Metabolic Pathways Research Articles

Bee Venom Toxic Effect on MDA-MB-231 Breast Cancer Cells and Caenorhabditis Elegans.

Bee venom has therapeutics and pharmacological properties. Further toxicological studies on animal models are necessary due to the severe allergic reactions caused by this product. Here, Caenorhabditis elegans was used as an in vivo toxicity model, while breast cancer cells were used to evaluate the pharmacological benefits. The bee venom utilized in this research was collected from Apis mellifera species found in Northeast Brazil. The cytotoxicity caused by bee venom was measured by MTT assay on MDA-MB-231 and J774 A.1 cells during 24 - 72 hours of exposure. C. elegans at the L4 larval stage were exposed for three hours to M9 buffer or bee venom. Survival, behavioral parameters, reproduction, DAF-16 transcription factor translocation, the expression of superoxide dismutase (SOD), and metabolomics were analyzed. Bee venom suppressed the growth of MDA-MB-231 cancer cells and exhibited cytotoxic effects on macrophages. Also, decreased C. elegans survival impacted its behaviors by decreasing C. elegans feeding behavior, movement, and reproduction. Bee venom did not increase the expression of SOD-3, but it enhanced DAF-16 translocation from the cytoplasm to the nucleus. C. elegans metabolites differed after bee venom exposure, primarily related to aminoacyl- tRNA biosynthesis, glycine, serine and threonine metabolism, and sphingolipid and purine metabolic pathways. Our findings indicate that exposure to bee venom resulted in harmful effects on the cells and animal models examined. Thus, due to its potential toxic effect and induction of allergic reactions, using bee venom as a therapeutic approach has been limited. The development of controlled-release drug strategies to improve this natural product's efficacy and safety should be intensified.

LncRNA NORAD alleviates dysfunction of renal proximal tubular epithelial cells during the sepsis-associated acute kidney injury by modulating the miR-155-5p-PDK1 axis.

The sepsis-associated acute kidney injury (Sa-AKI) is closely related to high mortality rates worldwide. Injury to the renal proximal tubular epithelial cells (RPTECs), caused by pathological conditions, is a major cause of acute kidney injury (AKI). The lncRNA NORAD has been reported to be positively associated with kidney cancers. However, the biological roles and underlying mechanisms of NORAD in RPTECs during AKI are still unclear. In this study, we found that NORAD was significantly downregulated in RPTECs from AKI tissues. Overexpression of NORAD alleviated RPTECs injury induced by lipopolysaccharide (LPS). Additionally, glucose metabolism was significantly impaired during AKI, and LPS treatment inhibited glucose metabolism in RPTECs. We demonstrated that NORAD rescued the LPS-induced inhibition of glucose metabolism in RPTECs. Furthermore, miRNA-155-5p was significantly upregulated in RPTECs from AKI. Through bioinformatics analysis, RNA pull-down, RNA IP, and luciferase assays, we showed that NORAD directly associated with miR-155-5p to downregulate its expression. Moreover, overexpression of miR-155-5p inhibited glucose metabolism by directly targeting the 3'UTR of the glucose metabolism enzyme, pyruvate dehydrogenase kinase 1 (PDK1). Finally, rescue experiments validated that NORAD's protective effect on RPTECs injury was mediated through modulation of the miR-155-5p-PDK1-glucose metabolism pathway. In summary, these results reveal that lncRNA NORAD can alleviate RPTECs dysfunction by targeting the miR-155-5p-PDK1 axis, suggesting that NORAD has the potential to contribute to the development of therapeutic approaches against Sa-AKI.

Comparative Extracellular Vesicles Proteomics unravels host-pathogen interactions: New insights in bacterial and fungal endophthalmitis in murine models

PurposeEndophthalmitis, an intraocular infection, often results in devastating outcomes due to frequent misdiagnosis and delayed treatment initiation. Extracellular Vesicles (EVs) have long been lauded for its potential as a biomarker in several infections. Previously, we have profiled EVs in bacterial and fungal infected murine model of endophthalmitis. In this study, we reported a comparative analysis of bacterial and fungal endophthalmitis to understand the disease pathobiology and identify a potential signature molecule for diagnosis of infectious endophthalmitis. MethodsEndophthalmitis was induced by intravitreal injection of bacteria (S. aureus and P. aeruginosa) and fungus (A. flavus and C. albicans) in C57BL/6 mice followed by enucleation at 24 hours. EVs were isolated by ultracentrifugation and total proteins were subjected to LC-MS/MS. A comparative analysis of the EV protein cargo during bacterial and fungal endophthalmitis was performed in this study along with the pathway assessment by Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology. ResultsProteome analysis of EVs revealed the presence of over 1500 proteins in each of the infected and control groups. Comparative (bacteria versus fungal) study revealed that the protein cargo of the EVs was very distinct among the infected sets with a very few common proteins. Crucial differentially expressed proteins (DEPs) common to both infections were Complement Cascade 8-alpha (C8α), chymase, sorting nexin-29 and glutathione-S-transferase and common pathways were metabolic pathways, Staphylococcus aureus infection, PPAR signalling pathway, cAMP signalling pathway, TGFβ signalling pathway and HIF-1 signalling pathway. ConclusionThis study comprehensively investigates the global proteome of EVs derived from mice model of bacterial and fungal endophthalmitis. Proteomic analysis reveals the disparate EV protein cargo underlining the differences in the pathogenesis of bacterial and fungal endophthalmitis with C8α, chymase, sorting nexin 29 and glutathione-S-transferase common to both infections.

Effects of Liquid Nitrogen Freezing, Immersion Freezing, and Air Freezing on Properties of Perca fluviatilis Fillets and Analysis of Potential Protein Markers Based on Label-Free Proteomics

The effects of liquid nitrogen freezing (LNF), immersion freezing (IF), and air freezing (AF) combined with thawing in running water at 20°C on the quality of Perca fluviatilis fillets were investigated using label-free proteomics technology. The ice crystal equivalent diameter (12.30±0.33 μm) and ice crystal area ratio (7.61±2.81%) of LNF were significantly lower than IF and AF (P < 0.05). The ice crystals of LNF were small and evenly distributed, and the mechanical damage to the cell structure is small. LNF samples were closer to fresh samples regarding texture. Proteomic analysis identified a total of 11 differentially abundant proteins (DAPs) associated with LNF, IF, and AF. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these DAPs were primarily catalytic proteins, metabolic enzymes, and structural proteins involved in metabolic pathways such as pyruvate metabolism, glycolysis, and arginine and proline metabolism. Among them, tubulin beta chain (A0A8C3G6F1), carbonic anhydrase (A0A2P1JP97), immunoglobulin-like and fibronectin type III domain-containing protein 1 (A0A484DE91), and tubulin are predicted to serve as potential protein markers for freezing, thawing loss, hardness, and springiness of Perca fluviatilis fillets post-thawing. These findings provide a basis for further research into the quality change induced by protein degradation of frozen Perca fluviatilis.

Gut-brain axis system updates: Optimizing microbiome biomarkers for psychiatry and neurology

Technological advances in nucleic acid sequencing in recent years effectively launched and propelled a new age of the microbiome. A mechanism known as the gut-brain axis has been adopted by psychiatric and neurological researchers, as another possible way to reconcile gene-by-environmental and other hypotheses of how serious brain disorders develop. Toward this end, the microbiome, may represent an informative biomarker, or series of biomarkers, of cellular, molecular, and metabolic pathways that are altered in disease. As with any field projected to be an enormous influence on the future of medicine, early studies of the microbiome are numerous and sometimes afflicted with study design and data quality issues. Some progress in these areas is underway, and here we provide a brief update of the current state of the microbiome with a focus on clinical studies and the quests to better understand mechanistically what functional outcomes in neuropsychiatric disorders might be mediated by microbes. We also review the concept of the microbiome biomarker as a dynamic and evolving measure that keeps improving as technology flourishes. In vitro gut systems that merge innervation and vascularization of epithelial organoids exemplify next-generation microbiome biomarkers.

Transcriptome analysis indicates the mechanisms of BmNPV resistance in Bombyx mori midgut

Bombyx mori nucleopolyhedrovirus (BmNPV) caused serious economic losses in sericulture. Analyzing the molecular mechanism of silkworms (B. mori) resistance to BmNPV is of great significance for the prevention and control of silkworm virus diseases and the biological control of agricultural lepidopteran pests. In order to clarify the defense mechanisms of silkworms against BmNPV, we constructed a near isogenic line BC8 with high resistance to BmNPV through the highly BmNPV-resistant strain NB and the highly BmNPV-susceptible strain 306. In this study, RNA-Seq technique was used to analyze the transcriptome level differences in the midgut of BC8 and 306 following BmNPV infection. A total of 1350 DEGs were identified. Clustering analysis showed that these genes could be divided into 8 clusters with different expression patterns. Functional annotations based on GO and KEGG analysis indicated that they were involved in various metabolism pathways. Finally, 32 BmNPV defense responsive genes were screened. They were involved in metabolism, reactive oxygen species (ROS), signal transduction and immune response, and insect hormones. The further verification shows that HSP70 should participate in resistance responses of anti-BmNPV. These findings have paved way in further functional characterization of candidate genes and subsequently can be used in breeding of BmNPV resistance dominant silkworms.

The CfKOB1 gene related to cell apoptosis is required for pathogenicity and involved in mycovirus-induced hypovirulence in Colletotrichum fructicola

Colletotrichum fructicola is a globally significant phytopathogenic fungus. Mycovirus-induced hypovirulence has great potential for biological control and study of fungal pathogenic mechanisms. We previously reported that the mycovirus Colletotrichum alienum partitivirus 1 (CaPV1) is associated with the hypovirulence of C. fructicola, and the present study aimed to further investigate a host factor and its roles in mycovirus-induced hypovirulence. A gene named CfKOB1, which encodes putative protein homologous to the β-subunit of voltage-gated potassium channels and aldo–keto reductase, is downregulated upon CaPV1 infection and significantly upregulated during the early infection phase of Nicotiana benthamiana by C. fructicola. Deleting the CfKOB1 gene resulted in diminished vegetative growth, decreased production of asexual spores, hindered appressorium formation, reduced virulence, and altered tolerance to abiotic stresses. Transcriptome analysis revealed that CfKOB1 regulates many metabolic pathways as well as the cell cycle and apoptosis. Furthermore, enhanced apoptosis was observed in the ΔCfKOB1 mutants. Viral RNA accumulation was significantly increased in the CfKOB1 deletion mutant. Additionally, our findings demonstrated that CaPV1 infection in the WT strain also induced cell apoptosis. Collectively, these results highlight the diverse biological roles of the CfKOB1 gene in the fungus C. fructicola, while it also participates in mycovirus-induced hypovirulence by regulating apoptosis.

Effect of immersion time on bacterial community structure and sulfur metabolism in biofilm on concrete surface in sewer environment

This study focuses on an overlooked but critical issue: the composition and functional expression of microbial communities on the concrete surface in different areas of sewer pipes. Three immersion conditions were applied to simulate the duration of concrete in different areas ofsewers exposed to sewage, including short-term (L1), long-term (L2) and permanent immersion (L3). The properties of concrete under different immersion conditions and the bacterial diversity and functional capabilities in biofilms on the concrete surface were analyzed. Results showed that the L1 group was dominated by Halothiobacillus, whereas Desulfomicrobium was prominent in the L3 group. Significant differences in the predominant functional microbial communities and metabolic functional genes further confirmed the strong impact of immersion time on the pathways of microbial sulfur metabolism and concrete performance in sewer environment. Compared with the L2 and L3 groups, the decreased sewage immersion time resulted in an increase in the abundance and metabolic activity of sulfur-oxidizing bacteria in the L1 group. Hence, greater mass loss and gypsum production of concrete was found in the L1 group. The structural and functional differentiation of bacterial communities on the concrete surface observed in this study contributes to a better understanding of the uneven corrosion in real sewer pipes.

Comprehensive physiology and proteomics analysis revealed the molecular toxicological mechanism of Se stress on indica and japonica rice

Selenium pollution can lead to a decrease in crop yield and quality. However, the toxicological mechanisms of high Se concentrations on crops remain unclear. This study aimed to elucidate the physiological and proteomic molecular responses to Se stress in Oryza sativa. The results showed that under selenium stress, enzymatic activities of catalase, peroxidase, and superoxide dismutase in indica rice decreased by 61%, 28%, and 68%, respectively. The contents of non-enzymatic antioxidant substances ascorbic acid, glutathione, cysteine, proline, anthocyanidin, and flavonoids were decreased by 13%, 39%, 46%, 32%, 20%, and 5%, respectively, which significantly inhibited the antioxidant stress process of plants. At the same time, the results of proteomics analysis showed that rice seedlings, under Se stress, are involved in photosynthesis, photosynthesis-antenna proteins, carbon fixation, porphyrin metabolism, glyoxylate, and dicarboxylate. The differentially expressed proteins in metabolism and glutathione metabolism pathways showed a downward trend. It significantly inhibited the anti-oxidative stress, photosynthesis, and energy cycling process in plant cells, destroyed the homeostasis balance of rice plants, and inhibited the growth and development of rice. This finding reveals the molecular toxicological mechanism of Se stress on rice seedlings and provides a possible way to improve Se-resistant rice seedlings.

Differential metabolite analysis of the pharmacodynamic differences between different ratios of Dahuang ()-Taoren () herb pair.

To explore the material basis of the difference of efficacy of Dahuang (Radix Et Rhizoma Rhei Palmati)-Taoren (Semen Persicae) (DT) drugs with different proportions. Samples of different ratios of Dahuang (Radix et Rhizoma Rhei Palnati, DH) to Taoren (Semen Persicae, TR) (Group A 1:1, B 2:3, C 3:2) were analyzed based on gas chromatography time-of-flight mass spectrometry untargeted metabolomics technique. A total of 240 primary metabolites were detected. Forty-one differential metabolites involved nine differential metabolic pathways, of which four were closely related to the efficacy of DT in the treatment of heat and blood stasis syndrome. These pathways included the biosynthesis of amino acid (phenylalanine tyrosine and tryptophan), flavonoids, unsaturated fatty acids, and the glycolysis/glycogenesis pathway. There are significant differences in the efficacy of different ratios of DT drugs, and their optimal ratio for the treatment of heat and blood stasis syndrome should be 1:1.

Metabolite profiling, antioxidant and anti-glycemic activities of Tartary buckwheat processed by solid-state fermentation(SSF)with Ganoderma lucidum

The aim of this study was to investigate the effect of Ganoderma lucidum fermentation on antioxidant and anti-glycemic activities of Tartary buckwheat. Xylanase, total cellulase (CMCase and FPase) and β-glucosidase in fermented Tartary buckwheat (FB) increased significantly to 242.06 U/g, 17.99 U/g and 8.67 U/g, respectively. And the polysaccharides, total phenols, flavonoids and triterpenoids, which is increased by 122.19%, 113.70%, 203.74%, and 123.27%, respectively. Metabolite differences between non-fermented Tartary buckwheat (NFB) and FB pointed out that 445 metabolites were substantially different, and were involved in related biological metabolic pathways. There was a considerable rise in the concentrations of hesperidin, xanthotoxol and quercetin 3-O-malonylglucoside by 240.21, 136.94 and 100.77 times (in Fold Change), respectively. The results showed that fermentation significantly increased the antioxidant and anti-glycemic activities of buckwheat. This study demonstrates that the fermentation of Ganoderma lucidum provides a new idea to enhance the health-promoting components and bioactivities of Tartary buckwheat.

Dopamine‑iron homeostasis interaction rescues mitochondrial fitness in Parkinson's disease

Imbalances of iron and dopamine metabolism along with mitochondrial dysfunction have been linked to the pathogenesis of Parkinson's disease (PD). We have previously suggested a direct link between iron homeostasis and dopamine metabolism, as dopamine can increase cellular uptake of iron into macrophages thereby promoting oxidative stress responses. In this study, we investigated the interplay between iron, dopamine, and mitochondrial activity in neuroblastoma SH-SY5Y cells and human induced pluripotent stem cell (hiPSC)-derived dopaminergic neurons differentiated from a healthy control and a PD patient with a mutation in the α-synuclein (SNCA) gene. In SH-SY5Y cells, dopamine treatment resulted in increased expression of the transmembrane iron transporters transferrin receptor 1 (TFR1), ferroportin (FPN), and mitoferrin2 (MFRN2) and intracellular iron accumulation, suggesting that dopamine may promote iron uptake. Furthermore, dopamine supplementation led to reduced mitochondrial fitness including decreased mitochondrial respiration, increased cytochrome c control efficiency, reduced mtDNA copy number and citrate synthase activity, increased oxidative stress and impaired aconitase activity. In dopaminergic neurons derived from a healthy control individual, dopamine showed comparable effects as observed in SH-SY5Y cells. The hiPSC-derived PD neurons harboring an endogenous SNCA mutation demonstrated altered mitochondrial iron homeostasis, reduced mitochondrial capacity along with increased oxidative stress and alterations of tricarboxylic acid cycle linked metabolic pathways compared with control neurons. Importantly, dopamine treatment of PD neurons promoted a rescue effect by increasing mitochondrial respiration, activating antioxidant stress response, and normalizing altered metabolite levels linked to mitochondrial function. These observations provide evidence that dopamine affects iron homeostasis, intracellular stress responses and mitochondrial function in healthy cells, while dopamine supplementation can restore the disturbed regulatory network in PD cells.

Effect of surfactant's charge properties on behavior, physiology, and biochemistry and the release of microcystins of Microcystis aeruginosa

Surfactant pollution is escalatitheng in eutrophic waters, but the effect of surfactant charge properties on the physiological and biochemical properties of toxin-producing microalgae remains inadequately explored. To address this gap, this study explores the effects and mechanisms of three common surfactants―cetyltrimethylammonium bromide (CTAB, cationic), sodium dodecyl sulfate (SDS, anionic), and Triton X-100 (nonionic)―found in surface waters, on the agglomeration behavior, physiological indicators, and Microcystin-LR (MC-LR) release of Microcystis aeruginosa (M. aeruginosa) by using UV-visible spectroscope, Malvern Zetasizer, fluorescence spectrometer, etc. Results suggest that charge properties significantly affect cyanobacterial aggregation and cellular metabolism. The CTAB-treated group demonstrates a ∼5.74 and ∼9.74 times higher aggregation effect compared to Triton X-100 and SDS (300 mg/L for 180 min) due to strong electrostatic attraction. Triton X-100 outperforms CTAB and SDS in polysaccharide extraction, attributed to its higher water solubility and lower critical micelle concentration. CTAB stimulates cyanobacteria to secrete proteins, xanthohumic acid, and humic acids to maintain normal physiological cells. Additionally, the results of SEM and ion content showed that CTAB damages the cell membrane, resulting in a ∼90% increase in the release of intracellular MC-LR without cell disintegration. Ionic analyses confirm that all three surfactants alter cell membrane permeability and disrupt ionic metabolic pathways in microalgae. This study highlights the relationship between the surface charge properties of typical surfactants and the dispersion/agglomeration behavior of cyanobacteria. It provides insights into the impact mechanism of exogenous surfactants on toxic algae production in eutrophic water bodies, offering theoretical references for managing surfactant pollution and treating algae blooms.

Studying the role of Bombyx mori molybdenum cofactor sulfurase in Bombyx mori nucleopolyhedrovirus infection.

Molybdenum cofactor sulfurase (MoCoS) is a key gene involved in the uric acid metabolic pathway that activates xanthine dehydrogenase to synthesise uric acid. Uric acid is harmful to mammals but plays crucial roles in insects, one of which is the immune responses. However, the function of Bombyx mori MoCoS in response to BmNPV remains unclear. In this study, BmMoCoS was found to be relatively highly expressed in embryonic development, gonads and the Malpighian tubules. In addition, the expression levels of BmMoCoS were significantly upregulated in three silkworm strains with different levels of resistance after virus infection, suggesting a close link between them. Furthermore, RNAi and overexpression studies showed that BmMoCoS was involved in resistance to BmNPV infection, and its antivirus effects were found to be related to the regulation of uric acid metabolism, which was uncovered by inosine- and febuxostat-coupled RNAi and overexpression. Finally, the BmMoCoS-mediated uric acid pathway was preliminarily confirmed to be a potential target to protect silkworms from BmNPV infection. Overall, this study provides new evidence for elucidating the molecular mechanism of silkworms in response to BmNPV infection and new strategies for the prevention of viral infections in sericulture.

Setd1A-mediated methylation of h3k4me3 inhibits ferroptosis in non-small cell lung cancer by regulating the WTAPP1/WTAP axis.

SETD1A is upregulated in non-small cell lung cancer (NSCLC) tissues. This study investigated the molecular mechanism of the SETD1A/WTAPP1/WTAP axis in NSCLC. Ferroptosis is a unique cell death mode driven by iron-reliant phospholipid peroxidation, which is regulated by multiple cellular metabolic pathways, including REDOX homeostasis, iron metabolism, mitochondrial activity and metabolism of amino acids, lipids and sugars. Thus, the levels of ferroptosis markers (MDA, SOD, GSH) were measured in vitro, and NSCLC cell behaviors were assessed. SETD1A-mediated H3K4me3 methylation was analyzed. SETD1A-exerted effects on ferroptosis and tumor growth in vivo were verified in nude mouse models. SETD1A was highly expressed in NSCLC cells. Silencing SETD1A suppressed NSCLC cell proliferation and migration, inhibited MDA, and enhanced GPX4, SOD, and GSH levels. SETD1A elevated WTAP expression through WTAPP1 upregulation by mediating H3K4me3 methylation in the WTAPP1 promoter region. WTAPP1 overexpression partly averted the promotional effect of silencing SETD1A on NSCLC cell ferroptosis. WTAP interference abrogated the inhibitory effects of WTAPP1 on NSCLC cell ferroptosis. Silencing SETD1A facilitated ferroptosis and accelerated tumor growth in nude mice through the WTAPP1/WTAP axis. SETD1A amplified WTAP expression through WTAPP1 upregulation by mediating H3K4me3 modification in the WTAPP1 promoter region, thus promoting NSCLC cell proliferation and migration and inhibiting ferroptosis.

Loss of the histone chaperone UNC-85/ASF1 inhibits the epigenome-mediated longevity and modulates the activity of one-carbon metabolism.

Histone H3/H4 chaperone anti-silencing function 1 (ASF1) is a conserved factor mediating nucleosomal assembly and disassembly, playing crucial roles in processes such as replication, transcription, and DNA repair. Nevertheless, its involvement in aging has remained unclear. Here, we utilized the model organism Caenorhabditis elegans to demonstrate that the loss of UNC-85, the homolog of ASF1, leads to a shortened lifespan in a multicellular organism. Furthermore, we show that UNC-85 is required for epigenome-mediated longevity, as knockdown of the histone H3 lysine K4 methyltransferase ash-2 does not extend the lifespan of unc-85 mutants. In this context, we found that the longevity-promoting ash-2 RNA interference enhances UNC-85 activity by increasing its nuclear localization. Finally, our data indicate that the loss of UNC-85 increases the activity of one-carbon metabolism, and that downregulation of the one-carbon metabolism component dao-3/MTHFD2 partially rescues the short lifespan of unc-85 mutants. Together, these findings reveal UNC-85/ASF1 as a modulator of the central metabolic pathway and a factor regulating a pro-longevity response, thus shedding light on a mechanism of how nucleosomal maintenance associates with aging.

Elucidation of novel drought-responsive genes from tuber transcriptome of cassava under water deficit stress

Cassava (Manihot esculenta Carntz) is the major starchy root crop grown in the tropical parts of the world. Two cassava clones contrasting for their drought tolerance capacity (8S501- drought tolerant and H97-drought sensitive) were selected and grown in the field for studying the agronomical and molecular changes in both the clones under drought stress conditions. A reduction in the number of tuberous roots per plant, tuberous root length, average single tuber weight and tuber yield per plant was observed under drought stress when compared with the control conditions and also significantly lower mean values were observed for the sensitive clone H97 than that of the tolerant clone 8S501 when measured at 60 days of stress. Transcriptome sequencing of the tuber tissues of the two clones was done at 60 days of imposing drought stress. Different genes belonging to various groups like aquaporins, transporter genes, growth regulator related genes, calcium binding and mineral transfer-related genes, transferase genes and transcription factors were differentially expressed in the tubers under drought stress. Comparative transcriptomics revealed that acyl-CoA oxidase, primary-amine oxidase, glutathione peroxidase, vesicle transport, late embryogenesis abundant protein related, histone demethylase, BR-signaling kinase, palmitoyltransferase, DNA mismatch repair protein, heat shock protein related, starch/sucrose metabolic pathway related and MFS transporter genes were differentially expressed in the tubers of the tolerant clone 8S501 relative to the susceptible clone H97.

Prolactin receptor potentiates chemotherapy through miRNAs-induced G6PD/TKT inhibition in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a notoriously dismal prognosis. As a competitive inhibitor of DNA synthesis, gemcitabine is the cornerstone drug for treating PDAC at all stages. The therapeutic effect of gemcitabine, however, is often hindered by drug resistance, and the underlying mechanisms remain largely unknown. It is unclear whether their response to chemotherapeutics is regulated by endocrine regulators, despite the association between PDAC risk and endocrine deregulation. Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both invitro and invivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR-4763-3p and miR-3663-5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. We demonstrate that two key enzymes of the pentose phosphate pathway (PPP), G6PD and TKT, are directly targeted by miR-4763-3p and miR-3663-5p. Notably, miR-4763-3p and miR-3663-5p diminish the nucleotide synthesis of the PPP pathway, thereby increasing gemcitabine sensitivity. As a result, PRLR harnesses these two miRNAs to suppress PPP and nucleotide synthesis, subsequently elevating the gemcitabine sensitivity of PDAC cells. Also, PDAC tissues and tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, and PDX1-cre (KPC) mice exhibit downregulation of PRLR. Bisulfite sequencing of PDAC tissues revealed that PRLR downregulation is due to epigenetic methylation. In this study, we show for the first time that the endocrine receptor PRLR improves the effects of gemcitabine by boosting two new miRNAs that block the PPP pathway and nucleotide synthesis by inhibiting two essential enzymes concurrently. The PRLR-miRNAs-PPP axis may serve as a possible therapeutic target to supplement chemotherapy advantages in PDAC.

Biodegradation of Pharmaceutical Pollutants Using Fungal Enzyme

Abstract: The potential of filamentous fungi and their enzymes are investigated for bioremediating pharmaceutical pollutants from wastewater thereby addressing the growing concern of emerging pollutants in water resources. Among the various microorganisms, the current abstract discusses the role of fungi in degrading antibiotics and persistent pharmaceutical compounds. These fungi allow the biodegradation via the formation of highly oxidative hydroxyl radicals. It summarizes the role of both intra (cytochrome P450) and extracellular (laccase) enzyme systems for the bioremediation of emerging clinical pollutants. It emphasizes the importance of both biosorption and biodegradation for effective pollutant removal by breaking down pharmaceuticals (e.g. antibiotics) and other hazardous compounds (e.g. endocrine-disrupting compounds, polycyclic aromatic hydrocarbons). Although the enzymes CYP450 are not directly engaged, their metabolic pathways execute mechanisms such as oxidation, the formation of reactive intermediates, and chemical modification, all of which result in the degradation of clinical pollutants. Amongst all enzyme systems in the case of laccase which oxidise a wide spectrum of substrates, converts them to free radicals. Additionally, the role of recombinant enzyme production and transgenic strains for pollutant degradation has also been elaborated. These considerations emphasise the need for ongoing research and biotechnological advancements to address the growing concern of pharmaceuticals and personal care product pollutants in water systems.

Effects of essential oils on heat-stressed poultry: A review.

While certain animal species are sensitive to heat stress, poultry particularly modern breeds, are more susceptible to high ambient temperatures. This has major implications for the poultry industry, as heat stress causes large financial losses. These economic losses will probably increase as a consequence of a predicted rise in global temperatures. Heat stress adversely affects various aspects of poultry, including physiological responses, growth and production performance, meat quality, egg quality, and reproductive activities. These effects occur through specific molecular and metabolic pathways. To mitigate the impacts of heat stress, it is crucial to go beyond administrative practices and implement dietary interventions during high ambient temperature. Such interventions aim to optimize the development of stressed bird species in terms of performance, health, and profitability. Essential oils have shown promising in mitigating the negative effects of heat stress and improved antioxidant status, growth and yield performance, as well as meat and egg quality in poultry. They actively participate in certain metabolic and molecular pathways that help to counteract the effects of heat stress. The article discusses the impacts of essential oil supplementation on the relationships between antioxidant enzyme activity, these molecular, and metabolic pathways, as well as various parameters such as growth and yield performance, and product quality heat-stressed poultry.