Search Results (31,088)

Per- and polyfluoroalkyl substances (PFASs) are widespread in the environment, bioaccumulate in humans, and lead to disease and organ injury, such as liver steatosis. However, we lack a clear understanding of how these chemicals cause organ-level toxicity. Here, we aimed to analyze PFAS-induced metabolic perturbations in male and female rat livers by combining a genome-scale metabolic model (GEM) and toxicogenomics. The combined approach overcomes the limitations of the individual methods by taking into account the interaction between multiple genes for metabolic reactions and using gene expression to constrain the predicted mechanistic possibilities. We obtained transcriptomic data from an acute exposure study, where male and female rats received a daily PFAS dose for five consecutive days, followed by liver transcriptome measurement. We integrated the transcriptome expression data with a rat GEM to computationally predict the metabolic activity in each rat’s liver, compare it between the control and PFAS-exposed rats, and predict the benchmark dose (BMD) at which each chemical induced metabolic changes. Overall, our results suggest that PFAS-induced metabolic changes occurred primarily within the lipid and amino acid pathways and were similar between the sexes but varied in the extent of change per dose based on sex and PFAS type. Specifically, we identified that PFASs affect fatty acid-related pathways (biosynthesis, oxidation, and sphingolipid metabolism), energy metabolism, protein metabolism, and inflammatory and inositol metabolite pools, which have been associated with fatty liver and/or insulin resistance. Based on these results, we hypothesize that PFAS exposure induces changes in liver metabolism and makes the organ sensitive to metabolic diseases in both sexes. Furthermore, we conclude that male rats are more sensitive to PFAS-induced metabolic aberrations in the liver than female rats. This combined approach using GEM-based predictions and BMD analysis can help develop mechanistic hypotheses regarding how toxicant exposure leads to metabolic disruptions and how these effects may differ between the sexes, thereby assisting in the metabolic risk assessment of toxicants. Full article

Background: Alzheimer’s disease (AD) is largely linked with oxidative stress, the accumulation of amyloid-β plaques, and hyperphosphorylated τ-protein aggregation. Alterations in dopaminergic and serotonergic neurotransmission have also been implicated in various AD-related symptoms. Methods: To explore new therapeutic agents, a series of bicyclic and tricyclic thieno-oxazepine derivatives were synthesized as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. The resultant compounds were purified via HPLC and characterized using spectral analysis techniques. Histopathological examinations, other antioxidants, and anti-inflammatory biomarkers were evaluated, and in silico ADMET calculations were performed for synthetic hybrids. Molecular docking was utilized to validate the new drugs’ binding mechanisms. Results: The most powerful AChE inhibitors were 14 and 16, with respective values of IC₅₀ equal to 0.39 and 0.76 µM. Derivative 15 demonstrated remarkable BChE-inhibitory efficacy, on par with tacrine, with IC₅₀ values of 0.70 µM. Hybrids 13 and 15 showed greater selectivity towards BChE, despite substantial inhibition of AChE. Compounds 13 and 15 reduced escape latency and raised residence time, with almost equal activity to donepezil. Conclusions: According to these findings, the designed hybrids constitute multipotent lead compounds that could be used in the creation of novel anti-AD medications. Full article

Valorization of ricotta cheese exhausted whey (RCEW), a dairy by-product generated in large quantities worldwide, is essential to mitigate its environmental impact and unlock its economic potential. This study explores the use of RCEW as a substrate for polyhydroxyalkanoate (PHA) production by Azohydromonas lata DSM 1123. The substrate was characterized by low protein and fat contents and a relevant lactose concentration (3.81%, w/v). Due to A. lata’s inability to directly metabolize lactose, β-galactosidase supplementation was necessary. Mineral supplementation of pasteurized RCEW significantly improved both microbial biomass and PHA synthesis, achieving up to 25.94% intracellular PHA content, whereas pre-adaptation trials failed to enhance strain performance. Moderate nitrogen limitation in the substrate (C/N ratio 44) favored PHA synthesis (0.55 g/L) and 32.74% intracellular accumulation. Thermal treatments decreased initial microbial contamination, hence a balanced mixture of pasteurized–sterilized (75:25) substrate was used to modulate RCEW protein content without the inclusion of additional technological or chemical processing steps and without lactose loss or dilution. Bioreactor trials using optimized RCEW pre-treatment conditions led to a further increase in biomass (2.36 g/L) and PHA production (0.88 g/L), especially under fed-batch conditions. The extracted polymer was confirmed to be polyhydroxybutyrate (PHB), with high thermal stability and a molecular weight of 5.9 KDa. Full article

The molecular basis for the distinct intestinal tropism of infectious bronchitis virus (IBV) strains remains poorly understood. This study identifies the S2 subunit of the spike glycoprotein as the critical determinant conferring duodenal tropism to the IBV CSL strain. Comparative pathogenesis in specific-pathogen-free (SPF) chicks revealed that the CSL strain achieved significantly higher viral titers in the duodenum compared to strains D90, PYG QX1, and XXX QX5. This duodenal replication was associated with severe epithelial inflammation, characterized by upregulation of pro-inflammatory cytokines (IL-6, IL-17A, IL-22, TNF-α, IFN-β, IFN-γ) and disruption of barrier integrity via downregulation of tight junction proteins (Occludin, Claudin-1, ZO-1). Crucially, reverse genetics using the non-enterotropic D90 backbone demonstrated that recombinant viruses carrying the CSL-S2 gene (rD90-ΔS/CSL and rD90-ΔS2/CSL), but not those carrying CSL-S1 (rD90-ΔS1/CSL), replicated efficiently and induced inflammation in the duodenum, phenocopying wild-type CSL. In contrast, renal tropism was independent of the S2 subunit. These findings establish the S2 subunit as both necessary and sufficient for IBV duodenal tropism, uncoupling it from renal pathogenicity. This identifies S2 as a prime molecular target for developing next-generation vaccines against intestinal IBV pathotypes. Full article

Objectives: The construction of subunit vaccines based on antigens that can induce strong cellular immunity is a widely accepted strategy to develop new tuberculosis vaccines. This study screens immunogens with potential for subunit vaccine development from seven candidate antigens and then verifies their vaccine efficacy. Design: C57BL/6 mice were immunized subcutaneously with purified PPE19, PPE50, FadD21, Rv1505c, Rv1506c, Rv2035, and Rv0976c proteins formulated with Freund’s adjuvant to evaluate both the antigen-specific Th1 cellular immune responses and IgG level. After the vaccination of mice with recombined pcDNA3.1 expressing Rv0976c, intravenous or aerosol infection with M. tb were further challenged to assess protective efficacy. Results: Purified PPE19, PPE50, FadD21, and Rv0976c proteins generated strong antigen-specific Th1 cellular immune responses in mice. Compared to Ag85A, Rv0976c also stimulated higher IgG antibody level in mice. In particular, Rv0976c stimulated high and specific IgG antibody levels in serum from TB patients. The vaccination of mice with DNA vaccines expressing Rv0976c, followed by intravenous challenge with Bacillus Calmette–Guerin (BCG) Pasteur or M. tb, resulted in significant levels of protection that are comparable to or better than that afforded by the two leading antigens, Ag85A and PPE18. Conclusions: These results indicated that Rv0976c was a better protective antigen. Future studies to combine Rv0976c with other antigens and evaluate its effectiveness as a booster of BCG or as a therapeutic vaccine are warranted. Full article

Sarcopenia and type 2 diabetes mellitus (T2DM) are chronic conditions that gradually affect the elderly, often coexisting and interacting in complex ways. Sarcopenia, which is characterized by the progressive loss of muscle mass and function, is frequently observed in individuals with T2DM. Although the clinical association is well known, the molecular mechanisms remain unclear. Gene expression datasets were retrieved from the Gene Expression Omnibus database. DEGs were identified using the limma package in R (R 4.4.0). Shared DEGs were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Protein–protein interaction networks were constructed using the STRING database and were visualized with Cytoscape. Hub genes were identified via six topological algorithms in the CytoHubba plugin. Pearson’s correlation analysis was conducted between hub genes and selected metabolic regulators. GO and KEGG enrichment analyses indicated that mitochondrial function, oxidative phosphorylation, and immune–inflammatory responses were significantly enriched. A PPI network revealed a mitochondrial hub of five key genes involved in energy metabolism, whose downregulation suggests mitochondrial dysfunction as a shared mechanism in sarcopenia and T2DM. Our results provide new insight into the molecular overlap between T2DM and sarcopenia, highlighting potential biomarkers and therapeutic targets for addressing both metabolic disruption and muscle decline. Full article

Chlorpyrifos (CPF), an organophosphate pesticide, is known to induce pulmonary toxicity through oxidative stress, mitochondrial dysfunction, and inflammation. Astaxanthin (ASX), a xanthophyll carotenoid derived primarily from marine microalgae (Haematococcus pluvialis), possesses strong antioxidant properties and has demonstrated cellular protective effects in numerous oxidative stress studies. However, its efficacy against CPF-induced lung cell damage remains uncharacterized. This study revealed the protective role of ASX, as a pretreatment and co-treatment, against CPF-induced cytotoxicity in human A549 lung adenocarcinoma cells by assessing cell viability, intracellular reactive oxygen species (IROS), total oxidative status (TOS), total antioxidant capacity (TAC), mitochondrial membrane potential (MMP), intracellular calcium ions (Ca²⁺), lactate dehydrogenase (LDH) release, malondialdehyde (MDA) levels, glutathione peroxidase (GPx) activity, superoxide dismutase (SOD) activity, DNA fragmentation, and apoptosis/inflammation-associated gene expression. CPF treatment significantly decreased cell viability and TAC, while elevating IROS, TOS, MMP, intracellular Ca²⁺, and LDH release. CPF also increased MDA levels and suppressed GPx and SOD activities. DNA fragmentation and quantitative polymerase chain reaction (qPCR) analysis revealed upregulation of pro-apoptotic and inflammatory markers such as BCL2-associated X protein (BAX), caspase-3 (CASP3), tumor protein p53 (TP53), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), nuclear factor kappa B (NFκB), and voltage-dependent anion-selective channel protein 1 (VDAC1) and suppression of anti-apoptotic B-cell lymphoma 2 (BCL2) and antioxidant defense genes nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). ASX treatment, particularly when administered as a pretreatment, significantly reversed CPF-induced oxidative and inflammatory responses by restoring SOD, GPx, and TAC levels, reducing IROS, TOS, MDA, and LDH release, and downregulating apoptotic and inflammatory gene expressions. ASX pretreatment notably decreased MMP and intracellular Ca²⁺ levels, indicating protection against mitochondrial dysfunction and calcium dysregulation. ASX upregulated Nrf2 and HO-1 expression and restored the BCL2/BAX balance, suggesting inhibition of mitochondrial-mediated apoptosis. Additionally, ASX significantly attenuated CPF-induced anti-angiogenic effects in the in ovo Hen’s Egg Test Chorioallantoic Membrane (HET-CAM) assay. These findings demonstrate, for the first time, that ASX exerts a broad spectrum of protective effects against CPF-induced cytotoxicity in lung cells, mainly through the stabilization of mitochondrial redox status and modulation of apoptosis- and inflammation-related gene pathways, highlighting ASX as a promising candidate for further therapeutic development. Furthermore, the pronounced efficacy observed in the pretreatment regimen suggests that ASX can be evaluated as a potential nutritional preventive strategy in high-risk populations with occupational or environmental CPF exposure. Full article

The escalating challenge of resistance to insecticides among agricultural and public health pests poses a significant threat to global food security and vector-borne disease control. This review synthesizes current understanding of the molecular mechanisms underpinning resistance, including well-characterized pathways such as target-site mutations affecting nicotinic acetylcholine receptors (nAChRs), acetylcholinesterase (AChE), voltage-gated sodium channels (VGSCs), and γ-aminobutyric acid (GABA) receptors, and metabolic detoxification mediated by cytochrome P450 monooxygenases (CYPs), esterases, and glutathione S-transferases (GSTs). Emerging resistance mechanisms are also explored, including protein sequestration by odorant-binding proteins and post-transcriptional regulation via non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Focused case studies on Aedes aegypti and Spodoptera frugiperda illustrate the complex interplay of genetic and biochemical adaptations driving resistance. In Ae. aegypti, voltage-gated sodium channel (VGSCs) mutations (V410L, V1016I, F1534C) combined with metabolic enzyme amplification confer resistance to pyrethroids, accompanied by notable fitness costs and ecological impacts on vector populations. In S. frugiperda, multiple resistance mechanisms, including overexpression of cytochrome P450 genes (e.g., CYP6AE43, CYP321A8), target-site mutations in ryanodine receptors (e.g., I4790K), and behavioral avoidance, have rapidly evolved across global populations, undermining the efficacy of diamide, organophosphate, and pyrethroid insecticides. The review further evaluates integrated pest management (IPM) strategies, emphasizing the role of biopesticides, biological control agents, including entomopathogenic fungi and parasitoids, and molecular diagnostics for resistance management. Taken together, this analysis underscores the urgent need for continuous molecular surveillance, the development of resistance-breaking technologies, and the implementation of sustainable, multifaceted interventions to safeguard the long-term efficacy of insecticides in both agricultural and public health contexts. Full article

Early diagnosis of lung cancer, essential for reducing its high mortality rate, is currently challenging, partly due to the lack of specific biomarkers. Here, we attempted to develop a noninvasive and potentially sensitive screening method based on the proteomic analysis of unstimulated and stimulated saliva samples, collected by passive drooling and salivary swabs, respectively, from healthy heavy smokers enrolled in a nonprofit screening project. Protein content analyzed before and after sample cryopreservation for various periods and the associated two-dimensional electrophoresis revealed that protein extraction after short-term cryopreservation prevented the loss of detectable proteins. Mass spectrometric analysis of these electrophoretically resolved proteins revealed the presence of salivary proteins whose levels may be dysregulated in various types of lung cancer. Finally, in pilot experiments conducted on stimulated saliva from a patient with a lung cancer nodule, we detected altered content or selective presence of proteins involved in lung carcinogenesis, such as serpin B3 or the proteins S100A14 and aldoketoreductase-A1, respectively. While acknowledging that these findings require further validation, we believe that the use of saliva and related proteomic analyses may contribute to the identification of potential early lung cancer biomarkers, which could hopefully improve clinical management of the tumor and patient survival. Full article

Sepsis is a life-threatening condition caused by an abnormal host response to infection, leading to organ dysfunction and potentially death. Acute kidney injury (AKI) is a critical complication of sepsis. Various pathways, especially signaling through Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, contribute to inflammation and tissue damage. Cilastatin, a renal dehydropeptidase I inhibitor, has shown promise in protecting against AKI induced by nephrotoxic drugs. This study assessed cilastatin’s effectiveness in preventing AKI and inflammation caused by sepsis and its impact on survival. Sepsis was induced in male Sprague-Dawley rats using the cecal ligation puncture (CLP) model, with four groups: sham (control), CLP, sham+cilastatin, and CLP+cilastatin. Cilastatin (150 mg/kg) was administered immediately and 24 h after sepsis induction. Kidney injury was evaluated 48 h later by assessing serum creatinine, blood urea nitrogen, glomerular filtration rate, proteinuria, kidney injury molecule-1 levels, and renal morphology. Inflammatory and fibrotic biomarkers, particularly related to the TLR4 and NLRP3 pathways, were also measured. Cilastatin treatment prevented kidney dysfunction, reduced inflammatory markers, and improved survival by 33%. These results suggest that cilastatin could be a beneficial therapeutic strategy for sepsis-related AKI, improving outcomes and reducing mortality. Full article

Plant architecture is a crucial agronomic trait significantly impacting soybean (Glycine max) yield. Traditional breeding has made some progress in optimizing soybean architecture, but it is limited in precision and efficiency. The Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein (CRISPR/Cas) system, a revolutionary gene-editing technology, provides unprecedented opportunities for plant genetic improvement. This review outlines CRISPR’s development and applications in crop improvement, focusing specifically on progress regulating soybean architecture traits affecting yield, such as node number, internode length, branching, and leaf morphology. It also discusses the technical challenges for CRISPR technology in enhancing soybean architecture, including that the regulatory network of soybean plant architecture is complex and the development of multi-omics platforms helps gene mining. The application of CRISPR enables precise the regulation of gene expression through promoter editing. Meanwhile, it is also faced with technical challenges such as the editing of homologous genes caused by genome polyploidy, the efficiency of editing tools and off-target effects, and low transformation efficiency. New delivery systems such as virus-induced genome editing bring hope for solving some of these problems. The review emphasizes the great potential of CRISPR technology in breeding next-generation soybean varieties with optimized architecture to boost yield potential. Full article

Aralia chinensis L. has shown potential in breast cancer treatment, yet its pharmacodynamically active components and mechanisms remain undefined. To systematically identify the bioactive constituents absorbed into the bloodstream and elucidate their multi-target mechanisms against breast cancer, we employed ultra-high-performance liquid chromatography in conjunction with Q Exactive Orbitrap mass spectrometry (UHPLC-Q Exactive Orbitrap-MS) alongside serum pharmacochemistry to analyze the chemical constituents of total saponins derived from A. chinensis (TSAC) and to identify the blood-absorbed prototypes in a rat model. Network pharmacology predicted targets and pathways of serum prototypes, validated by molecular docking and in vitro experiments. We identified 38 triterpenoid saponins, 3 steroidal saponins, and 8 triterpenoids in TSAC, with 22 prototype compounds detected in serum. An integrative analysis encompassing 486 compound targets and 1747 genes associated with breast cancer elucidated critical pathways, notably the PI3K-Akt signaling pathway and resistance mechanisms to EGFR tyrosine kinase inhibitors. Molecular docking confirmed strong binding of araloside A and elatoside L to SRC, PIK3R1, PIK3CA, STAT3, and EGFR. In MCF-7 cells, TSAC suppressed proliferation and migration while downregulating Src, PI3K, and EGFR expression at the gene and protein levels. This study successfully identified TSAC’s serum-absorbed bioactive components and demonstrated their anti-breast cancer effects via multi-target mechanisms involving the Src/PI3K/EGFR axis, providing a crucial pharmacological foundation for developing A. chinensis-derived breast cancer therapies. Full article

Human fungal infections comprise systemic mycoses as well as various skin diseases. Rising case numbers along with inefficient therapies and the appearance of drug-resistant strains unleashed a considerable health problem over the last years. Thus, the identification and development of new antifungal drugs is mandatory, which can include the design of new antifungals, or, more time saving, the repurposing of known drugs already applied for the therapy of other human diseases. The orally applicable gold-based drug auranofin has been used for the treatment of rheumatoid arthritis since the 1980s. However, auranofin also showed marked activity against various cancers, microbes, parasites, and viruses. Facing a pressing need to find new drug candidates against mycoses, especially against those listed in the WHO fungal pathogen priority list, we have summarized the eminent antifungal activities of auranofin in this review. Given its established safety profile and broad-spectrum activity, auranofin represents a promising candidate for repurposing in antifungal therapy. The mechanism of action of auranofin was correlated with thioredoxin reductase inhibition, but other modes of action such as interference with mitochondrial protein import and NADH kinase were also described and discussed. A selection of promising antifungal gold complexes was also provided. Pertinent literature is covered until 2025. Full article

Apolipoprotein A (ApoA) proteins, ApoA-I, ApoA-II, ApoA-IV, and ApoA-V, play critical roles in lipid metabolism, neuroinflammation, and blood–brain barrier integrity, making them pivotal in neurological diseases such as Alzheimer’s disease (AD), stroke, Parkinson’s disease (PD), and multiple sclerosis (MS). This review synthesizes current evidence on their structural and functional contributions to neuroprotection, highlighting their dual roles as biomarkers and therapeutic targets. ApoA-I, the most extensively studied, exhibits anti-inflammatory, antioxidant, and amyloid-clearing properties, with reduced levels associated with AD progression and cognitive decline. ApoA-II modulates HDL metabolism and stroke risk, while ApoA-IV influences neuroinflammation and amyloid processing. ApoA-V, although less explored, is implicated in stroke susceptibility through its regulation of triglycerides. Genetic polymorphisms (e.g., APOA1 rs670, APOA5 rs662799) further complicate disease risk, showing population-specific associations with stroke and neurodegeneration. Therapeutic strategies targeting ApoA proteins, including reconstituted HDL, mimetic peptides, and gene-based approaches, show promise in preclinical models but face translational challenges in human trials. Clinical trials, such as those with CSL112, highlight the need for neuro-specific optimization. Further research should prioritize human-relevant models, advanced neuroimaging techniques, and functional assays to elucidate ApoA mechanisms inside the central nervous system. The integration of genetic, lipidomic, and clinical data offers potential for enhancing precision medicine in neurological illnesses by facilitating the generation of ApoA-targeted treatments and bridging current deficiencies in disease comprehension and therapy. Full article

Toxic shock syndrome (TSS) is a serious, often fatal disease, rarely occurring in dogs via infection with Staphylococcus and Streptococcus. The development of TSS is mainly dependent on the presence of bacterial toxins recognized to be potent superantigens causing the release of massive amounts of host inflammatory cytokines, notably TNF-α, progressing to high fever, hypotension, haemoconcentration, thrombosis and neutrophil and endothelial activation with multiple organ failure. Rarely, TSS is associated with erythematous and exfoliative dermatitis progressing to ulceration with extremely extensive dermo-epidermal detachment, which is often very painful. Like in humans, very little is known about the transmission and prevention of this condition. In our paper, a case of TSS-like caused by a mixed bacterial infection with Staphylococcus aureus, Streptococcus halichoeri and Dermatophilus spp. has been described in an 11 year-old, cross-breed male dog, most probably following injury due to biting and fighting. Lesions consisted of severe and diffuse ulceration on the dorsum, and bacterial culture/cytology led to the isolation and identification of Gram-positive staphylococci and streptococci associated with an intense neutrophil reaction. Dermatophilus spp. was presumed morphologically based on cytological preps, not by culture or molecular analysis. PCR demonstrated the presence of the nuc thermonucleaze gene (for S. aureus confirmation) together with the genes encoding enterotoxin H (seh), protein A (spa), toxic shock syndrome toxin TSST-1 (tst) and methicillin resistance (mecC); the exfoliative toxins (eta, etb) were detected. Clinical signs, cytology, bacterial culture and the response to systemic antibiotic therapy were compatible with a TSS-like diagnosis. The patient has completely recovered after 1 year of treatment. Full article