Age differences in the impact of dietary salt on metabolism, blood pressure and cognitive function in male rats.

The influence of salt consumption on physiological processes, especially blood pressure (BP), metabolism, and cognition, remains a topical concern. While guidelines endorse reduced salt diets, there are gaps in understanding the age-specific implications and challenges in adherence. The present study delved into the differential effects of salt intake on young adult and aged male rats over a 12-week period, using control, low-, and high-salt diets. Key metrics, such as BP, cognition, and general parameters, were monitored. Our findings revealed significant age-dependent effects of salt intake on survival rates, body weight, blood sodium, blood glucose, blood lipids, BP, heart rates, and cognition. Notably, young adult rats did not show significant sodium level changes on a high-salt diet, whereas aged rats experienced increased sodium levels even on a normal salt diet. Blood glucose levels decreased significantly in aged rats on a high-salt diet but remained stable in young adults. Aged rats had the highest survival rates on low-salt diets. Low-salt diets led to reduced BP in both age groups, more significantly in young adults. Young adult rats displayed increased BP variability on both high- and low-salt diets, while a decrease in BP variability was exclusive to aged rats on a low-salt diet. There were significant differences across age groups in short-term memory, but not in long-term memory. The study provides a nuanced understanding of the age-dependent physiological effects of salt intake, suggesting the necessity of age-specific guidelines for public health.

Design, synthesis, and anticancer evaluation of arylurea derivatives as potent and selective type II irreversible covalent FGFR4 inhibitors.

Aberrant FGF19/FGFR4 signaling has been demonstrated to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC). At present, the development of FGFR4-specific drugs has become a hotspot in tumor-targeted therapy research. However, no selective FGFR4 inhibitors have been approved by FDA so far. Currently, most of the reported FGFR4 inhibitors that use a covalent targeting strategy to be selective are typical type I inhibitors with a single type. Here, based on Ponatinib, we designed and synthesized a series of arylurea derivatives as novel type II irreversible covalent inhibitors of FGFR4. Among them, the representative compound 6v exhibited an IC50 value of 74 nM against FGFR4 and antiproliferative potency of 0.25 µM and 0.22 µM against Huh7 and Hep3B cell lines. Western blotting results showed that compound 6v significantly inhibited the phosphorylation of FGFR4 and its downstream signaling factors AKT and ERK in a dose-dependent manner in Hep3B cell. These results showed that this series of compounds, as type II irreversible FGFR4 inhibitors, are worthy of further research and structural optimization.

PROTACS: A technology with a gold rush-like atmosphere.

Abnormally expressed or malfunctioning proteins may affect or even damage cells, leading to the onset of diseases. Proteolysis targeting chimera (PROTAC) technology has been proven to be a fresh therapeutic strategy, superior to conventional small molecule inhibitors for the treatment of diseases caused by pathogenic proteins. Unlike conventional small molecule inhibitors that are occupancy-driven, PROTACs are heterobifunctional small molecules with catalytic properties. They combine with E3 ligases and target proteins to form a ternary complex, rendering the target protein ubiquitous and subsequently degraded by the proteasome. This paper focuses first on significant events in the development of PROTAC technology from 2001 to 2022, followed by a brief overview of various PROTACs categorized by target proteins. In addition, the applications of PROTACs in the treatment of diseases and fundamental biology are also under discussion.

Two Cladosporium Fungi with Opposite Functions to the Chinese White Wax Scale Insect Have Different Genome Characters.

Insects encounter infection of microorganisms, and they also harbor endosymbiosis to participate in nutrition providing and act as a defender against pathogens. We previously found the Chinese white wax scale insect, Ericerus pela, was infected and killed by Cladosporium sp. (pathogen). We also found it harbored Cladosporium sp. (endogensis). In this study, we cultured these two Cladosporium fungi and sequenced their genome. The results showed Cladosporium sp. (endogensis) has a larger genome size and more genes than Cladosporium sp. (pathogen). Pan-genome analysis showed Cladosporium sp. (endogensis)-specific genes enriched in pathways related to nutrition production, such as amino acid metabolism, carbohydrate metabolism, and energy metabolism. These pathways were absent in that of Cladosporium sp. (pathogen). Gene Ontology analysis showed Cladosporium sp. (pathogen)-specific genes enriched in the biosynthesis of asperfuranone, emericellamide, and fumagillin. These terms were not found in that of Cladosporium sp. (endogensis). Pathogen Host Interactions analysis found Cladosporium sp. (endogensis) had more genes related to loss of pathogenicity and reduced virulence than Cladosporium sp. (pathogen). Cytotoxicity assay indicated Cladosporium sp. (pathogen) had cytotoxicity, while Cladosporium sp. (endogensis) had no cytotoxicity. These characters reflect the adaptation of endosymbiosis to host-restricted lifestyle and the invader of the entomopathogen to the host.

Discovery of 4,6-Disubstituted Pyrimidine Derivatives as Novel Dual VEGFR2/FGFR1 Inhibitors.

Abnormalities in the FGFRs signaling pathway and VEGFR2 amplification often occur in a variety of tumors, and they synergistically promote tumor angiogenesis. Studies have shown that the up-regulation of FGF-2 is closely related to the resistance of VEGFR2 inhibitors. Activation of the FGFRs signal is a signal of compensatory angiogenesis after VEGFR2 resistance. Dual VEGFR2/FGFR1 inhibitors contribute to overcoming the resistance of VEGFR2 inhibitors and inhibit tumor growth significantly. Based on this, we designed and synthesized a series of 4,6-disubstituted pyrimidine derivatives as dual VEGFR2/FGFR1 inhibitors by the molecular hybridization strategy. 3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)amino]pyrimidin-4-yl}-1-methylurea (8b) had the best inhibitory activities against VEGFR2 and FGFR1 at 10 µM (82.2 % and 101.0 %, respectively), it showed moderate antiproliferative activities against A549 and KG-1 cell lines as well. Besides, molecular docking was also carried out to study the binding mode of 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[(4-methoxyphenyl)-amino]-pyrimidin-4-yl}-1-methylurea (8b) with VEGFR2 and FGFR1. These studies reveal that this series of compounds deserve further optimization.

Design, synthesis and anticancer evaluation of 3-methyl-1H-indazole derivatives as novel selective bromodomain-containing protein 4 inhibitors.

Bromodomain-containing Protein 4 (BRD4), an 'epigenetic reader', regulates chromatin structure and gene expression via recognizing and binding acetylated lysine in histones. BRD4 has become a therapeutic target for cancers because it promotes the expression of the tumor genes, such as c-Myc, NF-κB, and Bcl-2. In this study, a new series of 3-methyl-1H-indazole derivatives were designed via virtual screening and structure-based optimization. All compounds were synthesized and evaluated for their inhibitory activities to BRD4-BD1 and their antiproliferative effects in cancer cell lines. Among them, several compounds (such as 9d, 9u and 9w) exhibited strong BRD4-BD1 affinities and inhibition activities, and potently suppressed MV4;11 cancer cell line proliferation. Among them, compound 9d showed excellent selectivity for BRD4 and effectively suppressed c-Myc, the downstream protein of BRD4. This study provided new lead compounds for further biological evaluation on BRD4.

Discovery of 4-amino-1H-pyrazolo[3,4-d]pyrimidin derivatives as novel discoidin domain receptor 1 (DDR1) inhibitors.

DDR1 is a receptor tyrosine kinase that is activated by triple-helical collagens and has become an attractive target for anticancer therapy given its involvement in tumor growth, metastasis development, and tumor dormancy. Several drugs on the market, such as dasatinib and nilotinib, were reported to potently suppress the function of DDR1 and show significant therapeutic benefits in a variety of preclinical tumor models. Whereas only a few selective DDR1 inhibitors were disclosed in recent years. A series of 4-amino-1H-pyrazolo[3,4-d]pyrimidin derivatives were designed and synthesized. All compounds were evaluated via DDR1 kinase inhibition assay and cell anti-proliferative assay. One of the representative compounds, 6c, suppressed DDR1 kinase activity with an IC50 value of 44 nM and potently inhibited cell proliferation in DDR1-overexpressing cell lines HCT-116 and MDA-MB-231 with IC50 value of 4.00 and 3.36 µM respectively. Further molecular docking study revealed that 6c fitted ideally into DDR1 binding pocket and maintained the crucial hydrogen bonds with DDR1 kinase domain. Overall, these results suggest that the compound 6c is a potential DDR1 inhibitor deserving further investigation for cancer treatment.

PROTAC: A promising technology for cancer treatment.

Proteolysis-targeting chimeric molecules (PROTACs), which attract much more attention today, may be a potential way to treat cancer. PROTACs are made up of ligands of target proteins, E3 ligase recruiting elements and linkers. PROTACs can hijack the intracellular inherent ubiquitin proteasome system in cells to degrade different target proteins. PROTACs targeting different cancer-related proteins have been successfully developed and outperform small inhibitors, the traditional way of treating cancer. In this review, we focus on PROTACs targeting cancer-related proteins and their superiority over inhibitors.

Yin Yang 1 Dynamically Regulates Antiviral Innate Immune Responses During Viral Infection.

BACKGROUND/AIMS: Type I interferon (IFN-1) production and IFN-1 signaling play critical roles in the host antiviral innate immune responses. Although transcription factor Yin Yang 1 (YY1) has been reported to have a dual activator/repressor role during the regulation of interferon beta (IFN-ß) promoter activity, the roles of YY1 in the regulation of upstream signaling pathways leading to IFN-1 induction and IFN-1 signaling during viral infection remain to be elucidated. METHODS: The roles of YY1 in IFN-1 production and IFN-1 signaling were investigated using immunoblotting, real-time PCR, small interfering RNA (siRNA)-mediated YY1 knockdown, YY1 overexpression by transient transfection, and co-immunoprecipitation, using mouse cells. RESULTS: YY1 was shown to interact with STAT1 in the absence of viral infection. Following viral infection, YY1 protein expression levels were decreased. YY1 knockdown led to a considerable downregulation of phosphorylated (p) TBK1 and pIRF3 expressions, while YY1 overexpression significantly upregulated pTBK1 and pIRF3 expression levels and promoted virus-induced IFN-ß production. Additionally, YY1 knockdown led to a significant upregulation of pSTAT1, pSTAT2 and antiviral interferon-stimulated genes, and inhibited viral replication. CONCLUSION: We demonstrated here that YY1 interacts with STAT1 and dynamically regulates the induction of IFN-1 production and activation of IFN-1 signaling in different stages during viral infection.

[Experimental Research of Hg2+Removal by TiO2/Bentonite Composite].

The TiO2/bentonite composite was synthesized by modifying calcium-based bentonite with Nano-TiO2. The products before and after modification were characterized via the approach of X-ray power diffraction(XRD) and scanning electron microscope(SEM).The effect of TiO2/bentonite composite on mercury removal from aqueous solutions of HgCl2was studied at different dosage, pH, adsorption time and the initial concentration of Hg2+ was investigated and compared with the bentonite by indoor simulation experiment, as well as the orthogonal experiments to determine the optimal condition of Hg2+ adsorption. The experimental results showed:after modified by TiO2, TiO2/bentonite composite particles were apparently smaller, the basal spacing was increased and with a loose and porous structure. The adsorption rates of TiO2/bentonite composite on Hg2+ were increased compared with bentonite. The Hg2+ adsorption rates were increased with the increasing dosages, pH and adsorption time. The adsorption rates were higher than 98.0% when the dosage was 1.5 g·L-1, pH 7.0, and the adsorption time was 120 min. The adsorption rates became smaller with increasing initial concentration of Hg2+. False secondary dynamic equation could describe the adsorption of TiO2/bentonite composite on Hg2+, and the chemical adsorption was dominant. The adsorption isotherm of Hg2+ conformed to Langmuir equation, indicating that the adsorption of Hg2+ was typical monolayer adsorption. The optimal experimental condition was:dosage of 2.0 g·L-1, pH 8.0, adsorption time of 16 h and the initial Hg2+concentration of 45 mg·L-1. Under this condition, the adsorption rate was 99.9%, and the equilibrium concentration of Hg2+ was 0.034 mg·L-1.

[Effect of Nano-TiO2 on Release and Speciation Changes of Heavy Metals in Soil].

The effects of nano-TiO2 on migration and transformation of heavy metals in soil were investigated by outdoor flooding simulation experiments. Cr, Pb, Zn, Cd and Cu contents of different forms were determined in soil of typical fluctuating zone of Three Gorges Reservoir. The results showed that, after flooding months, both addition of 4 g · kg⁻¹ of rutile and anatase particles resulted in the release of about 30% Cr into the water. Nano-TiO2 particles mainly promoted the dissolution of oxidizable residual Cr, and elevated its ecological risk. Thus nano-TiO2promoted the activation of chromium and improved the mobility of chromium in soil. 4 g · kg⁻¹ of rutile particles caused the decrease of acid exchangeable lead by 25.92% and oxidizable lead by 33.09%, and enhanced the mobility of Pb. However, anatase particles caused the increase of oxidizable zinc by 30% in soil, which facilitated fixing of zinc. In addition, two types of nano-TiO2particles had no significant effect on the speciation changes of Cu and Cd. Therefore, the effect of nano-TiO2 on release and transformation of Cr in soil was the largest, followed by Pb and Zn. This needs special attention when using nano-TiO2 to remediate heavy metals contaminated soil and assessing its environmental risk.

[Experimental Research of Hg (II) Removal from Aqueous Solutions of HgCl2 with Nano-TiO2].

Mercury removal from aqueous solutions of HgCl2 was studied by indoor simulation experiments, and the effects of three different diameter of particles of Nano-TiO2 ( Nano-Titanium Dioxide) at different dosage, pH, adsorption time and the initial concentration of Hg2+ on the mercury adsorption from simulated wastewater were investigated. The single factor experiments showed that the optimal conditions were: 7.5 g x L(-1) of 5 nm TiO2 or 2.0 g x L(-1) of 100 nm TiO2, pH 8.0, initial concentration of Hg2+ 15 x mg x L(-1) adsorption time 5 min, and under these conditions the adsorption rates reached 99.5% and 99.3%, relatively. When the content of 25 nm TiO2 was 10 g x L(-1), and the other conditions were pH 8.0, initial concentration of Hg2+ 15 mg x L(-1), adsorption time 60 min, the adsorption rate was 62.8%. The Hg(II) removal effects of the TiO2 particles with different diameters followed the order of 100 nm TiO2 > 5 nm TiO2 > 25 nm TiO2. Component adsorption results showed that the 5 nm TiO2 component adsorption effect was superior to its single adsorption effect, while there was little difference between 100 nm TiO2 component adsorption effect and its single adsorption effect. The results of orthogonal experiments indicated that the influencing factors of the adsorption rate followed the order of pH > the initial concentration of Hg2+ > time > dosage. The optimal experiment scheme was: pH 8.0, a dosage of 100 nm Nano-TiO2 of 2.0 g x L(-1) an initial Hg2+ concentration of 25 mg x L(-1) and adsorption time of 10 min. Under the experimental conditions, the maximum adsorption rate reached 99.9%, at the same time, the equilibrium concentration of Hg(II) was 0.033 mg x L(-1) < 0.05 mg x L(-1), below the current enterprise rules of water pollutants in mercury emissions limits. In addition, the maximum adsorptive capacity was 26.95 mg x g(-1). The adsorption isotherm was in line with the Langmuir isotherm equation, indicating that the Hg(II) uptake by 100 nm Nano-TiO2 was typical monolayer adsorption.

[Release of mercury from soil and plant in water-level-fluctuating zone of the Three Gorges Reservoir area and its accumulation in zebrafish].

To investigate the production, distribution and bioavailability of methylmercury (MMHg) in soil and plants of the water-level-fluctuating zone (WLFZ) of the Three Gorges Reservoir area, simulation experiments were conducted in laboratory. Results indicated that the level of total mercury (THg) in soil decreased with the lengthening of submerging time while that in water increased obviously. The level of MMHg in inundated soil and water increased, especially in the water treated by Echinochloa crusgalli and soils. And the MMHg level in that treatment was 2.52 times higher than that treated only by soils for 21 days. This indicated that soil and plants of WLFZ were important sources of mercury in the water of the reservoir. Echinochloa crusgalli as the tested plant was decomposed after being submerged, leading to lower pH and DO and higher DOC, which had little effect on MMHg in soil but significant effect on MMHg in water. The level of THg in the head, viscera and muscle of zebrafish increased obviously, which had a significant correlation with that in water (P < 0.01). MMHg levels accumulated in the head, viscera and muscle of zebrafish differed to some degree, particularly in the head and muscle. After treated in the soils for 21 days, MMHg levels in the head, viscera and muscle of zebrafish were 1.75-6.25, 3.53-8.38 and 2.22-3.36 times higher than those in the control groups, respectively. While for the treatment of Echinochloa crusgalli and soil, MMHg levels in zebrafish's head, viscera and muscle were 3.57, 2.37 and 1.52 times higher than those treated only by soil, respectively. Therefore, submerged soil was the main source of MMHg in fish. And submerged plants changed the water condition and affected the release of mercury to water so as to cause elevated levels of MMHg in fish.

[Distribution and risk assessment of mercury species in soil of the water-level-fluctuating zone in the Three Gorges Reservoir].

To investigate pollution level and ecological risk of mercury in soils of the water-level-fluctuating zone in the Three Gorges Reservoir Region, 192 surface soil samples from 14 counties (districts) in Chongqing were obtained. Concentrations of THg and Hg species, bioavailable Hg were analyzed and discussed. Geoaccumulation index (I(geo)) and Håkanson potential ecological risk index (E(r)) were applied to assess the pollution status and potential ecological risk of THg and Hg species, respectively. The results showed that significant differences in the concentration of THg were found in soils of water-level-fluctuating zone in the Three Gorges Reservoir. The THg concentration ranged from 22.4 to 393.5 microg x kg(-1), with an average of (84.2 +/- 54.3) microg x kg(-1). 76.6% of the samples' THg content was higher than the soil background value in the Three Gorges Reservoir Region. The percentage of five mercury species (water-soluble Hg, HCl-soluble Hg, KOH-soluble Hg, H2O2-soluble Hg, residue Hg) in soils were 4.1%, 15.5%, 18.3%, 10.9%, 51.3%, respectively. The average concentrations of bioavailable mercury varied between 19.7-36.6 microg x kg(-1), and the percentage of bioavailable Hg was 22.1%-51.6% of THg. According to the geoaccumulation index, the soils were lightly polluted by Hg. Håkanson single potential ecological risk index evaluation showed that Hg species had a low potential ecological risk, moreover, soils of water-level-fluctuating zone in the Three Gorges Reservoir were at low ecological risk levels as evaluated by bioavailable Hg. While, the assessment results based on THg of soils was much higher than that based on the Hg species. Two methods of evaluation showed that the I(geo) and E(r) values calculated based on the Hg species better reflected the actual pollution levels of soils and its hazard to aquatic organisms.

Beneficial effects of natural Jeju groundwaters on lipid metabolism in high-fat diet-induced hyperlipidemic rats.

BACKGROUND: Groundwater is believed to possess many beneficial effects due to its natural source of various minerals. In this study, we examined the effects of natural Jeju groundwater S1 (Samdasoo™), S2 and S3 pumped up from different locations of Jeju Island, Korea, along with local tap water, on body weight gain, serum lipids and lipoproteins, and liver histopathology in high-fat diet-induced hyperlipidemic rats. MATERIALS/METHODS: Rats were randomly and equally divided into 6 groups. Different water samples were supplied to the hyperlipidemic rats as their daily drinking water and the widely-used anti-hyperlipidemic drug simvastatin was used as a positive control. Body weight, serum lipids and lipoproteins were measured weekly. Liver weight, liver index and liver histopathology were examined after the execution of the rats. RESULTS: After drinking Jeju groundwaters for two months, S2 but not S3 significantly reduced weight growth and serum triglycerides levels and increased high density lipoprotein-C (HDL-C) without affecting total cholesterol or LDL-C. S1 and particularly S2 significantly reduced the severity of liver hypertrophy and steatosis. All Groundwaters had much higher contents of vanadium (S3>S2>S1>>tap water) whereas S1 and S2 but not S3 markedly blocked autoxidation of ferrous ions. CONCLUSION: Jeju Groundwater S1 and particularly S2 exhibit protective effects against hyperlipidemia and fatty liver and hypothesize that the beneficial effect of Jeju Groundwaters may be contributed from blockade of autoxidation of ferrous ions rather than their high contents of vanadium.

[Effect of nano-TiO2 on the release and activation of mercury in sediment].

To investigate the effects of nano-TiO2 on mercury release and activation in sediment, flooding simulation experiments were conducted. The impacts of nano-TiO2 on total mercury and methylmercury concentrations in overlying water were analyzed. And the influences of nano-TiO2 on the migration and transformation of mercury were discussed based on changes of mercury speciation in sediment. The results indicated that nano-TiO2 promoted the release of mercury in sediment, leading to more mercury released into the water. Compared with the control, 4 g x kg(-1) TiO2 nanoparticles increased the total mercury by 91.32%, when the concentration of total mercury in overlying water was the highest. Release of mercury in soil was increased by approximately 10% finally. The main reason may be that the dissolution of oxidation state mercury was improved by nano-TiO2. It indicated that the risk of mercury contamination in water may increase. Moreover, under the experimental conditions, nano-TiO2 may reduce the formation of methylmercury in sediment in the short-term, but no significant effects in the long-term. Generally, the effects of nano-TiO2 on the release and transformation of mercury in sediment showed concentration dependence. Thus, with increasing nano-TiO2 content in sediment or soil, its impact on the geochemical cycle of mercury may increase.

[Mercury speciation transformation in soil of the water-level-fluctuating zone in the Three Gorges area under alternative dry-wet condition].

The speciation transformation, influencing factors, as well as bioavailability of mercury (Hg) in soil of the water-level-fluctuating zone in the Three Gorges Reservoir Area were simulated. The results showed that Hg in soil under alternative dry-wet condition could be transformed and released. The total Hg content in the soil was decreased by 28.9% after two "wet-dry" cycles. The percentages of the six Hg species (water-soluble, exchangeable, carbonate-bound, humics-bound, organic-sulf and residual Hg) were 6.1%-16.8%, 5.8% -12.9%, 4.5%-17.7%, 12.5%-29.9%, 5.3%-12.8%, and 34.5%-51.6%, respectively. It was found that Hg in soils was dominantly residue Hg, whose percentage tended to decrease under alternative dry-wet condition. The percentage of humics-bound Hg increased gradually and an increase of the percentage of bioavailable Hg (including water-soluble, exchangeable, carbonate-bound, and humics-bound Hg) after two wet-dry cycles were observed. Bioavailable Hg could be easily absorbed by aquatic organisms to enter the food chain, which might increase the ecological risk of Hg in the reservoir.

Preparation of the albumin nanoparticle system loaded with both paclitaxel and sorafenib and its evaluation in vitro and in vivo.

Paclitaxel and sorafenib loaded albumin nanoparticles (PTX-SRF-BSA-NPs) were prepared and studied here to avoid the toxicities from the excipients in the Taxol® and explore the effect of such combination on the antitumour efficacy and toxicity. PTX-BSA-NPs and so on were used as controls. The particle size, zeta potential, encapsulation efficiency and morphology were evaluated. Less than 70% of each drug released within 24 h. PTX and SRF existed as molecular or amorphous form in the PTX-SRF-BSA-NPs. The particle size did not change much after 2-month storage in freeze-dried form or 24 h in suspension. The treatment with PTX-SRF-BSA-NPs (7.5 mg kg(-1) PTX + 7.5 mg kg(-1) SRF) exhibited lower myelosuppression than PTX-BSA-NPs (15 mg kg(-1) PTX) while it remained or increased the antitumour effect in mice tumour models. Compared with the solution containing the same level of PTX and SRF, PTX-SRF-BSA-NPs demonstrated significantly lower haemolysis and myelosuppression effect.

Evaluation and structure-activity relationship study of acute toxicity of naphthoquinones to Photobacterium phosphoreum, Photobacterium T3B.

The acute toxicities of five naphthoquinone compounds to Photobacterium phosphoreum were determined. We evaluated the mechanism of toxicity using the structure-activity relationship technique. The results showed that some factors, including the species of substituents, shape/size of molecule and oil-water partition coefficient (log P) played the important roles in the interaction between the naphthoquinones and the target. Among of these, the toxicities of Atovaquone and Buparvaquone were lower than the other naphthoquinones we tested because of the alkyl-substitution with the bigger volume and strong hydrophobicity. Conversely, Menadione had the highest toxicity because of the appropriate log P and shape/size of molecule resulting in the easier interaction with the target.