Search Results (4,091)

Two-pore channel 2 (TPC2) is a member of the endolysosomal ion channel family, playing critical roles in intracellular calcium signaling and endomembrane dynamics. This review provides an in-depth analysis of TPC2, covering its structural and functional properties, physiological roles, and involvement in human diseases. We discuss current experimental approaches to studying TPC2, including heterologous expression in plant vacuoles and computational modeling strategies. Particular emphasis is placed on the structural determinants of ion permeation, with a focus on the selectivity filter and the central cavity’s influence on channel kinetics. Furthermore, we explore emerging roles of TPC2 in viral infections, particularly SARS-CoV-2, and in cancer, including melanoma progression and neoangiogenesis. The inhibitory potential of natural compounds, such as naringenin, is also examined. By offering a comprehensive overview of current knowledge and methodologies, this review underscores the potential of TPC2 as a promising pharmacological target in both infectious and neoplastic diseases. Full article

Phosphorus is a key macronutrient central to the processes of energy and information storage and exchange in the cell. Single-celled photosynthetic organisms, including microalgae, accumulate intracellular reserves of phosphorus (mostly in the form of polyphosphate) essential for the maintenance of cell homeostasis during fluctuations of external phosphorus availability. The polyphosphate reserves in microalgal cells are formed by polyphosphate polymerases—a ubiquitous enzyme family represented mainly by prokaryotic (PPK-type, typical of prokaryotes, e.g., cyanobacteria) and VTC-type polyphosphate polymerases harbored by eukaryotic microalgae, although certain species possess both PPK and VTC types of the enzyme. This enzyme is important for the environmental fitness of microalgae dwelling in diverse habitats, as well as for the efficiency of microalgae-based systems for the biocapture of phosphate from waste streams and for upcycling this valuable nutrient to agricultural ecosystems via biofertilizer from microalgal biomass. This review summarizes the recent progress in the field of structure, regulation, and functioning of VTC in microalgae. In conclusion, biotechnological implications and perspectives of VTC as a target of microalgal cell engineering and bioprocess design for improved phosphate bioremoval efficiency and culture robustness are considered. Full article

Human cryptosporidiosis caused by the zoonotic apicomplexan parasite Cryptosporidium parvum represents a neglected and re-emerging poverty-related disease. C. parvum possesses minimalistic metabolic capacities and highly depends on its intestinal epithelial host cell for intracellular replication. Based on previous results showing that glycolysis and glutaminolysis inhibition diminished C. parvum replication in vitro, we here investigated the impact of the olive oil component oleocanthal on C. parvum infection in HCT-8 cells under physioxia (5% O₂) and hyperoxia (21% O₂). Oleocanthal targets a broad spectrum of regulatory molecules, amongst which mTOR represents a master regulator of glycolysis and glutaminolysis. Using a host cell pre-treatment as well as a pre- and post-infection treatment protocol, 5 µM oleocanthal reduced C. parvum infection rates between 51% and 94%. Host cellular metabolic conversion rates linked oleocanthal-induced inhibition of C. parvum infection with an impairment in glutaminolysis, representing an important metabolic pathway in intestinal cells. The principal involvement of mTOR in C. parvum inhibition was confirmed by another mTOR-inhibitor (PP242, 0.5 µM), which also reduced C. parvum infection by 70–77%. Given that oleocanthal is not a selective mTOR inhibitor, we assume that this compound drives a multi-target-based inhibition of asexual C. parvum replication, amongst which mTOR is addressed. Full article

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Iron metabolism and chronic inflammation are two interrelated processes that significantly influence the initiation and progression of CRC. Iron is essential for cell proliferation, but its excess promotes oxidative stress and DNA damage, while inflammation driven by cytokine-regulated pathways accelerates tumourigenesis. We therefore conducted this narrative review to collate the available evidence on the link between iron homeostasis and inflammatory signalling in CRC and highlight potential diagnostic and therapeutic applications. Methods: This narrative review of preclinical and clinical studies explores the molecular and cellular pathways that connect iron regulation and inflammation to CRC. Key regulatory molecules, such as the transferrin receptor (TFRC), ferroportin (SLC40A1), ferritin (FTH/FTL), hepcidin, and IL-6, were reviewed. Additionally, we summarised the findings of transcriptomic, epigenomic, and proteomic studies. Relevant therapeutic approaches, including iron chelation, ferroptosis induction, and anti-inflammatory strategies, were also discussed. Results: Evidence suggests that CRC cells exhibit altered iron metabolism, marked by the upregulation of transferrin receptor (TFRC), downregulation of ferroportin, and dysregulated expression of ferritin. Inflammatory mediators such as IL-6 activate hepcidin and STAT3 signalling, which reinforce intracellular iron retention and oxidative stress. Increased immune evasion, epithelial proliferation, and genomic instability appear to be linked to the interaction between inflammation and iron metabolism. Other promising biomarkers include ferritin, hepcidin, and composite gene expression signatures; however, their clinical application remains limited. Although several preclinical studies support the use of targeted iron therapies and combination approaches with anti-inflammatory agents or immunotherapy, there is a lack of comprehensive clinical validation confirming their efficacy and safety in humans. Conclusion: Although preclinical studies suggest that iron metabolism and inflammatory signalling form an interconnected axis closely linked to CRC, translating this pathway into reliable clinical biomarkers and effective therapeutic strategies remains a significant challenge. Future biomarker-guided clinical trials are essential to determine the clinical relevance and to establish precision medicine strategies targeting the iron–inflammation crosstalk in CRC. Full article

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta (Aβ) peptide, intracellular neurofibrillary tangles (NFTs), severe neuronal loss, and a marked decline in cholinergic function. Due to the limited efficacy of currently available therapies, the search for new chemical scaffolds able to target multiple pathological mechanisms remains an urgent priority. Among the most promising strategies are heterocyclic frameworks that can simultaneously interact with cholinesterase (ChE) enzymes and inhibit amyloid-β (Aβ) aggregation while also exhibiting antioxidant activity. In this context, we report a series of quinazoline derivatives synthesized via a sequential, one-pot multicomponent reaction, in good yields. Several of these compounds demonstrated notable antioxidant properties, as well as inhibitory effects on ChE activity and Aβ_1-42 self-aggregation, highlighting their potential as multifunctional agents for the treatment of neurodegenerative disorders. Notably, 2-ethyl-4-(3,4-Dimethoxyphenyl)aminoquinazoline (3h) demonstrated the most balanced biological profile among the tested compounds, exhibiting an ORAC value of 5.73 TE, an acetylcholinesterase (AChE) inhibition IC₅₀ = 6.67 μM, and 36.68% inhibition of Aβ_1–42 aggregation, closely approaching the activity of curcumin. These findings highlight compound 3h as a promising quinazoline-based hit for the development of multifunctional agents targeting AD. Full article

Today, science and medicine are striving to develop novel techniques for treating deadly diseases, including a wide range of cancers. Efforts are being made to better understand the molecular and biochemical mechanisms of tumor cell functioning, but a particular emphasis has recently been given to investigating immune cells residing in the tumor microenvironment, which may lead to revolutionary benefits in the design of new immunotherapies. Among these cells, tumor-associated macrophages (TAMs) are highly abundant and act as critical regulators of ovarian cancer progression, metastasis, and resistance to therapy. Their dual nature—as drivers of malignancy and as potential therapeutic mediators—has positioned them at the forefront of research into next-generation immunotherapies. As therapeutic targets, approaches include blocking macrophage recruitment (e.g., CSF-1/CSF-1R inhibitors), selectively depleting subsets of TAMs (e.g., via Folate Receptor Beta), or reprogramming immunosuppressive M2-like macrophages toward an anti-tumor M1 phenotype. On the other hand, macrophages can also serve as a therapeutic tool—they may be engineered to enhance anti-tumor immunity, as exemplified by the development of Chimeric Antigen Receptor Macrophages (CAR-Ms), or leveraged as delivery vehicles for targeted drug transport into the tumor microenvironment. A particularly innovative strategy involves Macrophage–Drug Conjugates (MDCs), which employs the transfer of iron-binding proteins (TRAIN) mechanism for precise intracellular delivery of therapeutic agents, thereby enhancing drug efficacy while minimizing systemic toxicity. This review integrates current knowledge of TAM biology, highlights emerging therapeutic approaches, and underscores the promise of macrophage-based interventions in ovarian cancer. By integrating macrophage-targeting strategies with advanced immunotherapeutic platforms, novel treatment paradigms may be determined that could substantially improve outcomes for patients with ovarian cancer and other solid tumors. Our work highlights that macrophages should be a particular area of research interest in the context of cancer treatment. Full article

The cellular membrane is a dynamic structure composed of lipids and proteins organized into specialized domains that facilitate interactions between extracellular molecules and the intracellular environment. Tetraspanins are a family of transmembrane proteins involved in diverse cellular processes, including membrane stabilization and fusion, endocytosis, extracellular vesicle formation, and the organization of proteins and lipids at specific membrane sites known as Tetraspanin-Enriched Microdomains (TEMs). These lipid–protein interactions play a critical role in the replicative cycle of Orthoflavivirus, including dengue, Zika, and West Nile, by facilitating viral entry, replication, assembly, and egress. In addition, tetraspanins also regulate the biogenesis and function of extracellular vesicles, contributing to viral dissemination, persistent infection, and immune evasion. This review summarizes the current knowledge on the structural and functional aspects of tetraspanins, their interplay with lipids, and their emerging roles in the Orthoflavivirus replicative cycle. We also discuss how these insights may inform the development of antiviral strategies targeting membrane organization and virus–host interactions. Full article

Hypophosphatemia, defined as serum phosphate levels below 2.5 mg/dL, is a common yet underrecognized electrolyte disturbance in critically ill patients, with prevalence estimates reaching up to 80%. This review explores the intricate bidirectional relationship between hypophosphatemia and hyperventilation, emphasizing its profound implications for respiratory function and critical care management. Hypophosphatemia impairs oxygen delivery by depleting 2,3-diphosphoglycerate (2,3-DPG), disrupts central respiratory drive, and weakens respiratory muscles, leading to hyperventilation, ventilatory failure, and prolonged mechanical ventilation. Conversely, hyperventilation exacerbates hypophosphatemia through respiratory alkalosis, triggering intracellular phosphate shifts and metabolic cascades that rapidly deplete serum levels. This cycle creates significant challenges for ventilator weaning and increases morbidity and mortality. Underlying mechanisms include impaired ATP synthesis, altered chemoreceptor sensitivity, and systemic inflammatory responses. Hypophosphatemia-induced hyperventilation manifests as unexplained tachypnea and respiratory alkalosis, often misdiagnosed as anxiety or pain, while hyperventilation-induced hypophosphatemia contributes to diaphragmatic dysfunction and poor ventilatory performance. Common precipitating factors include refeeding syndrome, diabetic ketoacidosis, continuous renal replacement therapy, and malnutrition. Complications extend beyond respiratory dysfunction to include cardiac depression, immune dysfunction, prolonged ICU stays, and increased healthcare costs. Current diagnostic approaches rely on serum phosphate measurements, which poorly reflect total body stores due to significant intracellular shifts. Emerging biomarkers such as fibroblast growth factor 23 (FGF23) and advanced monitoring technologies, including continuous phosphate tracking, may enhance recognition. Treatment strategies emphasize targeted phosphate repletion based on severity, with intravenous supplementation and ventilatory support tailored to minimize complications. Preventive measures, including risk stratification, prophylactic supplementation, and ventilator management, are critical for high-risk populations. Despite advances, knowledge gaps persist in optimizing monitoring and repletion protocols, understanding genetic variations, and identifying ideal phosphate targets for improved respiratory outcomes. This review provides a comprehensive framework for recognizing and managing hypophosphatemia’s impact on respiratory dysfunction in critically ill patients. Adopting evidence-based interventions and leveraging emerging technologies can significantly improve clinical outcomes, reduce ICU complications, and enhance recovery in this vulnerable population. Full article

Even though Pt(II)-based drugs represent the standard in cancer therapy, their use is seriously limited by severe side-effects (renal toxicity, allergic reactions, gastrointestinal disorders, hemorrhage and hearing loss), drug resistance and a grim prognosis. This review presents the results of multiple studies showing different nanoparticle-based platforms as delivery agents in order to overcome these drawbacks. The approach of using nanoparticle-based drug delivery systems of Pt drugs and prodrugs is promising due to key advantages like specific targeting and thereby reduced toxicity to healthy cells; increased stability in the bloodstream; multiple mechanisms of action such as stimulating anti-tumor immunity, responding to environmental stimuli (light, pH, etc.), or penetrating deeper into tissues; enhanced efficacy by their combination with other therapies (chemotherapy, gene therapy) to amplify the anti-tumor effect. However, certain challenges need to be overcome before these solutions can be widely applied in clinics. These include issues related to biocompatibility, large-scale production, and regulatory approvals. In conclusion, using nanoparticles to deliver Pt-based drugs represents an advanced and highly promising strategy to make chemotherapy more effective and less toxic. Nonetheless, further studies are required for the better understanding of intracellular mechanisms of action, toxicity and the pharmacokinetics of nanoparticles, and physical–chemical standardization. Full article

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite responsible for toxoplasmosis, a disease with significant health implications for humans and animals. The surface antigen 1 (SAG1) of T. gondii is a major immunodominant protein that facilitates host cell invasion, making it an ideal target for diagnostic and therapeutic interventions. Immunoglobulin Y (IgY), the primary antibody in avian species, offers unique advantages over mammalian IgG, including easier animal care, lower costs, high-yield production, and potential passive immunization. Objectives: This study aimed to induce, purify, and characterize IgY antibodies targeting T. gondii SAG1 from hen egg yolks. Methods: The coding region of the mature portion of T. gondii SAG1 was amplified by PCR, cloned into the pET32a(+) vector for heterologous expression in E. coli. The recombinant SAG1 (rSAG1) was purified by affinity chromatography and used to immunize hens. IgY was extracted from egg yolks using PEG. SDS-PAGE and spectrophotometry were used to evaluate purity and concentration. By ELISA, Western blot, and flow cytometry, the specificity of IgY was assessed against recombinant and endogenous, native, and denatured SAG1. Results: Purified IgY demonstrated strong recognition of both recombinant and native SAG1 in ELISA and Western blot, and against T. gondii tachyzoites by flow cytometry. Conclusions: SAG1-specific IgY was produced in a pure form; it could be helpful in research, diagnosis, and treatment at low costs on a larger production scale, with minimal animal harm. Full article

Gossypol, a polyphenolic naphthalene derivative and yellow polyphenolic pigment found in cotton seed glands, presents notable environmental, animal, and human health hazards. To screen for yeast strains capable of utilizing gossypol and to investigate their removal efficiency and mechanisms. Yeast strains capable of utilizing gossypol as the exclusive carbon source were isolated from cotton field soil. The identification of these strains involved assessment of colony morphology, physiological and biochemical characteristics, and phylogenetic analysis utilizing 26S rDNA gene sequences. Safety evaluations included hemolytic and antibiotic susceptibility tests. The growth responses of the selected strains to varying temperatures and pH levels were determined. Using cotton meal as the solid fermentation substrate, the effects of single factors on gossypol removal by the strains were determined. The intracellular and extracellular localization as well as the nature of the gossypol-removing active components in the strains were characterized, followed by an investigation into the molecular mechanism of gossypol removal using LC-MS analysis. A total of 17 gossypol-utilizing strains were isolated from cotton field soil samples, with strain ZYS-3 demonstrating superior removal capability. Strain ZYS-3 was identified as Meyerozyma guilliermondii, exhibiting no hemolytic activity and susceptibility to nine commonly used antifungal agents. The optimal growth parameters for this strain were determined to be a temperature of 30 °C and a pH of 5.0. In solid-state fermentation using cotton meal at 30 °C with initial fermentation conditions (10% corn flour added as an external carbon source, 40% moisture content, and 6% inoculum concentration) for 3 days, strain ZYS-3 achieved a gossypol removal rate of 73.57%. Subsequent optimization of the fermentation process, including the addition of 10% corn flour as an external carbon source, adjustment of moisture content to 55%, and inoculum concentration to 10%, resulted in an increased gossypol removal rate of 89.77% after 3 days of fermentation, representing a 16.2% enhancement over the initial conditions. Assessment of gossypol removal activity revealed that strain ZYS-3 predominantly removes gossypol through the secretion of extracellular enzymes targeting specific active groups (phenolic hydroxyl groups and aldehyde groups) within the gossypol molecule. These enzymes facilitate oxidation and elimination reactions, leading to the opening of the naphthalene ring and subsequent removal of gossypol. Full article

Fatty acid-binding proteins (FABPs) represent a superfamily of intracellular lipid chaperones essential for the transport of lipids and homeostatic lipid metabolism. Although well-known for their role in systemic metabolic diseases, emerging evidence has identified brain-expressed FABPs as core players in neurodegeneration. This review focuses on brain-expressed FABPs, synthesizing recent advancements that link their role in metabolic dysregulation to neurotoxicity. We present a system that integrates these proteins within a multi-tiered complex pathobiological system that involves: an advanced glial “meta-inflammation” paradigm; a novel view on proteotoxicity via liquid–liquid phase separation (LLPS); changes in the gut–brain axis; and an involvement in the regulation of ferroptosis. Additionally, we also discuss the emerging pharmacological pipeline, highlighting notable preclinical ligands and drawing important lessons from systemic disease first-in-class-targeted FABPs. These first-in-class therapies have successfully validated this target family in systemic diseases. Finally, we explore future therapeutic strategies, where we emphasize the challenges and the precision cell-type-specific delivery approaches to harness the full therapeutic potential of these pivotal proteins. Full article

Porcine epidemic diarrhea virus (PEDV), the causative agent of porcine epidemic diarrhea (PED), induces vomiting, watery diarrhea, and severe dehydration in pigs. It exhibits particularly high lethality in neonatal piglets, posing a significant threat to the global swine industry and inflicting substantial economic losses. The host innate immune system serves as the primary defense against viral invasion; however, PEDV employs multiple strategies to evade this response. This review systematically summarizes the multiple molecular mechanisms by which PEDV evaded the host’s innate immunity, including interfering with host intracellular signaling pathways by virally encoded proteins, antagonizing the host’s antiviral factors and related immune genes to suppress the innate immune responses, and regulating the autophagy process of the host cells, thereby achieving the escape of the host’s innate immunity. A comprehensive understanding of how PEDV subverts innate immunity is crucial for developing effective control strategies and therapeutics. This review aims to provide novel insights and potential targets for combating PED. Full article

Numerous studies over three decades have confirmed the significant role of S100A4/FSP1 in the development of metastasis, the formation of the cellular and inflammatory components of the tumor microenvironment, and the development of fibrosis. S100A4 is a promising biomarker whose detection is associated with predicting overall survival in cancer patients. The action of S100A4 is mediated by extra- and intracellular signaling pathways involving targets currently used in the development of therapeutic agents, including monoclonal antibodies and drugs for targeted protein degradation. This review is devoted to the analysis of publications from the perspective of developing diagnostic predictive platforms and modern targeted antitumor therapy aimed at inhibiting the effects of S100A4, which allows avoiding the development of side effects and effectively modulates the tumor microenvironment to overcome immunosuppression and chemoresistance. Full article

Intracellular lipid-binding proteins (iLBPs) are key mediators of intracellular transport for fatty acids and retinoids, functioning as lipid chaperones. Beyond lipid transport, iLBPs regulate signalling pathways, gene expression, oxidative balance, and inflammation. Furthermore, they are increasingly recognised for their involvement in gastrointestinal (GI) diseases, especially in cancer. iLBPs are classified into four different subfamilies, each displaying distinct tissue distributions and ligand preferences. Functional roles are context-dependent, for instance, CRABP2 may act as either tumour suppressor or promoter, and FABP4 exhibits metabolic state dependent effects. These proteins also influence drug resistance, immune evasion, and lipid-mediated signalling. Overall, iLBPs extend beyond lipid trafficking to intersect with oncogenic pathways, influence cell fate, and affect treatment response, highlighting their potential as biomarkers and therapeutic targets in GI oncology. Full article