Search Results (538)

Chronic kidney disease (CKD) remains a global health burden, with limited therapeutic options that effectively target the underlying pathophysiology. Nuclear factor erythroid 2-related factor 2 (NRF2), a key regulator of oxidative stress and inflammation, has garnered significant attention as a potential therapeutic target in CKD. Despite encouraging preclinical results, no NRF2-targeted agents have achieved clinical approval for CKD treatment. This review synthesizes emerging evidence showing substantial heterogeneity in NRF2 activity across CKD subtypes, influenced by disease etiology, CKD stage, and rate of disease progression. We elucidate the key therapeutic implications across diverse CKD etiologies and highlight that the therapeutic efficacy of NRF2 activation depends on precise modulation tailored to disease context. Although NRF2 overactivation and the need for stage-dependent modulation are increasingly recognized, this review further delineates the consequences of indiscriminate NRF2 activation, demonstrating that its effects diverge across CKD etiologies and cellular contexts. These insights support a nuanced, context-specific approach to NRF2-targeted strategies and provide a framework to guide future drug development in CKD. Full article

Cardiorenal syndrome (CRS) is a multifactorial clinical condition characterized by the bidirectional deterioration of cardiac and renal function, driven by mechanisms such as renin–angiotensin–aldosterone system (RAAS) overactivation, systemic inflammation, oxidative stress, endothelial dysfunction, and fibrosis. The aim of this narrative review is to explore the key molecular pathways involved in CRS and to highlight emerging therapeutic approaches, with a special emphasis on nutritional interventions. We examined recent evidence on the contribution of mitochondrial dysfunction, uremic toxins, and immune activation to CRS progression and assessed the role of dietary and micronutrient factors. Results indicate that a high dietary intake of sodium, phosphorus additives, and processed foods is associated with volume overload, vascular damage, and inflammation, whereas deficiencies in potassium, magnesium, and vitamin D correlate with worse clinical outcomes. Anti-inflammatory and antioxidant bioactives, such as omega-3 PUFAs, curcumin, and anthocyanins from maqui, demonstrate potential to modulate key CRS mechanisms, including the nuclear factor kappa B (NF-κB) pathway and the NLRP3 inflammasome. Gene therapy approaches targeting endothelial nitric oxide synthase (eNOS) and transforming growth factor-beta (TGF-β) signaling are also discussed. An integrative approach combining pharmacological RAAS modulation with personalized medical nutrition therapy and anti-inflammatory nutrients may offer a promising strategy to prevent or delay CRS progression and improve patient outcomes. Full article

Fecal microbiota transplantation (FMT) promotes growth performance and intestinal development in yellow-feathered broilers, but whether the virome and metabolites contribute to its growth-promoting effect remains unclear. This study removed the microbiota from FMT filtrate using a 0.45 μm filter membrane, retaining the virome and metabolites to perform fecal virome transplantation (FVT), aiming to investigate its regulatory role in broiler growth. Healthy yellow-feathered broilers with high body weights (top 10% of the population) were used as FVT donors. Ninety-six 8-day-old healthy male yellow-feathered broilers (95.67 ± 3.31 g) served as FVT recipients. Recipient chickens were randomly assigned to a control group and an FVT group. The control group was gavaged with 0.5 mL of normal saline daily, while the FVT group was gavaged with 0.5 mL of FVT solution daily. Growth performance, immune and antioxidant capacity, intestinal development and related gene expression, and microbial diversity were measured. The results showed that FVT improved the feed utilization rate of broilers (the feed conversion ratio decreased by 3%; p < 0.05), significantly increased jejunal length (21%), villus height (69%), and crypt depth (84%) (p < 0.05), and regulated the jejunal barrier: insulin-like growth factor-1 (IGF-1) (2.5 times) and Mucin 2 (MUC2) (63 times) were significantly upregulated (p < 0.05). FVT increased the abundance of beneficial bacteria Lactobacillales. However, negative effects were also observed: Immunoglobulin A (IgA), Immunoglobulin G (IgG), Immunoglobulin M (IgM), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6), Tumor Necrosis Factor-alpha (TNF-α), and Interferon-gamma (IFN-γ) in broilers were significantly upregulated (p < 0.05), indicating immune system overactivation. Duodenal barrier-related genes Mucin 2 (MUC2), Occludin (OCLN), Claudin (CLDN1), and metabolism-related genes solute carrier family 5 member 1 (SLC5A1) and solute carrier family 7 member 9 (SLC7A9) were significantly downregulated (p < 0.05). The results of this trial demonstrate that, besides the microbiota, the gut virome and metabolites are also functional components contributing to the growth-promoting effect of FMT. The differential responses in the duodenum and jejunum reveal spatial heterogeneity and dual effects of FVT on the intestine. The negative effects limit the application of FMT/FVT. Identifying the primary functional components of FMT/FVT to develop safe and targeted microbial preparations is one potential solution. Full article

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease characterized by chronic inflammation, vascular remodeling, and immune dysregulation. COVID-19, caused by SARS-CoV-2, shares several systemic immunohematologic disturbances with IPF, including cytokine storms, endothelial injury, and prothrombotic states. Unlike general comparisons of viral infections and chronic lung disease, this review offers a focused analysis of the shared hematologic and immunologic mechanisms between COVID-19 and IPF. Our aim is to better understand how SARS-CoV-2 infection may worsen disease progression in IPF and identify converging pathophysiological pathways that may inform clinical management. We conducted a narrative synthesis of the peer-reviewed literature from PubMed, Scopus, and Web of Science, focusing on clinical, experimental, and pathological studies addressing immune and coagulation abnormalities in both COVID-19 and IPF. Both diseases exhibit significant overlap in inflammatory and fibrotic signaling, particularly via the TGF-β, IL-6, and TNF-α pathways. COVID-19 amplifies coagulation disturbances and endothelial dysfunction already present in IPF, promoting microvascular thrombosis and acute exacerbations. Myeloid cell overactivation, impaired lymphocyte responses, and fibroblast proliferation are central to this shared pathophysiology. These synergistic mechanisms may accelerate fibrosis and increase mortality risk in IPF patients infected with SARS-CoV-2. This review proposes an integrative framework for understanding the hematologic and immunologic convergence of COVID-19 and IPF. Such insights are essential for refining therapeutic targets, improving prognostic stratification, and guiding early interventions in this high-risk population. Full article

Background/Objectives: Early diagnosis of stroke is crucial for effective treatment with tissue plasminogen activator (tPA) and endovascular thrombectomy. Emergency medical services (EMSs) screening and the early activation of emergency department (ED) stroke protocols reduce treatment times and improve patient outcomes. This study aims to validate ED stroke protocol activation by EMSs in a large stroke center. Methods: This retrospective cross-sectional study was conducted at Magen David Adom and Shamir Medical Center between 1 January 2019 and 31 December 2019. Data were categorized into patients suspected by EMSs of having a stroke and those not suspected by EMSs but diagnosed as having a stroke in the ED. The primary outcome was the accuracy of EMSs in activating ED stroke protocols. Results: In this study, there were 23,061 patients, of which 11,841 (51.9%) were females. The mean age was 61.4 (SD = 22.72) years old. EMSs suspected 743 (3.22%) patients were having a stroke. In 587 (79%), EMSs activated ED stroke protocols. There were 88 cases where strokes were diagnosed in the ED when EMSs did not suspect a stroke. The overall EMSs negative predictive value (NPV) was 100% while the positive predictive value (PPV) was 20%. Conclusions: While Israeli EMSs over-activate the ED stroke protocol, stroke patients are almost never missed, achieving the goal of prehospital stroke screening. To prevent resource waste, all involved teams should be notified, and the actual activation of the stroke protocol should be carried out by an ED physician upon patient arrival. Communication between all levels regarding stroke protocol should also be increased to decrease the time to treatment. Full article

Industrial development has increased environmental dioxin concentrations, sparking concern about human health impacts. Examining dioxin neurotoxicity has highlighted associations with cognitive impairment and behavioral abnormality. Dioxins are ligands of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor; it is speculated that dioxin-induced AHR activation is pivotal for toxic effects. Accurate AHR-expressing cell identification is therefore indispensable for understanding the molecular and cellular mechanisms of dioxin toxicity. Herein, current knowledge regarding AHR expression in the mammalian brain is summarized, and dioxin neurotoxicity mechanisms are discussed. Histological studies show AHR-expressing neurons in multiple brain regions, including the hippocampus and cerebral cortex. Dopaminergic and noradrenergic neurons exhibit AHR expression, suggesting possible roles in the monoaminergic system. AHR overactivation evokes dendritic arborization atrophy, whereas its deficiency increases complexity, implying that AHR-mediated signaling is crucial for neuronal growth and maturation. AHR is also involved in neurogenesis and neuronal precursor migration. Collectively, these findings support the notion that dioxin-induced AHR overactivation in individual neurons disrupts neural circuit structure, ultimately leading to impaired brain function. However, as AHR downstream signaling is intertwined with various molecules and pathways, the precise mechanisms remain unclear. Further studies on the expression, signaling, and roles of AHR are needed to clarify dioxin neurotoxicity. Full article

In this study several phosphorus fertilizers were evaluated under controlled production conditions using Lactuca sativa var. baby leaf and a clay-loam soil of pH 6.5 as a plant–soil model system. Various inorganic (phosphate rock, monoammonium phosphate, struvite), organic (bone meal and bone meal pelletized with compost) and organomineral fertilizers (phosphate rock, monoammonium phosphate, struvite pelletized with compost) were compared. The soil properties, crop yield, morphological aspects and metabolomics of the plants were analyzed. After 45 days of the growing cycle, the organomineral fertilizers (OMFs) composed of compost and monoammonium phosphate (OMF₂(MAP+C)) or struvite (OMF₃(STR+C)) exhibited the best yield results: 101.37 g and 83.21 g, respectively. These treatments also exhibited the best phosphorus use efficiency (PUE) results: 7.40% and 8.33%, respectively. The yield of plants treated with MAP was 56.01 g, and its PUE was 5.33%. The yield of plants treated with STR was 62.10 g and the PUE was 4.67%. Accordingly, the development of OMFs with compost had a positive effect regarding MAP and STR fertilization. Lettuce fertilized with organic bone meal fertilizers had the lowest yield and nutrient use efficiency. The non-targeted metabolic study of green tissue revealed an overactivation of the TriCarboxylic Acids-TCA cycle and amino acid biosynthesis in plants fertilized with bone meal and phosphate rock treatments, likely as a plant stress response. The overall conclusion of this work is that the development of OMFs with compost is a good strategy to increase soil P availability and, accordingly, plant P uptake and %PUE. Full article

Background: An acute angle-closure attack (AAC) is an ocular emergency that results from a rapid increase in intraocular pressure (IOP). Sustained IOP elevation induces severe degeneration of retinal ganglion cells (RGCs) without treatment. Overactivated microglia, key participants in innate immune responses, have critical roles in the pathogenesis of IOP-induced RGC death, although precise mechanisms remain unclear. In the present study, we used a rat ex vivo acute glaucoma model to investigate the role of microglial signaling in RGC death and examined whether pharmacological depletion of microglia using a CSF-1R inhibitor, PLX5622, exerts neuroprotection against pressure-induced retinal injury. Methods: Ex vivo rat retinas were exposed to hydrostatic pressure (10 mmHg or 75 mmHg) for 24 h. Pressure-dependent changes in retinal microglia and RGCs were detected by immunofluorescence. Morphological changes in the retina and RGC apoptosis were examined using light microscopy and TUNEL staining, respectively. The expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β were examined using Western blotting. Effects of PLX5622, an agent that depletes microglia, were examined in morphology, apoptosis, and protein expression assays, while TAK-242, a TLR4 inhibitor, was examined against protein expression. Results: Pressure loading at 75 mmHg markedly increased activated microglia and apoptotic RGCs in the isolated retinas. Western blotting revealed increases in expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg compared to 10 mmHg. Inhibition of pressure-induced increases in NLRP3 by TAK-242 indicates that pressure elevation induces RGC death via activation of the TLR4–NLRP3 inflammasome cascade. PLX5622 depleted microglia at 75 mmHg and significantly decreased expression of NLRP3, active caspase-1, pro IL-1β, and IL-1β at 75 mmHg, resulting in preservation of RGCs. Conclusions: These results indicate that pressure elevation induces proliferation of inflammatory microglia and promotes IL-1β production via activation of the TLR4–NLRP3 inflammasome cascade, resulting in RGC death. Pharmacological depletion of microglia with PLX5622 could be a potential neuroprotective approach to preserve RGCs from inflammatory cytokines in AAC eyes. Full article

Psoriasis is a chronic, immune-mediated inflammatory skin disease with complex genetic, environmental, and immunological determinants. Beyond the skin, it affects multiple systems, including the joints and cardiovascular system. A hallmark of psoriasis is an overactivation of the innate and adaptive immune responses, leading to dysregulated cytokine signaling, altered keratinocyte function, and aberrant expression of structural and regulatory proteins. In recent years, growing attention has been given to the skin as a neuro–immuno–endocrine organ, with evidence showing the role of stress-related neuropeptides, UVB-induced immune modulation, and vitamin D signaling in the disease pathogenesis. This review highlights emerging evidence on key multifunctional proteins—elafin, chemerin, and NAMPT (visfatin)—that exert both pro- and anti-inflammatory actions. Although still underexplored, these molecules appear to contribute significantly to the psoriatic microenvironment by modulating inflammation, immunity, and skin barrier function. Their dual roles suggest complex interactions within the cutaneous immune–neuroendocrine network, positioning them as potential biomarkers or therapeutic targets in psoriasis. By integrating insights into classical and emerging mediators, this review aims to provide a comprehensive perspective on the evolving landscape of psoriasis pathophysiology. Full article

Triple-negative breast cancer is the most aggressive subtype of breast cancer and is associated with the worst prognosis. Conventional chemotherapy remains the gold standard treatment for this disease but is associated with a high relapse rate, highlighting the urgent need for effective targeted therapies. The PI3K/Akt/mTOR pathway, dysregulated in nearly 60% of these cancers, appears to be a prime target. It involves a signaling cascade beginning with PI3K activation followed by activating phosphorylation of Akt and then mTOR complex, which activates oncogenic processes by enhancing protein synthesis, inhibiting apoptosis, dysregulating autophagy and promoting DNA repair that supports tumor cell survival. Moreover, the PI3K/Akt/mTOR pathway plays a central role in the development of chemoresistance. Numerous alterations (activating the mutation of PIK3CA or the loss of tumor suppressor PTEN) may lead to its overactivation. Targeted inhibitors of PI3K, Akt and mTOR have been developed to counteract this dysregulation. However, numerous cancer resistance mechanisms have emerged, reducing their efficacy, for example, reactivation of Akt following mTOR blockade, reactivation of the pathway by insulin signaling or activation of compensatory pathways such as the MAPK pathway, thus limiting their integration into routine practice. To counteract these resistances, combination therapies currently being investigated in clinical trials aim to improve clinical outcomes of PI3K/Akt/mTOR pathway inhibition. The aim of this review was to summarize current therapies developed to target this pathway in TNBC, with a focus on the resistance mechanisms that limit their effectiveness. Full article

Protein kinase CK2 has emerged as a pivotal regulator of cellular processes involved in skin homeostasis, including cell proliferation, differentiation and inflammatory response regulation. In fact, CK2 activity dysregulation is implicated in the pathogenesis of different skin diseases, such as psoriasis, cancer and inflammatory dermatoses. CK2 overactivation fosters keratinocyte proliferation and pro-inflammatory cytokine production through the STAT3 and Akt pathways in psoriasis, thus contributing to epidermal hyperplasia and inflammation. In the realm of oncology, CK2 overexpression correlates with tumor progression, facilitating cell survival and metastasis in melanoma and non-melanoma skin cancers. Pharmacological inhibition of CK2 has demonstrated therapeutic potential, with CX-4945 (Silmitasertib) as the most studied adenosine triphosphate-competitive inhibitor (ATP-competitive inhibitor). Preclinical models reveal that CK2 inhibitors effectively mitigate pathological features of psoriasis, regulate keratinocyte differentiation, and suppress tumor growth in skin cancers. These inhibitors also potentiate the efficacy of conventional chemotherapeutics and exhibit anti-inflammatory effects in dermatological conditions. Future research will aim to enhance the specificity and delivery of CK2-targeting therapies, including topical formulations, to minimize systemic side effects. Combination therapies integrating CK2 inhibitors with other agents might offer synergistic benefits in managing skin diseases. This review underscores CK2’s critical role in skin and its therapeutic potential as a pharmacological target, advocating for innovative approaches to harness CK2 inhibition in dermatology. Full article

Heat stress (HS), an important environmental stressor for healthy poultry farming, has been shown to have a detrimental effect on production performance and induce serious diseases through immune system damage. As the avian peripheral immune system’s primary organ, spleen is subject to complex biological processes in response to HS injury. Histopathological characterization demonstrated that HS resulted in the destruction of the splenic red and white medulla, a decrease in cell density and organ atrophy. These changes directly impaired pathogen clearance and immune surveillance. At the physiological level, the impact of HS is characterized by disrupted metabolic homeostasis through interrupting neuroendocrine function. This, in turn, results in a significant suppression of humoral immune response. The oxidative-inflammatory cascade constitutes the core pathology of this disease. Energy metabolism disorder triggered by mitochondrial dysfunction and redox imbalance form a vicious circle, which promotes apoptosis signaling cascade. Meanwhile, over-activation of intrinsic immune system triggers a series of inflammatory factors, which further amplifies effects of tissue damage. The present prevention and control strategies are centered on synergistic anti-inflammatory and antioxidant interventions with nutrient modulators and plant actives. Nevertheless, it is imperative for future studies to incorporate multi-omics technologies in order to analyze the metabolic mechanisms and patterns of stress and establish a precise intervention strategy based on immune homeostatic regulation. This review systematically investigated the multilevel regulatory mechanisms of HS-induced spleen injury, which provides a theoretical basis for the mechanistic analysis and technological innovation of the prevention and control of HS syndrome in poultry. Full article

Age-related macular degeneration (AMD), the leading cause of irreversible blindness worldwide, represents a complex neurodegenerative disorder whose pathogenesis remains elusive. At the core of AMD pathophysiology lies the retinal pigment epithelium (RPE), whose epithelial–mesenchymal transition (EMT) has emerged as a critical pathological mechanism driving disease progression. This transformative process, characterized by RPE cell dedifferentiation and subsequent extracellular matrix remodeling, is orchestrated through a sophisticated network of molecular interactions and cellular signaling cascades. Our review provides a comprehensive analysis of the molecular landscape underlying RPE EMT in AMD, with particular emphasis on seven interconnected pathological axes: (i) oxidative stress and mitochondrial dysfunction, (ii) hypoxia-inducible factor signaling, (iii) autophagic flux dysregulation, (iv) chronic inflammatory responses, (v) complement system overactivation, (vi) epigenetic regulation through microRNA networks, and (vii) key developmental signaling pathway reactivation. Furthermore, we evaluate emerging therapeutic strategies targeting EMT modulation, providing a comprehensive perspective on potential interventions to halt AMD progression. By integrating current mechanistic insights with therapeutic prospects, this review aims to bridge the gap between fundamental research and clinical translation in AMD management. Full article

Virtual reality (VR) is a promising tool in spinal cord injury (SCI) rehabilitation, particularly through virtual adaptations of functional tests like the Box and Block test (BBT). However, a comprehensive dynamic comparison between real and virtual BBT is lacking. This study investigates the kinematic and electromyographic (EMG) differences between healthy individuals and SCI patients performing both real (RBBT) and virtual (VBBT) versions of the BBT. An electromagnetic motion-tracking system, an instrumented glove, and surface EMG electrodes were used to capture hand trajectories, joint angles, and forearm muscle activation. The analysis included cycle-averaged and temporal kinematic and EMG parameters. Our findings reveal that both groups showed increased trajectory length and velocity peaks during the VBBT, with more pronounced increases in SCI patients. Unlike healthy individuals, SCI patients also showed increased finger and thumb flexion during VBBT. Cycle-averaged EMG values were lower in healthy participants during VBBT, likely due to reduced motor demands and lack of real grasping. Conversely, SCI patients exhibited higher muscle activity, suggesting impaired coordination and compensatory overactivation. Healthy individuals showed consistent temporal kinematic synergies and muscle activation, whereas they were altered in SCI patients, especially during reaching. These findings highlight the need for rehabilitation strategies to improve motor control and feedback integration. Full article

Psoriasis pathogenesis involves dysregulated immune responses, yet the role of protein prenylation (particularly PGGT1B-mediated geranylgeranylation) in macrophage-driven inflammation remains poorly understood. This study aims to explore the role and molecular mechanism of protein geranylgeranyltransferase type I subunit beta (PGGT1B) in the development of psoriasis. Myeloid cell-specific PGGT1B gene knockout mice were generated, and a mouse psoriasis model was established with imiquimod to study the role and mechanism of PGGT1B gene downregulation-induced macrophage activation in the pathogenesis of psoriasis. Bone marrow-derived macrophages (BMDMs) from wild-type and PGGT1B knockout mice were cultured and stimulated with resiquimod (R848) to simulate the immune microenvironment of psoriasis. In addition, the differentially expressed genes induced by PGGT1B knockout were analyzed using RNA-seq, and bioinformatics analysis was carried out to study the possible biological process of PGGT1B regulation. Finally, PMA-THP-1 was co-cultured with HaCaT cells to study the effect of PGGT1B deletion in macrophages on the proliferation and differentiation of keratinocytes. Bone marrow PGGT1B deficiency aggravated the psoriasis-like lesions induced by imiquimod in mice. In BMDMs with PGGT1B deficiency, the NF-κB signaling pathway was over-activated by R848, and the expressions of proinflammatory cytokines IL-1β, IL-6, and TNF-α were significantly increased. Activation of cell division cycle 42 (CDC42) may mediate the activation of the NF-κB pathway in PGGT1B-deficient BMDMs. PGGT1B deletion can promote the proliferation and inhibit the differentiation of HaCaT cells. Reduced PGGT1B levels can increase the expression of CDC42, which further activates NLRP3 inflammation in macrophages through NF-κB signaling, further aggravating the inflammatory state of psoriasis. Psoriasis-like lesions induced by IMQ are aggravated when PGGT1B expression is reduced in mouse bone marrow cells. A possible mechanism for this is that PGGT1B-deficient macrophages migrate to the epidermis more easily during psoriasis, which leads to the activation of Cdc42, NF-κB signaling, and NLRP3 inflammatory corpuscles. Full article