Proteomic Profiles and Tropism of Small Tumor-Derived Extracellular Vesicles to Promote Immune Cell Infiltration.

High-frequency irreversible electroporation (H-FIRE) is a nonthermal tumor ablation technique that disrupts the blood-brain barrier (BBB) in a focal and reversible manner. However, the mechanisms underlying this disruption remain poorly understood, particularly the role of small tumor-derived extracellular vesicles (sTDEVs) released from ablated tumor cells. In this study, we investigate the proteomic and functional alterations of sTDEVs released from F98 glioma and LL/2 Lewis lung carcinoma cells following H-FIRE ablation. Mass spectrometry analysis revealed 108 unique proteins in sTDEVs derived from ablative doses of H-FIRE, which are capable of disrupting the BBB in an in vitro model. Proteomic analysis of TDEVs highlights key changes in pathways related to integrin signaling, Platelet-derived growth factor receptor (PDGFR) signaling, and ubiquitination, which may underline their interactions with brain endothelial cells. These "disruptive" sTDEVs exhibit enhanced tropism for cerebral endothelial cells both in vitro and in vivo, where they persist in the brain longer than sTDEVs released after non-ablative H-FIRE doses. Notably, when introduced into a healthy Fischer rat model, disruptive sTDEVs are associated with increased recruitment of Iba1+ immune cells, suggesting a potential role in modulating post-ablation immune responses. However, despite their altered protein composition, these vesicles do not directly increase BBB permeability in vivo. This study is the first to demonstrate that electroporation-based tumor ablation significantly alters the composition and functionality of tumor-derived extracellular vesicles, potentially influencing the tumor microenvironment post-ablation. These findings have important implications for developing multimodal treatment strategies that combine H-FIRE with systemic therapies to enhance efficacy while managing the peritumoral microenvironment.

Animals↗
PubMed2026

Brassinosteroids as Central Regulators of Plant Growth, Stress Tolerance, and Agricultural Resilience.

Brassinosteroids (BRs) are essential steroidal phytohormones that regulate plant growth, development, and responses to environmental stresses. Recent studies have demonstrated the important roles of BRs in enhancing plant tolerance to abiotic stresses, including drought, salinity, temperature extremes, heavy metal toxicity, and oxidative stress, as well as biotic stresses caused by pathogens and herbivores. This review summarizes current advances in BR biosynthesis, metabolism, transport, and signaling pathways, focusing on key components that mediate stress adaptation. We discuss the physiological and molecular mechanisms through which BRs improve stress tolerance, including regulation of antioxidant defense, ion homeostasis, osmotic adjustment, and stress-responsive gene expression. Particular attention is given to the extensive cross talk between BRs and other phytohormones, such as abscisic acid, jasmonic acid, salicylic acid, ethylene, auxin, and gibberellins, which enables plants to balance growth and defense under adverse conditions. Furthermore, we highlighted the potential applications of BRs in crop improvement through exogenous treatments, genetic engineering, and genome-editing approaches. However, the effectiveness of BR-based strategies is highly dependent on crop species, developmental stage, stress type, BR concentration, application method, and environmental conditions. In addition, excessive BR accumulation or application may result in undesirable growth responses, and further multi-location field validation is required before widespread agricultural implementation. Finally, we discuss emerging research trends, current knowledge gaps, and future perspectives for exploring BR signaling to develop climate-resilient crops. Overall, BRs represent promising targets for improving crop stress resilience; however, optimizing BR-mediated strategies and validating their long-term performance under diverse field conditions will be essential for their successful application in sustainable agriculture.

abiotic stress↗
PubMed2000

Patterns of expression of Rb and p16 in astrocytic gliomas, and correlation with survival.

The retinoblastoma pathway is a key cell cycle regulatory complex that controls the passage of cells through the G1 checkpoint and is a frequent target of genetic alterations in gliomas. In this study, we examined the expression of Rb and p16 in 170 primary astrocytic gliomas by immunohistochemical techniques, and correlated the expression with overall survival to determine their prognostic value as immunomarkers. There were 130 patients with glioblastoma multiforme (GBM) and 40 with anaplastic astrocytoma (AA). Alterations in the levels of Rb or p16 expression were seen in the majority (>90%) of the gliomas studied. The expression of Rb was completely absent or low in 47.5% of the GBM and 67.5% of the AA. The remainder of the tumors was immunopositive for Rb to varying degrees. Immunoreactivity for p16 was absent in 56% of the GBM and 77.5% of the AA. Kaplan-Meier survival plots (log-rank test) and Cox proportional hazards regression analysis, adjusted for age and histology, showed that neither Rb nor p16 expression independently predicted survival. The results of our study suggest that although genetic alterations of Rb and p16 are common in gliomas, immunohistochemical analysis of these markers correlates poorly with prognosis.

Adolescent↗
PubMed2000

In situ amplification of 5-lipoxygenase and 5-lipoxygenase-activating protein in allergic airway inflammation and inhibition by leukotriene blockade.

Leukotrienes are important mediators of the eosinophilic influx and mucus hypersecretion in the lungs in a murine model of asthma. We used in situ PCR in this model of human asthma to detect lung mRNA for 5-lipoxygenase (5-LO) and 5-LO-activating protein (FLAP), key proteins necessary for leukotriene synthesis. Lung tissue was obtained on day 28 from mice treated with i.p. (days 0 and 14) and intranasal (days 14, 25, 26, and 27) OVA or saline. After fixation, the tissue sections underwent protease- and RNase-free DNase digestion, before in situ RT-PCR using target-specific cDNA amplification. 5-LO and FLAP-specific mRNA was visualized by a digoxigenin detection system, and positive cells were analyzed by morphometry. 5-LO and FLAP-specific mRNA and protein were associated primarily with eosinophils and alveolar macrophages in the airways and pulmonary blood vessels in OVA-sensitized/challenged mice. 5-LO and FLAP protein expression increased on a per-cell basis in alveolar macrophages of OVA-treated mice compared with saline controls. Pulmonary blood vessel endothelial cells were also positive for 5-LO, FLAP mRNA, and protein. 5-LO inhibition significantly decreased 5-LO and FLAP-specific mRNA and protein expression in the lung inflammatory cells and endothelial cells. These studies demonstrate a marked increase in key 5-LO pathway proteins in the allergic lung inflammatory response and an important immunomodulatory effect of leukotriene blockade to decrease 5-LO and FLAP gene expression.

5-Lipoxygenase-Activating Proteins↗
PubMed2001

ATP stimulates human macrophages to kill intracellular virulent Mycobacterium tuberculosis via calcium-dependent phagosome-lysosome fusion.

Advances in therapy for tuberculosis will require greater understanding of the molecular mechanisms of pathogenesis and the human immune response in this disease. Exposure of Mycobacterium tuberculosis-infected human macrophages to extracellular ATP (ATP(e)) results in bacterial killing, but the molecular mechanisms remain incompletely characterized. In this study, we demonstrate that ATP(e)-induced bactericidal activity toward virulent M. tuberculosis requires an increase in cytosolic Ca(2+) in infected macrophages. Based on our previous work with primary infection of human macrophages, we hypothesized that the Ca(2+) dependence of ATP-induced killing of intracellular M. tuberculosis was linked to promotion of phagosome-lysosome fusion. Using confocal laser-scanning microscopy, we demonstrate that ATP(e) induces fusion of the M. tuberculosis-containing phagosome with lysosomes, defined by accumulation of three lysosomal proteins and an acidophilic dye. Stimulation of phagosome-lysosome fusion by ATP(e) exhibited distinct requirements for both Ca(2+) and phospholipase D and was highly correlated with killing of intracellular bacilli. Thus, key signal transduction pathways are conserved between two distinct models of human macrophage antituberculous activity: primary infection of naive macrophages and physiologic stimulation of macrophages stably infected with M. tuberculosis.

Adenosine Triphosphate↗
PubMed2005

Regulation of p38 MAPK by MAPK kinases 3 and 6 in fibroblast-like synoviocytes.

The p38 MAPK signal transduction pathway is a key regulator of IL-1 and TNF-alpha production in rheumatoid arthritis. Previous studies demonstrated that upstream MAPK kinases (MKK3 and MKK6) that regulate p38 are activated in rheumatoid arthritis synovium. However, their functional relevance in fibroblast-like synoviocytes (FLS) has not been determined. To investigate the relative contribution of MKK3 and MKK6 to p38 activation, the effect of dominant-negative (DN) MKK3 and MKK6 constructs on cultured FLS was evaluated. Cultured FLS were stimulated with medium or IL-1beta, and immunoblotting was performed. In some experiments, cells were lysed and immunoprecipitated with anti-p38 Ab, followed by in vitro kinase assay with [gamma-(32)P]ATP and GST-activating transcription factor-2 as substrate. IL-1beta rapidly induced p38 phosphorylation in cells transfected with empty vector (pcDNA3.1), but was inhibited by 25% in cells expressing DN MKK3 or DN MKK6. Cotransfection with both DN plasmids decreased phospho-p38 by almost 75%. In vitro kinase assays on IL-1-stimulated FLS also showed that the combination of DN MKK3 and DN MKK6 markedly decreased kinase activity compared with empty vector or the individual DN plasmids. Furthermore, IL-1beta-induced IL-8, IL-6, and matrix metalloproteinase-3 protein production was significantly inhibited in DN MKK3/DN MKK6-transfected cells. The constructs had no effect on the respective mediator mRNA levels. These data demonstrate that MKK3 and MKK6 make individual contributions to p38 activation in FLS after cytokine stimulation, but that both must be blocked for maximum inhibition.

Arthritis, Rheumatoid↗
PubMed2005

TRAIL: at the center of drugable anti-tumor pathways.

Molecular analysis, in vivo and in vitro has identified TRAIL as a central component of anti-cancer networks in the cell. More recently, TRAIL has been shown to be involved in the selective apoptosis of AML cells by histone deacetylase inhibitors (HDACi). Here we summarize findings that the TRAIL pathway is a key factor in the apoptotic action of HDACi, as well as, retinoids and retinoid-combinations.

Apoptosis Regulatory Proteins↗
PubMed2026

Spindle Cell Predominant Anaplastic Pleomorphic Xanthoastrocytoma (WHO Grade 3) With Focal Piloid Features: A Rare Case Study With Comprehensive Molecular Profiling.

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic tumor of the central nervous system. The typical form demonstrates relatively low-grade histologic features, whereas an anaplastic variant shows more aggressive behavior, including increased mitotic activity and necrotic changes. These tumors are often associated with alterations involving key growth signaling pathways and cell cycle regulatory genes, with molecular features that may resemble those seen in other high-grade astrocytic neoplasms. We describe an unusual example of an anaplastic pleomorphic xanthoastrocytoma showing focal piloid differentiation. The patient presented with acute neurologic symptoms, and imaging demonstrated a large, enhancing, well-circumscribed cerebral lesion with limited surrounding edema. Histologic evaluation revealed a highly cellular astrocytic neoplasm composed of spindle-shaped cells with marked pleomorphism, including scattered multinucleated forms, brisk mitotic activity, and necrotic areas. At the periphery, regions with elongated bipolar glial cells and occasional cytoplasmic inclusions suggestive of piloid morphology were identified. Molecular analysis demonstrated an activating alteration in the mitogen-activated protein kinase (MAPK) pathway along with additional genomic abnormalities, while mutations commonly associated with diffuse gliomas were not detected. The presence of piloid features within an otherwise anaplastic tumor is rare and may be relevant to the relatively favorable outcome observed during extended follow-up.

anaplastic↗
PubMed1999

Stress, superoxide, and signal transduction.

A variety of stressful events can trigger the production of free radicals by exposed cells. For years, the effect of such highly reactive radicals was expected to be damaging to cells, altering their biology irreversibly. However, many recent reports have shown that reactive oxygen species can have additional functions, and contribute to important signaling pathways to regulate key biological responses, including cell migration, mitosis, and apoptosis. With this review, we address the role of the small GTP binding protein, Rac, as a regulatory protein that controls superoxide production, and the effect of superoxide and derived oxidants in cell signaling.

Actins↗
PubMed1999

Angiogenesis in ischemic disease.

Angiogenic growth factors and their endothelial receptors function as major regulators of blood vessel formation. The VEGF/VEGFR and the Angiopoietin/Tie2 receptor systems represent key signal transduction pathways involved in the regulation of embryonic vascular development. Inactivation of any of the genes encoding these molecules results in defective vascular development and lethality between embryonic day 8.5 and 12.5. In addition, VEGF and its receptors are also critically involved in the regulation of pathological blood vessel growth in the adult during various angiogenesis-dependent diseases that are associated with tissue hypoxia, such as solid tumor growth and ischemic diseases. It is now well established that therapeutic angiogenesis can be achieved in animal models of hind limb and myocardial ischemia by exogenously adding VEGF and/or other angiogenic growth factors. Available clinical data from human trials also suggests that patients with severe cardiovascular diseases could potentially benefit from such therapies. However, much more work needs to be done to compare the potency of different angiogenic factors or the combination thereof, as well as the best way of delivery, either as recombinant proteins, as naked DNA or via adenoviral vectors. Nevertheless, the therapeutic efficacy of simply injecting naked plasmid DNA or proteins into ischemic tissue to deliver secreted angiogenic factors is an encouraging finding. Time will show whether the adverse side effects of therapeutic angiogenesis, mainly vascular permeability and edema formation, can be minimized and angiogenic factors can be used as an effective therapy in patients for the treatment of ischemic diseases such as arterial occlusive disease, myocardial infarction, and, eventually, also stroke.

Adult↗
PubMed2000

[Intracellular signal transduction pathway and its relation to lymphomagenesis].

An increasing number of reports have suggested that aberration in signal transduction and apoptosis is involved in the development of malignant lymphoma. This review summarizes the signal transduction pathway and the apoptotic cascade that are tightly regulated in relation to each other. Increased cell growth and proliferation is as important in lymphomagenesis as decreased programmed cell death. NPM/ALK chimeric protein and Bcl-2 overexpression are such good examples respectively. TNFR family including its viral analogue, LMP1 display diverse effects on cell proliferation and apoptosis through TRAF mediated NF-kappa B signaling pathway, and are key molecules especially in virus-associated lymphoma, such as EBV and HTLV-I.

Animals↗
PubMed2001

[Physiopathology of parkinsonism and dyskinesias: lessons from surgical observations]].

Current models about the organization of the basal ganglia have provided a resurgence of the surgical treatment of Parkinson's disease (PD). Surgical experience has served to corroborate many of the predictions supported by the model. For instance, hyperactivity of the subthalamopallidal pathway is the key feature in PD and its suppression is associated with an improvement of the cardinal signs and symptoms of the disease. Parkinsonian rest tremor may be related to the oscillatory activity of the subthalamic and pallidal neurons. However, some clinical observations can not be entirely explained by the model. The most important paradox is the disappearance of levodopa-induced dyskinesias after pallidal surgery. This review critically analyzes the validity of the current model based on the surgical observations.

Animals↗
PubMed2001

Transfer of E2F-1 to human glioma cells results in transcriptional up-regulation of Bcl-2.

Strong evidence exists to support the tenet that activation of E2F transcription factors, via alterations in the p16-cyclin D-Rb pathway, is a key event in the malignant progression of most human malignant gliomas. The oncogenic ability of E2F has been related to the E2F-mediated up-regulation of several proteins that positively regulate cell proliferation. However, E2F may indirectly enhance proliferation by activating antiapoptotic molecules. In this work, we sought to ascertain whether E2F-1-mediated events involve the up-regulation of the antiapoptotic molecule Bcl-2. Western blot analyses showed up-regulation of Bcl-2 but not of Bcl-x(L) by 24 h after the transfer of E2F-1. Northern blot studies showed that transfer of E2F-1 also up-regulated Bcl-2 RNA. In support of these findings and the concept that E2F-1 has a direct effect in the induction of Bcl-2, we found a putative E2F binding site within the Bcl-2 sequence. Subsequent gel-mobility shift and supershift experiments involving the CTCCGCGC site in the bcl-2 promoter showed that E2F-1 bound Bcl-2. Transactivation experiments consistently showed that ectopic E2F-1 activated responsive elements located in the -1448/-1441 region in the P1 promoter region of the bcl-2 gene. As expected, other members of the E2F family of transcription factors such as E2F-2 and E2F-4 also transactivated the bcl-2 promoter. Our results demonstrate that E2F-1 modulates the expression of the antiapoptotic molecule Bcl-2 and suggest that up-regulation of Bcl-2 may favor the oncogenic role of E2F-1 and other members of the E2F family of transcription factors.

Binding Sites↗
PubMed2001

[Influence of gravity change on EGF-induced signal transduction].

With the development of aerospace technology, biological effects induced by alteration of gravitation are drawing more and more attention. Among them the influence of alteration of gravitation on cytokine-induced signal transduction has been well studied recently. Epidermal growth factor (EGF)-induced signal transduction can activate increase of cell proliferation in most cell types, so it is always a hotspot in these years. Among the early effects evoked by EGF are receptor clustering, cell rounding, and early gene expression. After the study about the induction of EGF on human A431 cell line, it was observed that EGF-induced c-fos and c-jun expression decreased in microgravity. This was caused by alteration of the EGF receptor and protein kinase C-mediated signal transduction pathways. Meanwhile the key component of cytoskeleton, the actin microfilament system, was found to be linked to the EGF-induced signal transduction cascades either. So it seems reasonable to suggest that the cytoskeleton constitutes the gravity-sensitive cell component.

Actin Cytoskeleton↗
PubMed2002

Targeting IL-15 as a therapeutic strategy in organ transplant rejection.

Much effort is currently directed towards generating and evaluating agents that target the individual components of the alloimmune response, with a view to promoting allograft survival accompanied by minimum side effects. Recently, there has been considerable interest in inhibiting individual cytokine/receptor interactions since they are key elements in pathways for differentiation of immune effector cells. This article examines the utility of targeting interactions of interleukin (IL)-15 with its receptor as a strategy for disabling the T-cell activation events following recognition of foreign major and minor histocompatibility antigens. Experimental evidence suggests that interrupting IL-15/IL-15R interaction may be of therapeutic value in preventing allograft rejection.

Animals↗
PubMed2002

Signal integration following Toll-like receptor triggering.

Innate immune cells sense infectious danger through recognition of pathogen-associated molecular patterns (PAMP). Toll-like receptors (TLRs) play a pivotal role in the recognition of PAMP. Although various TLRs with distinct ligand specificities are expressed almost completely and contemporaneously by innate immune cells, and although central key signal transduction pathways of TLRs are shared, the innate response pattern is not uniform. Innate immune cells organize their response dependent on spatial and temporal requirements and mount a pathogen-specific and microbial-adopted reaction. Thus, after triggering of TLRs, complex signaling interactions take place that control and shape the reactivity patterns of innate immune cells. Here we discuss the central signaling pathways of TLRs and their interconnection with other signaling pathways, with emphasis on Janus kinases/signal transducers and activators of transcription JAK/STAT)-dependent intracellular signals. Cis and trans acting signal convergence mechanisms and mutual influence of TLR and cytokine signaling pathways determine the response profile. Hence, in innate immune cells, integration and processing of microbial-dependent and immunologic signals is achieved within individual cells to ascertain an appropriate immune response. Knowledge of these complex mechanisms will help to clarify the critical events during initiation of infection, which in turn may lead to new strategies to control and overcome infectious disease.

Animals↗