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PLK1 is found to be highly expressed in various types of cancers, but the development of inhibitors for it has been slow. Most inhibitors are still in clinical stages, and many lack the necessary selectivity and anti-tumor effects. This study aimed to create new inhibitors for the PLK1-PBD by focusing on the PBD binding domain, which has the potential for greater selectivity. A 3D QSAR model was developed using a dataset of 112 compounds to evaluate 500 molecules. ADMET prediction was then used to select three molecules with strong drug-like characteristics. Scaffold hopping was employed to reconstruct 98 new compounds with improved drug-like properties and increased activity. Molecular docking was used to compare the efficient compound abbapolin, confirming the high-activity status of [(14S)-14-hydroxy-14-(pyridin-2-yl)tetradecyl]ammonium,[(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium. Molecular dynamics simulations and MMPBSA were conducted to evaluate the stability of the compounds in the presence of proteins. An in-depth analysis of [(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium identified them as potential candidates for PLK1 inhibitors.

As a newly approved oral hypoglycaemic agent, the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin, which is derived from the natural product phlorizin can effectively reduce blood glucose. Recent clinical studies have found that dapagliflozin alleviates non-alcoholic fatty liver disease (NAFLD), but the specific mechanism remains to be explored. This study aimed to investigate the underlying mechanism of dapagliflozin in alleviating hepatocyte steatosis in vitro and in vivo . We fed the spontaneous type 2 diabetes mellitus rats with high-fat diets and cultured human normal liver LO2 cells and human hepatocellular carcinoma HepG2 cells with palmitic acid (PA) to induce hepatocellular steatosis. Dapagliflozin attenuated hepatic lipid accumulation both in vitro and in vivo . In Zucker diabetic fatty (ZDF) rats, dapagliflozin reduced hepatic lipid accumulation via promoting phosphorylation of acetyl-CoA carboxylase 1 (ACC1), and upregulating lipid β -oxidation enzyme acyl-CoA oxidase 1 (ACOX1). Furthermore, dapagliflozin increased the expression of the autophagy-related markers LC3B and Beclin1, in parallel with a drop in p62 level. Similar effects were observed in PA-stimulated LO2 cells and HepG2 cells. Dapagliflozin treatment could also significantly activated AMPK and reduced the phosphorylation of mTOR in ZDF rats and PA-stimulated LO2 cells and HepG2 cells. We demonstrated that dapagliflozin ameliorates hepatic steatosis by decreasing lipogenic enzyme, while inducing fatty acid oxidation enzyme and autophagy, which could be associated with AMPK activation. Moreover, our results indicate that dapagliflozin induces autophagy via the AMPK-mTOR pathway. These findings reveal a novel clinical application and functional mechanism of dapagliflozin in the treatment of NAFLD.

USP7 is highly expressed in a variety of tumors and is thought to play a major role in cancer development. However, there are no drugs available to target USP7, so there is a need to develop new USP7 inhibitors. In this study, AutoQSAR, multiple linear regression, and Naive Bayesian models were constructed using 543 compounds and used to analyze marine compounds. After selecting 240 small molecules for molecular docking with Maestro, MOE, and GOLD, better small molecules than the positive compound P217564 were screened. The molecular structure of “1, 2-dibromobenzene” was optimized to improve the binding effect of the protein, and 10 optimized compounds in ADMET performed well during the screening process. To study the dynamic combination of protein–ligand effect consistency with static molecular docking, 100ns molecular dynamics simulations of candidate compound 1008-1, reference compound P217564, and negative-positive GNE2917 were conducted. The results of molecular docking and molecular dynamics simulation analysis showed that compound 1008-1 maintained a stable conformation with the target protein. Thus, the comprehensive analysis suggests that compound 1008-1 could provide new possibilities for USP7 covalent inhibitor candidates.

The prevalent use of foliar calcium fertilizers in peanut production is inorganic, but calcium absorbed from the foliar has poor availability. Sorbitol-chelated calcium is a novel organic foliar calcium fertilizer that has rarely been studied for application in peanut production. To explore whether calcium absorption and peanut yields can be affected by foliar application of sorbitol-chelated calcium, this study conducted two field experiments using Virginia peanut (Huayu-22) in 2020 and 2021. The five spray treatments included: deionized water (CK), sorbitol (Sor), calcium nitrate (CaN), a mixture of sorbitol and calcium nitrate (SN), and sorbitol-chelated calcium (SC). The yield of peanuts treated with sorbitol-chelated calcium was increased by 12.31-16.63%, 10.22-11.83%, 6.31-9.69%, and 4.18-6.99% compared to the CK, Sor, CaN, and SN treatments, respectively. Sorbitol-chelated calcium had the lowest contact angle due to the wetting effect of sorbitol, which promoted calcium absorption by leaves. Sorbitol-chelated calcium improved the leaf calcium concentration by 13.12-19.32% and kernel calcium concentration by 6.49-8.15% compared to the CK treatment. Foliar fertilization increased the calcium concentration of each subcellular fraction of leaves and changed the distribution of calcium in mesophyll cells. This change was directly observed by transmission electron microscopy. Additionally, spraying sorbitol alone obtained similar effects to spraying calcium nitrate alone, indicating that the benefits of sorbitol itself were not negligible. The results of the principal component and correlation analysis showed that the increase in calcium concentrations and the change in calcium distribution improved the pod traits of the peanut, thus affecting the peanut yield. The above results showed that from the perspective of calcium absorption and distribution, sorbitol-chelated calcium is a more effective foliar calcium fortifier for peanuts and effectively improves peanut yields.

As the global population ages, the risks associated with primary sarcopenia, including falls, fractures, functional decline, and frailty, are becoming increasingly apparent, all of which significantly impair the quality of life in older adults. Emerging evidence suggests that the gut microbiota plays a pivotal role in maintaining muscle physiology. Specific gut bacteria promote intramuscular protein synthesis through the production of certain amino acids (e.g., leucine, tryptophan), short-chain fatty acids (SCFAs), and hydrogen sulfide. Notably, Escherichia coli expressing the enzyme nicotinamidase (PncA) has been shown to enhance nicotinamide adenine dinucleotide (NAD+) synthesis, potentially improving mitochondrial function in muscle tissue. Furthermore, secondary bile acids and lactate influence the levels of fibroblast growth factor 15/19 and unacylated ghrelin in circulation by binding to receptors that are highly expressed in gut endocrine cells, thereby affecting muscle physiology. This review examines the characteristic composition of the gut microbiota in patients with sarcopenia, its role in primary sarcopenia, and potential therapeutic targets.

BackgroundPolyhalite fertilizer application is an effective way to alleviate a shortage of potassium. This study explored the effects of polyhalite fertilizer application as a total or partial replacement for conventional potassium fertilizer to improve peanut growth and soil quality.ResultsThe index of peanut yield and its economic benefits, the content and distribution of mineral nutrients in different organs, soil chemical properties, and rhizosphere microbial diversity in response to the treatments were examined. The results show that the M4P6T treatment (60% polyhalite fertilizer replacing potassium chloride as the base fertilizer, and 40% potassium chloride fertilizer applied as a topdressing) increased profit by 7.2% without affecting the yield. The M4P6T treatment significantly improved the accumulation and distribution of potassium, calcium and magnesium in the kernels compared with the M10B treatment (no polyhalite fertilizer; potassium chloride fertilizer only as the base fertilizer). Soil treated with polyhalite fertilizer had higher alpha-diversity values and greater relative abundance of microbes at the phylum and genus levels.ConclusionsPartial substitution of polyhalite for potassium chloride improved soil quality and peanut growth more than did single applications of polyhalite and potassium chloride.

Rapeseed ( Brassica napus L.) is grown extensively worldwide, including in areas with saline soils. In this study, sorbitol-chelated calcium was applied to rapeseed plants to investigate its effects on the tolerance of plants and soil quality under salt stress. We conducted a pot experiment to explore the effects of sorbitol-chelated calcium on the physiological parameters, plant nutritional status, soil quality, and rhizosphere bacterial community of rapeseed. Sorbitol-chelated calcium application increased the biomass and soluble sugar content, and decreased the malondialdehyde, proline, and soluble protein contents of rapeseed plants under salt stress. Sorbitol-chelated calcium application increased the calcium concentrations and reduced the sodium concentrations of plants and soil. Additionally, sorbitol-chelated calcium altered the soil enzyme activity and the rhizosphere microbial community composition. The exogenous application of sorbitol-chelated calcium shows promise in improving plant growth and soil properties while alleviating salt stress.

Sarcopenia is an age-related accelerated loss of muscle strength and mass. Bone and muscle are closely related as they are physically adjacent, and bone can influence muscle. However, the temporal association between bone mineral density (BMD) and muscle mass in different regions of the body after adjustment for potential indicators and the mechanisms by which bone influences muscle in sarcopenia remain unclear. Therefore, this study aimed to explore the temporal association between muscle mass and BMD in different regions of the body and mechanisms by which bone regulates muscle in sarcopenia. Here, cross-lagged models were utilized to analyze the temporal association between BMD and muscle mass. We found that low-density lipoprotein (LDL-C) positively predicted appendicular lean mass. Mean whole-body BMD (WBTOT BMD), lumbar spine BMD (LS BMD), and pelvic BMD (PELV BMD) temporally and positively predicted appendicular lean mass, and appendicular lean mass temporally and positively predicted WBTOT BMD, LS BMD, and PELV BMD. Moreover, this study revealed that primary mice femur osteoblasts, but not primary mice skull osteoblasts, induced differentiation of C2C12 myoblasts through exosomes. Furthermore, the level of long noncoding RNA (lncRNA) taurine upregulated 1 (TUG1) was decreased, and the level of lncRNA differentiation antagonizing nonprotein coding RNA (DANCR) was increased in skull osteoblast–derived exosomes, the opposite of femur osteoblast–secreted exosomes. In addition, lncRNA TUG1 enhanced and lncRNA DANCR suppressed the differentiation of myoblasts through regulating the transcription of oxidative stress–related myogenin (Myog) gene by modifying the binding of myogenic factor 5 (Myf5) to the Myog gene promoter via affecting the nuclear translocation of Myf5. The results of the present study may provide novel diagnostic biomarkers and therapeutic targets for sarcopenia.

Purpose Foliar calcium applications promote peanut growth, but inorganic calcium displays minimal bioavailability, so an organic calcium source is needed. Recent studies showed that sorbitol can convert inorganic calcium to an organic form. However, the effects of foliar applications of organic sorbitol-chelated calcium on peanut growth and phyllosphere bacterial community structure have not been elucidated. Methods We conducted a 2-year field trial to explore how foliar application of organic sorbitol-chelated calcium affected the seed quality, growth parameters, leaf nutritional status, and phyllosphere bacterial community of a Virginia-type peanut (Huayu-22). Results Foliar calcium fertilization promoted calcium absorption by peanut leaves, enhanced carbon and nitrogen metabolism, and promoted peanut growth. Sorbitol-chelated calcium was optimal in these respects. Kernel quality was less affected by foliar fertilization. Foliar fertilization did not affect phyllosphere bacterial community α-diversity but significantly changed the bacterial community structure via changes in the leaf soluble sugar and protein, total carbon, and calcium contents. Proteobacteria, Actinobacteria, Bacteroidetes, and Firmicutes were dominant phyla and the genera significantly enriched in different treatments differed. Peanut growth was positively correlated with the abundances of Quadrisphaera , Sphingomonas , and unclassified_ p_ Proteobacteria , whereas Klebsiella and Halomonas were negatively associated. Conclusions Overall, we identified an optimal calcium source for foliar application and enhanced the broader understanding of fertilizer-plant-microorganism interrelationships.

The Lower Triassic Feixianguan Formation at the well-known Puguang gasfield in the northeastern Sichuan Basin of southwest China produces a representa- tive oolitic reservoir, which has been the biggest marinesourced gasfield so far in China （discovered in 2003 with proven gas reserves greater than 350× 10^8 m3）. This study combines core, thin section, and scanning electron microscopy observations, and geochemical analysis （C, O, and Sr isotopes） in order to investigate the basic characteristics and formation mechanisms of the reservoir. Observations indicate that platform margin oolitic dolomites are the most important reservoir rocks. Porosity is dominated by intergranular and intragranular solution, and moldic pore. The dolomites are characterized by medium porosity and permeability, averaging at approximately 9% and 29.7 mD, respectively. ^87Sr/^86Sr （0.707536-0.707934） and δ^13CpDB （1.8 ‰--3.5 ‰） isotopic values indicate that the dolomitization fluid is predominantly concentrated seawater by evaporation, and the main mechanism for the oolitic dolomite formation is seepage reflux at an early stage of eodiagenesis. Both sedimentation and diagenesis （e.g., dolomitization and dissolution） have led to the formation of high-quality rocks to different degrees. Dolomite formation may have little contribution, karst may have had both positive and negative influences, and burial dissolution-TSR （thermochemical sulfate reduction） may not impact widely. The preservation of primary intergranular pores and dissolution by meteoric or mixed waters at the early stage of eogenesis are the main influences. This study may assist oil and gas explorationactivities in the Puguang area and in other areas withdolomitic reservoirs.