Search Results (365)

Background/Objective: Oncogenic tyrosine kinases (TKs) such as ALK and SRC promote cancer progression, but their effects on metabolic enzymes are still not well understood. This study examines how TK signaling regulates inosine monophosphate dehydrogenase 2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, and assesses its potential as a therapeutic target. Methods: Phosphoproteomic screening and in vitro kinase assays were used to identify phosphorylation sites on IMPDH2. Lipid-binding assays explored the role of phosphatidylinositol 3-phosphate (PI3P) in IMPDH2 regulation. Structure-based virtual screening discovered small-molecule allosteric inhibitors, which were tested in lymphoma cell models, including ALK and BTK-inhibitor resistant lines. Results: Here, we identify Inosine monophosphate dehydrogenase-2 (IMPDH2), a rate-limiting enzyme in purine biosynthesis, as a novel substrate of ALK and SRC. We show that phosphorylation at the conserved Y233 residue within the allosteric domain enhances IMPDH2 activity, linking TK signaling to metabolic reprogramming in cancer cells. We further identify PI3P as a natural lipid inhibitor that binds IMPDH2 and suppresses its enzymatic function. Using structure-based virtual screening, we developed Comp-10, a first-in-class allosteric IMPDH inhibitor. Unlike classical active-site inhibitors such as mycophenolic acid (MPA), Comp-10 decreases IMPDH1/2 protein levels, blocks filament (rod/ring) formation, and inhibits the growth of ALK and BTK inhibitor-resistant lymphoma cells. Comp-10 acts post-transcriptionally and avoids compensatory IMPDH upregulation observed with MPA (rod/ring) formation, and inhibited growth in TKI-resistant lymphoma cells. Notably, Comp-10 avoided the compensatory IMPDH upregulation observed with MPA. Conclusion: These findings uncover a novel TK–IMPDH2 signaling axis and provide mechanistic and therapeutic insight into the allosteric regulation of IMPDH2. Comp-10 represents a promising therapeutic candidate for targeting metabolic vulnerabilities in tyrosine kinase driven cancers. Full article

Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by motor symptoms such as tremor, bradykinesia, rigidity, and postural instability. In the absence of disease-modifying therapies, exercise remains one of the few interventions shown to effectively reduce fall risk and improve mobility. However, it remains unclear whether skeletal muscle ATP metabolism is impaired in PD, and whether the benefits of exercise arise primarily from improvements in central motor control or peripheral metabolic adaptations. Methods: Fourteen individuals with PD and five healthy controls underwent kinetic ³¹P Magnetic Resonance Spectroscopy (MRS) to assess resting muscle ATP synthesis and dynamic ³¹P MRS during in-magnet exercise to evaluate oxidative phosphorylation in active muscle. Results: At rest, ATP synthesis rates mediated by ATPase and creatine kinase (CK) were on average 46 ± 23% and 24 ± 9% lower, respectively, in the PD group compared to controls (p < 0.005), suggesting peripheral mitochondrial dysfunction. During plantar flexion exercise at 15% of lean body mass, range of motion (ROM) was reduced by 22 ± 5% in PD participants (p = 0.01). Despite this, post-exercise recovery of phosphocreatine (PCr) and inorganic phosphate (Pi) was similar between groups. Recovery time constants for PCr and Pi correlated with participants’ total weekly exercise time, indicating a metabolic adaptation to regular physical activity. Modest ROM improvements were observed in both groups following calf-raise exercise training. Conclusions: Reduced skeletal muscle ATP metabolism may contribute to peripheral weakness in PD. Regular exercise appears to promote adaptive metabolic responses, highlighting the need for therapeutic strategies targeting both central and peripheral components of PD. Full article

Typical fertilizer applicators are often restricted in performance due to non-uniformity in distribution, required labor and time intensiveness, high discharge rate, chemical input wastage, and fostering weed proliferation. To address this gap in production agriculture, an automated variable-rate fertilizer applicator was developed for the cotton crop that is based on deep learning-initiated electronic control unit (ECU). The applicator comprises (a) plant recognition unit (PRU) to capture and predict presence (or absence) of cotton plants using the YOLOv7 recognition model deployed on-board Raspberry Pi microprocessor (Wale, UK), and relay decision to a microcontroller; (b) an ECU to control stepper motor of fertilizer metering unit as per received cotton-detection signal from the PRU; and (c) fertilizer metering unit that delivers precisely metered granular fertilizer to the targeted cotton plant when corresponding stepper motor is triggered by the microcontroller. The trials were conducted in the laboratory on a custom testbed using artificial cotton plants, with the camera positioned 0.21 m ahead of the discharge tube and 16 cm above the plants. The system was evaluated at forward speeds ranging from 0.2 to 1.0 km/h under lighting levels of 3000, 5000, and 7000 lux to simulate varying illumination conditions in the field. Precision, recall, F1-score, and mAP of the plant recognition model were determined as 1.00 at 0.669 confidence, 0.97 at 0.000 confidence, 0.87 at 0.151 confidence, and 0.906 at 0.5 confidence, respectively. The mean absolute percent error (MAPE) of 6.15% and 9.1%, and mean absolute deviation (MAD) of 0.81 g/plant and 1.20 g/plant, on application of urea and Diammonium Phosphate (DAP), were observed, respectively. The statistical analysis showed no significant effect of the forward speed of the conveying system on fertilizer application rate (p > 0.05), thereby offering a uniform application throughout, independent of the forward speed. The developed fertilizer applicator enhances precision in site-specific applications, minimizes fertilizer wastage, and reduces labor requirements. Eventually, this fertilizer applicator placed the fertilizer near targeted plants as per the recommended dosage. Full article

Floodplain lakes play a significant role in maintaining biological diversity and providing a food base for aquatic organisms. In 2023–2024, for the first time, we studied phytoplankton of five floodplain lakes of the transboundary Irtysh River in Kazakhstan. A total of 149 species and forms of planktonic algae were recorded, with a low level of similarity between the lakes. The ratio of indicator species (predominance of eutraphents and meso-eutraphents), abundance (3301.6–168,961.1 thou. cells L⁻¹), biomass (2.41–83.67 mg L⁻¹) of phytoplankton communities, and composition of dominant phyla and species (Cyanobacteria: Microcystis pulverea, M. aeruginosa, Aphanizomenon flos-aquae; Chlorophyta: Volvox globator; Dinoflagellata: Ceratium hirundinella and others) testified to a high level of organic pollution of floodplain lakes. Chemical variables (nitrogen compound content, PI) supported this conclusion. Analysis of the RDA revealed that the biomass of Cyanobacteria was controlled by nitrate nitrogen, while phosphates controlled that of Chlorophyta. The applied integrated approach showed an improvement in the trophic status of lakes in a high-water year and can be useful in assessing the ecological state of aquatic ecosystems in other regions. Full article

Renal phosphate transporters NaPi-IIa (SLC34A1) and NaPi-IIc (SLC34A3) play a crucial role in phosphate reabsorption in the proximal tubule. Biallelic loss-of-function variants in SLC34A1 and SLC34A3 cause two rare phosphate-wasting tubulopathies: idiopathic infantile hypercalcemia (IIH) and hereditary hypophosphatemic rickets with hypercalciuria, respectively. The phenotypes associated with these diseases are highly variable and sometimes overlap. Here, we report a rare case of a six-month-old girl of consanguineous parents with symptoms related to these diseases, including failure to thrive, nephrocalcinosis, hypercalcemia, hypophosphatemia with low TRP, elevated levels of 1,25-(OH)₂D₃, and suppressed PTH. An exome sequencing analysis was carried out to determine the genetic variants associated with her disease. Bioinformatics tools were used to assess variant pathogenicity. We identify a novel homozygous mutation in the SLC34A1 gene, c.1361C>T; p.(T454M), and a previously described heterozygous SLC34A3 101 bp deletion. Mutation p.(T454M) affects transmembrane domain 5 of the NaPi-IIa protein, which is involved in substrate binding, probably impairing phosphate transport. Our results suggest the diagnosis of IIH type 2 in our patient and highlight the importance of exome analysis in diagnosing these tubulopathies. We suggest that the coexistent heterozygous SLC34A3 deletion could increase the risk of renal calcifications and the severity of other symptoms. Full article

The arbuscular mycorrhizal fungi (AMF) effect on the plant metabolome is an actual question of plant biology. Its alteration during host plant development and at different phosphorus supplies is of special interest. The aim of this study was to evaluate the effect of Rhizophagus irregularis (Błaszk., Wubet, Renker & Buscot) C. Walker & A. Schüßler inoculation and/or phosphorus treatment on the root metabolome of Medicago lupulina L. subsp. vulgaris Koch at the first true leaf, second leaf, third leaf development stages, the lateral branching initiation, the flowering and the mature fruit stages. The assessment of metabolic profiles was performed using GC-MS. In total, 327 metabolites were annotated: among them 20 carboxylic acids, 26 amino acids, 14 fatty acids and 58 sugars. The efficient AM was characterized by the upregulation of the metabolism of proteins, carbohydrates and lipids, as well as an increase in the content of phosphates. The tricarboxylic acid abundance was generally lower during mycorrhization. Fourteen metabolic markers of the efficient AM symbiosis were identified. The lateral branching initiation stage was shown to have key importance. Long-lasting metabolomic profiling indicated variances in mycorrhization and Pi supply effects at different key stages of host plant development. Full article

Ceramide 1-phosphate (C1P) is a key regulator of cell proliferation and survival in both normal and transformed cells. Major pathways implicated in the mitogenic actions of C1P include activation of the mitogen-activated protein kinases (MAPKs) ERK1-2 and JNK, as well as stimulation of the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, the product of retinoblastoma, or the sphingomyelin synthase (SMS)/diacylglycerol (DAG)/protein kinase C-alpha (PKC-α) pathway. C1P-stimulated cell proliferation can also be mediated through enhanced secretion of vascular endothelial growth factor (VEGF) in macrophages or by releasing lysophosphatidic acid (LPA) in myoblasts. Also, the production of low levels of reactive oxygen species (ROS) can mediate the stimulation of cell growth by C1P, particularly in macrophages. Upregulation of the PI3K/Akt/mTOR pathway is also involved in the inhibition of cell death by C1P, which can also contribute to cell survival by blocking the activity of the ceramide-generating enzymes acid sphingomyelinase (ASMase) and serine palmitoyl transferase (SPT). Moreover, C1P-promoted cell survival involves upregulation of inducible nitric oxide synthase (iNOS) and the subsequent production of nitric oxide (NO). Using photosensitive C1P analogues, it could be concluded that promotion of cell growth and inhibition of cell death were elicited by intracellularly generated C1P in a receptor-independent manner. The aim of the present review is to evaluate in detail the implication of the CerK/C1P axis in controlling cell proliferation and survival in mammalian cells, as well as to discuss and update on the molecular mechanisms by which C1P can accomplish these actions. Full article

In end-stage renal disease (ESRD), the accumulation of solutes normally excreted by the kidneys contributes to multiple complications, including vascular calcification (VC), a key factor in the heightened cardiovascular risk seen in these patients. Among VC drivers, hyperphosphatemia and the uremic milieu are major contributors. Kynurenine, a tryptophan metabolite classified as a uremic toxin, may further exacerbate this process. This study investigated whether kynurenine amplifies high phosphate (Pi)-induced calcification in human aortic endothelial cells (HAEC). Cells were treated with Pi and kynurenine for up to seven days. Kynurenine increased Pi-induced calcium deposition by 36%, accompanied by enhanced endothelial-to-mesenchymal transition (EndMT) and osteoblastic differentiation. Mechanistically, kynurenine activated the aryl hydrocarbon receptor (AhR) pathway, and pharmacological inhibition of AhR partially attenuated this effect. These findings suggest that kynurenine contributes to VC in ESRD by potentiating phosphate-induced endothelial dysfunction via AhR signaling. Full article

This study examined the membrane permeability of E. coli, which were exposed to a moderate pulsed electric field (PEF) (3.3 kV/cm). The membrane permeability of E. coli was examined as a function of time after exposure to PEF. When comparing the percentage of propidium iodide (PI) permeability at a given time from PEF exposure, it appeared that as the bacterial density increased, there was a decrease in PI permeability. The permeability to PI in the bacterial suspensions of 0.05, 0.1, and 0.5 OD, 90 min after exposure, was 56.4 ± 4.08%, 43.91 ± 0.75%, and 29.47 ± 3.31%, respectively. Membrane permeability was also examined in different phosphate-buffered saline (PBS) concentrations. At 0.05 OD there was a linear correlation between PBS concentrations (0.56, 0.75, and 1 mM) and PI permeability (28.36 ± 2.22%, 61.08 ± 3.17%, and 98.2 ± 0.9%, respectively). At the higher bacterial densities of 0.1 and 0.5 OD, this phenomenon was not evident. Examination of bacterial membrane permeability using 4, 70, and 250 kDa fluorescein isothiocyanate (FITC)-dextran revealed that PEF led to 4kDa FITC-dextran permeabilization of 27.94 ± 3.76%. The PEF parameters used did not influence the bacterial cell size and viability. This study shed light on bacterial membrane permeability as a function of conductivity and bacterial density under PEF exposure. Full article

Polarized fluorescence microscopy of “ghost” muscle fibers, containing fluorescently labeled F-actin, tropomyosin, and myosin, has provided new insights into the molecular mechanisms underlying muscle contraction. At low Ca²⁺, the troponin-induced overtwisting of the actin filament alters the configuration of myosin binding sites, preventing actin–myosin interactions. As Ca²⁺ levels rise, the actin filament undergoes untwisting, while tropomyosin becomes overtwisted, facilitating the binding of myosin to actin. In the weakly bound state, myosin heads greatly increase both the internal twist and the bending stiffness of actin filaments, accompanied by the untwisting of tropomyosin. Following phosphate (Pi) release, myosin induces the untwisting of overtwisted actin filaments, driving thin-filament sliding relative to the thick filament during force generation. Point mutations in tropomyosin significantly alter the ability of actin and tropomyosin filaments to respond to Pi release, with coordinated changes in twist and bending stiffness. These structural effects correlate with changes in actomyosin ATPase activity. Together, these findings support a model in which dynamic filament twisting is involved in the molecular mechanisms of muscle contraction together with the active working stroke in the myosin motor, and suggest that impairment of this ability may cause contractile dysfunction. Full article

Androgenetic alopecia (AGA), the most prevalent form of hair loss worldwide, faces significant therapeutic challenges due to high costs and limited efficacy of current interventions, necessitating safer and more effective solutions. Periplaneta americana (L.)-derived PA-011, endowed with anti-inflammatory and antioxidant properties, has demonstrated notable hair growth-promoting effects in AGA mouse models. This study employed LC-MS/MS, peptidomics, and network pharmacology to characterize PA-011’s chemical composition and predict its potential targets in AGA pathogenesis. Using Western blot and RT-qPCR, PA-011 intervention significantly inhibited inflammatory responses and oxidative stress levels in mouse skin tissues. Concurrently, PA-011 activated the proliferative potential of hair follicle stem cells, as demonstrated by upregulated expression of the cell proliferation marker Ki67, and activated the Wnt/β-catenin signaling pathway in DHT-induced AGA mice. Transcriptomic and metabolomic analyses revealed multi-target effects of PA-011, including modulation of PI3K-Akt/MAPK pathways, pentose phosphate metabolism, and amino acid biosynthesis. 16S rRNA sequencing and metagenomic analysis showed that AGA disrupts skin microbial homeostasis, while PA-011 intervention normalized the microbiota composition. Topical application of PA-011 promoted robust hair regrowth without detectable toxicity in safety assessments. This preclinical study establishes PA-011 as a promising candidate for AGA therapy, warranting further translational investigation. Full article

The Hetao irrigation area is one of the largest irrigation areas in the Yellow River Basin and a typical salinized agricultural area. Crop type shifts in this area can alter soil phosphorus (P) morphology and microbial functional diversity, thereby influencing soil P losses. However, few studies have elucidated the underlying mechanisms. In this study, soil samples were collected from four different crop planting areas: sunflower field (SF), corn field (CF), wheat land (WL), and vegetable and fruit land (VFL). Subsequently, the physicochemical properties, P fractions, and phosphate-solubilizing microorganisms (PSMs) were analyzed. The results indicated that when other lands shifted to SF, the soil pH increased significantly. Simultaneously, SOM, TN, and TP decreased significantly during the crop type conversion. Analysis of P fraction revealed that moderately active P, including NaOH-P_i, NaOH-P_o, and HCl-P_i, were the dominant fractions in the tested soils. Among them, HCl-P_i was the major component of moderately active P. The soil P leaching change point in the tested are was 6.25 mg Olsen-P kg⁻¹. The probabilities of P leaching in WL, VFL, CF, and SF were 91.7%, 83.8%, 83.8%, and 66.7%, respectively. Additionally, the sum of the relative abundances of the three PSMs in SF, VFL, WL, and CF were 8.81%, 11.88%, 8.03%, and 10.29%, respectively. The shift in crop type to SF exacerbated the soil degradation process. Both TP and residual P in the soil decreased. However, the NaHCO₃ slightly increased, which may have been due to the increased abundance of Thiobacillus and Escherichia. Full article

Measles, hepatitis C, and COVID-19 are significant human diseases caused by RNA viruses. While vaccines exist to prevent infections, there are a small number of currently available therapeutic agents that can effectively treat these diseases after infection occurs. This study explores a new therapeutic strategy using a small molecule designated polyprenyl immunostimulant (PI) to increase innate immune responses and combat viral infections. Using a multi-disciplinary approach, this study quantifies the effects of PI in mice and THP-1 cells using flow cytometry to identify immune phenotypic markers and mass spectroscopy to monitor the metabolomic profiles of immune cells perturbed by PI treatment. The metabolomic studies identified that sphinganine and ceramide, which are precursors of sphingosine-1-phosphate (S1P), were the common metabolites upregulated in THP-1 and mice blood. Sphingosine-1-phosphate can mediate the trafficking of T cells, whereas ceramide can signal the activation and proliferation of T cells, thereby modulating the mammalian host’s immunity. To demonstrate proof-of-principle, a case study was conducted to examine the benefit of administering PI to improve the outcomes of a feline co-infected with two distinct RNA viruses—feline leukemia virus and feline infectious peritonitis virus. Both viruses produce deadly symptoms that closely resemble RNA viruses that infect humans. The results identify quantifiable cellular and metabolic markers arising from PI treatment that can be used to establish a platform measuring the efficacy of PI in modulating the innate immune system. Full article

Epidemiological studies have linked higher serum and dietary phosphorus to an increased risk of prostate cancer (PC) and its lethal state. However, these findings do not distinguish between the impact of inorganic phosphorus (Pi) per se and the impacts of its homoeostatic regulators. Thus, this study aimed to determine the in vitro tumorigenic effects of elevated Pi concentrations per se on androgen-dependent epithelial-like PLum-AD murine PC cells at molecular and cellular levels. Physiologically attainable elevated levels and supraphysiological levels of sodium (NaPi) and potassium phosphate (KPi) were used to assess PLum-AD cell proliferation, viability, migration, and epithelial–mesenchymal transition (EMT) marker expression, which were determined by the thiazolyl blue tetrazolium bromide cell assay, trypan blue exclusion assay, wound healing assay, and immunofluorescence staining, respectively. Treatment of Plum-AD cells with supraphysiological levels of NaPi (20 mM) significantly reduced cell proliferation, whereas KPi did not, suggesting a potential sodium-dependent Pi uptake mechanism. Furthermore, physiologically relevant elevated concentrations of NaPi (3 mM) and KPi (1 and 3 mM) increased the relative vimentin expression of PLum-AD PC cells, a biomarker of EMT. Our findings suggest that elevated Pi levels per se, in the hyperphosphatemia range, can directly promote EMT in PC, highlighting the potential role of Pi in tumor progression. Full article

Phosphorus, as an essential nutrient, plays an important role in plant growth and development. Although Phosphate Starvation Response 1 (PHR1) or PHR1-like have been recognized as central regulators of phosphorus (Pi) homeostasis in several plants, they have not been systematically studied in Cucurbitaceae. In this study, 11, 10, 8, 12, 12, and 22 PHR genes were identified in cucumber, melon, bottle gourd, watermelon, wax gourd, and pumpkin, respectively, by genome-wide analysis. Phylogenetic analysis showed that the Cucurbitaceae PHR genes were divided into seven distinct subfamilies. These genes were further phylogenetically analyzed for their chromosomal localization, gene structure, protein structure, and synteny. Genomic homology analysis showed that many PHR genes existed in the corresponding homology blocks of six Cucurbitaceae species. qRT-PCR analysis showed that the CmoPHR genes exhibited differential expression under different concentrations of phosphate treatment. Transcriptional self-activation assays showed that CmoPHR2, CmoPHR9, CmoPHR16, and CmoPHR17 proteins had transcriptional self-activating activity. The results of this study provide a basis for the further cloning and functional validation of genes related to the phosphate regulatory network in pumpkin. Full article