Reversing the directionality of reactions between non-oxidative pentose phosphate pathway and glycolytic pathway boosts mycosporine-like amino acid production in Saccharomyces cerevisiae.

BACKGROUND: Mycosporine-like amino acids (MAAs) are a class of strongly UV-absorbing compounds produced by cyanobacteria, algae and corals and are promising candidates for natural sunscreen components. Low MAA yields from natural sources, coupled with difficulties in culturing its native producers, have catalyzed synthetic biology-guided approaches to produce MAAs in tractable microbial hosts like Escherichia coli, Saccharomyces cerevisiae and Corynebacterium glutamicum. However, the MAA titres obtained in these hosts are still low, necessitating a thorough understanding of cellular factors regulating MAA production. RESULTS: To delineate factors that regulate MAA production, we constructed a shinorine (mycosporine-glycine-serine) producing yeast strain by expressing the four MAA biosynthetic enzymes from Nostoc punctiforme in Saccharomyces cerevisiae. We show that shinorine is produced from the pentose phosphate pathway intermediate sedoheptulose 7-phosphate (S7P), and not from the shikimate pathway intermediate 3-dehydroquinate (3DHQ) as previously suggested. Deletions of transaldolase (TAL1) and phosphofructokinase (PFK1/PFK2) genes boosted S7P/shinorine production via independent mechanisms. Unexpectedly, the enhanced S7P/shinorine production in the PFK mutants was not entirely due to increased flux towards the pentose phosphate pathway. We provide multiple lines of evidence in support of a reversed pathway between glycolysis and the non-oxidative pentose phosphate pathway (NOPPP) that boosts S7P/shinorine production in the phosphofructokinase mutant cells. CONCLUSION: Reversing the direction of flux between glycolysis and the NOPPP offers a novel metabolic engineering strategy in Saccharomyces cerevisiae.

[Efficacy and safety analysis of hypoxia-inducible factor prolyl hydroxylase inhibitors for anemia in low-risk myelodysplastic syndromes patients].

Myelodysplastic syndromes is a heterogeneous group of myeloid neoplastic disorders originating from hematopoietic stem cells and manifesting as pathological bone marrow hematopoiesis and a high risk of transformation to acute myeloid leukemia. In low-risk patients, the therapeutic goal is to improve hematopoiesis and quality of life. Roxadustat is the world's first oral small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor, which, unlike conventional erythropoietin, corrects anemia through various mechanisms. In this study, we retrospectively analyzed the changes in anemia, iron metabolism, lipids and inflammatory indexes in patients with low-risk myelodysplastic syndromes to evaluate its therapeutic efficacy and safety, and to provide theoretical and practical data for the application of roxadustat in myelodysplastic syndromes.

[Efficacy and safety of roxadustat in the treatment of refractory non-severe aplastic anemia].

Objective: To evaluate the efficacy and safety of roxadustat in patients with refractory non-severe aplastic anemia (NSAA) . Methods: The clinical data of patients with refractory NSAA who had been treated with roxadustat continuously for at least 3 months and followed up for more than 6 months at Peking Union Medical College Hospital from October 2020 to August 2022 were retrospectively collected. The demographic information, clinical data, treatment efficacy, adverse reactions, and outcomes were evaluated, and the factors influencing efficacy were analyzed. Results: A total of 41 patients were included. The male-to-female ratio was 16∶25, and the median age was 52 (18-84) years. The median duration of roxadustat treatment was 5 (3-20) months, and the median follow-up was 15 (6-26) months. Hematologic improvement-erythroid (HI-E) was 12.2%, 29.3%, 46.3%, 43.9%, and 30.3% at 1, 2, 3, 6, and 12 months, respectively. The rate of transfusion independence was 28.5%, 38.1%, and 33.3% at 3, 6, and 12 months, respectively. Hemoglobin returned to normal in some patients after treatment with roxadustat. The incidence of adverse events was 22%, all of which were grade Ⅰ-Ⅱ and recoverable. No factors that could affect HI-E were identified. By the end of follow-up, 45% of the patients relapsed, with a median time to relapse of 7 (3-12) months. No clonal evolution was observed, and one patient died. Conclusion: Roxadustat effectively improved anemia with good tolerance in patients with refractory NSAA.

Three-dimensional polymer phenylethnylcopper/nitrogen doped graphene aerogel electrode coupled with Fe3O4 NPs nanozyme: Toward sensitive and robust photoelectrochemical detection of glyphosate in agricultural matrix.

BACKGROUND: Presently, glyphosate (Gly) is the most extensively used herbicide globally, Nevertheless, its excessive usage has increased its accumulation in off-target locations, and aroused concerns for food and environmental safety. Commonly used detection methods, such as high-performance liquid chromatography and gas chromatography, have limitations due to expensive instruments, complex pre-processing steps, and inadequate sensitivity. Therefore, a facile, sensitive, and reliable Gly detection method should be developed. RESULTS: A photoelectrochemical (PEC) sensor consisting of a three-dimensional polymer phenylethnylcopper/nitrogen-doped graphene aerogel (PPhECu/3DNGA) electrode coupled with Fe3O4 NPs nanozyme was constructed for sensitive detection of Gly. The microscopic 3D network of electrodes offered fast transfer routes for photo-generated electrons and a large surface area for nanozyme loading, allowing high signal output and analytical sensitivity. Furthermore, the use of peroxidase-mimicking Fe3O4 NPs instead of natural enzyme improved the stability of the sensor against ambient temperature changes. Based on the inhibitory effect of Gly on the catalytic activity Fe3O4 NPs, the protocol achieved Gly detection in the range of 5 × 10-10 to 1 × 10-4 mol L-1. Additionally, feasibility of the detection was confirmed in real agricultural matrix including tea, maize seedlings, maize seeds and soil. SIGNIFICANCE: This work achieved facile, sensitive and reliable analysis towards Gly, and it was expected to inspire the design and utilization of 3D architectures in monitoring agricultural chemicals in food and environmental matrix.

Multifunctional 2D hemin-bridged MOF for the efficient removal and dual-mode detection of organophosphorus pesticides.

The high-residual and bioaccumulation property of organophosphorus pesticides (OPs) creates enormous risks towards the ecological environment and human health, promoting the research for smart adsorbents and detection methods. Herein, 2D hemin-bridged MOF nanozyme (2D-ZHM) was fabricated and applied to the efficient removal and ultrasensitive dual-mode aptasensing of OPs. On the one hand, the prepared 2D-ZHM contained Zr-OH groups with high affinity for phosphate groups, endowing it with selective recognition and high adsorption capacity for OPs (285.7 mg g-1 for glyphosate). On the other hand, the enhanced peroxidase-mimicking biocatalytic property of 2D-ZHM allowed rapid H2O2-directed transformation of 3,3',5,5'-tetramethylbenzidine to oxidic product, producing detectable colorimetric or photothermal signals. Using aptamers of specific recognition capacity, the rapid quantification of two typical OPs, glyphosate and omethoate, was realized with remarkable sensitivity and selectivity. The limit of detections (LODs) of glyphosate were 0.004 nM and 0.02 nM for colorimetric and photothermal methods, respectively, and the LODs of omethoate were 0.005 nM and 0.04 nM for colorimetric and photothermal methods, respectively. The constructed dual-mode aptasensing platform exhibited outstanding performance for monitoring OPs in water and fruit samples. This work provides a novel pathway to develop MOF-based artificial peroxidase and integrated platform for pollutant removal and multi-mode aptasensing.

Effects of biochar and compost on microbial community assembly and metabolic processes in glyphosate, imidacloprid and pyraclostrobin polluted soil under freezethaw cycles.

Biochar and organic compost are widely used in agricultural soil remediation as soil immobilization agents. However, the effects of biochar and compost on microbial community assembly processes in polluted soil under freezingthawing need to be further clarified. Therefore, a freezethaw cycle experiment was conducted with glyphosate (herbicide), imidacloprid (insecticide) and pyraclostrobin (fungicide) polluted to understand the effect of biochar and compost on microbial community assembly and metabolic behavior. We found that biochar and compost could significantly promote the degradation of glyphosate, imidacloprid and pyraclostrobin in freezethaw soil decrease the half-life of the three pesticides. The addition of immobilization agents improved soil bacterial and fungal communities and promoted the transformation from homogeneous dispersal to homogeneous selection. For soil metabolism, the combined addition of biochar and compost alleviated the pollution of glyphosate, imidacloprid and imidacloprid to soil through up-regulation of metabolites (DEMs) in amino acid metabolism pathway and down-regulation of DEMs in fatty acid metabolism pathway. The structural equation modeling (SEM) results showed that soil pH and DOC were the main driving factors affecting microbial community assembly and metabolites. In summary, the combined addition of biochar and compost reduced the adverse effects of pesticides residues.

Engineering multi-degrading bacterial communities to bioremediate soils contaminated with pesticides residues.

Parallel to the important use of pesticides in conventional agriculture there is a growing interest for green technologies to clear contaminated soil from pesticides and their degradation products. Bioaugmentation i. e. the inoculation of degrading micro-organisms in polluted soil, is a promising method still in needs of further developments. Specifically, improvements in the understanding of how degrading microorganisms must overcome abiotic filters and interact with the autochthonous microbial communities are needed in order to efficiently design bioremediation strategies. Here we designed a protocol aiming at studying the degradation of two herbicides, glyphosate (GLY) and isoproturon (IPU), via experimental modifications of two source bacterial communities. We used statistical methods stemming from genomic prediction to link community composition to herbicides degradation potentials. Our approach proved to be efficient with correlation estimates over 0.8 - between model predictions and measured pesticide degradation values. Multi-degrading bacterial communities were obtained by coalescing bacterial communities with high GLY or IPU degradation ability based on their community-level properties. Finally, we evaluated the efficiency of constructed multi-degrading communities to remove pesticide contamination in a different soil. While results are less clear in the case of GLY, we showed an efficient transfer of degrading capacities towards the receiving soil even at relatively low inoculation levels in the case of IPU. Altogether, we developed an innovative protocol for building multi-degrading simplified bacterial communities with the help of genomic prediction tools and coalescence, and proved their efficiency in a contaminated soil.

Synthesis, antimicrobial activity, antioxidant activity and molecular docking of novel chitosan derivatives containing glycine Schiff bases as potential succinate dehydrogenase inhibitors.

Succinate dehydrogenase (SDH) is an important inner mitochondrial membrane-bound enzyme involved in redox reactions during the tricarboxylic acid cycle. Therefore, a series of novel chitosan derivatives were designed and synthesized as potential microbicides targeting SDH and precisely characterized by FTIR, 1H NMR and SEM. Their antifungal and antibacterial activities were evaluated against Botrytis cinerea, Fusarium graminearum, Staphylococcus aureus and Escherichia coli. The bioassays revealed that these chitosan derivatives exerted significant antifungal effects, with four of the compounds achieving 100 % inhibition of Fusarium graminearum merely at a concentration of 0.5 mg/mL. Additionally, CSGDCH showed 79.34 % inhibition of Botrytis cinerea at a concentration of 0.1 mg/mL. In vitro antibacterial tests revealed that CSGDCH and CSGDBH have excellent Staphylococcus aureus and Escherichia coli inhibition with MICs of 0.0156 mg/mL and 0.03125 mg/mL, respectively. Molecular docking studies have been carried out to explore the binding energy and binding mode of chitosan and chitosan derivatives with SDH. The analyses indicated that chitosan derivatives targeted the active site of the SDH protein more precisely, disrupting its normal function and ultimately repressing the growth of microbial cells. Furthermore, the chitosan derivatives were also evaluated biologically for antioxidation, and all of these compounds had a greater degree of reducing power, superoxide radical, hydroxyl radical and DPPH-radical scavenging activity than chitosan. This research has the potential for the development of agricultural antimicrobial agents.

Assessing glyphosate and AMPA pesticides in the Ofanto River waters and sediments.

In the present study, we determined glyphosate (GPS) and aminomethylphosphonic acid (AMPA) in the water and sediments of the Ofanto River (Italy), evaluating their transport from the mouth to the sea. Sediments were collected twice in 2021 during low and high tide; waters were sampled on a seasonal basis. The results showed the prevalence of GPS and AMPA in the water with concentrations equal to 190 and 3053 ng/l, respectively. We also found GPS and AMPA in the sediments with values of 0.95 and 11.34 ng/g. In water, pesticides were detected in all seasons with peaks in concentrations during summer and spring. A significant positive correlation between the pesticides in the sediments and the water pH and a negative correlation with salinity was observed. An estimation of the average loads revealed a discharge of 64.11 kg/yr. of GPS and 958.37 kg/yr. of AMPA from the river to the marine environment.

Adamantylglycine as a high-affinity peptide label for membrane transport monitoring and regulation.

The non-canonical amino acid adamantylglycine (Ada) is introduced into peptides to allow high-affinity binding to cucurbit[7]uril (CB7). Introduction of Ada into a cell-penetrating peptide (CPP) sequence had minimal influence on the membrane transport, yet enabled up- and down-regulation of the membrane transport activity.

Rapid determination of glyphosate and glufosinate in human blood by probe electrospray ionization tandem mass spectrometry.

In forensic science, glyphosate (GLYP) and glufosinate (GLUF), a class of non-selective broad-spectrum herbicides, have been frequently encountered in many fatal poisoning and suicide cases due to their widespread availability. Therefore, it is essential to develop an effective method for detecting these compounds. Some conventional methods, such as gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-mass spectrometry (LC-MS), have been reported to detect these compounds. However, these methods are not ideal for their time-consuming and non-sensitive feature. Herein, probe electrospray ionization (PESI) tandem mass spectrometry (MS/MS), a fast and sensitive technique, was applied for the determination of GLYP and GLUF in human blood, which can obtain analytical results within 0.5 min without derivatization and chromatographic separation. After protein precipitation of blood samples, the supernatant was mixed with isopropanol and ultra-pure water (1:1 v/v). Then, 8 µL of the mixture was introduced into the plastic sample plate for PESI-MS/MS analysis. The limits of detection (LODs) of the method were 0.50 µg/mL and 0.25 µg/mL for two analytes, and the limits of quantitation (LOQs) were both 1.00 µg/mL, which are higher than the concentration of reported poisoning and fatal cases. In the linear range of 1-500 µg/mL, the regression coefficients (r2) for GLYP and GLUF were over 0.99. The matrix effects ranged from 94.8 % to 119.5 %, and the biases were below 4.3 %. The recoveries ranged between 84.8 % and 107.4 %, and the biases were below 7.6 %. Meanwhile, the method was effectively utilized to detect and quantify the blood, urine, and other samples. Consequently, the results suggest that PESI-MS/MS is a straightforward, fast, and sensitive method for detecting GLUF and GLYP in forensics. In the future, PESI-MS/MS will become an indispensable technique for polar substances in grassroots units of public security where rapid detection is essential.

Physiological responses of the microalgae Thalassiosira weissflogii to the presence of the herbicide glyphosate in the medium.

We evaluated changes in growth, chlorophyll fluorescence and basic physiological and biochemical parameters of the microalgae Thalassiosira weissflogii cells under the influence of the herbicide glyphosate in concentrations 0, 25, 95 and 150µgL-1 . The toxic effect of glyphosate on algae is weakly dependent on the level of cell mineral nutrition. High concentrations of the herbicide do not lead to the death of microalgae but block the process of algae cell division. An increase in the glyphosate concentration in the medium leads to a slowdown or stop of algal growth, a decrease in their final biomass, an increase in the production of reactive oxygen species (ROS), depolarisation of mitochondrial membranes and metabolic activity of algae. Glyphosate inhibits the photosynthetic activity of cells and inhibits the relative rate of electron transport in the photosynthetic apparatus. Glyphosate at the studied concentrations does not affect the size characteristics of cells and the intracellular content of chlorophyll in T. weissflogii . The studied herbicide or products of its decay retain their toxic properties in the environment for at least 9days. This result shows the need for further in-depth studies to assess the physiological response and possible acclimation changes in the functional state of oxygenic phototrophs in response to the herbicide action. The species specificity of microalgae to the effects of glyphosate in natural conditions is potentially dangerous due to a possible change in the species structure of biocoenoses, in particular, a decrease in the contribution of diatoms.

Preparation and Evaluation of Chitosan Coated PLGA Nanoparticles Encapsulating Ivosidenib with Enhanced Cytotoxicity Against Human Liver Cancer Cells.

Purpose: Ivosidenib (IVO), an isocitrate dehydrogenase-1 (IDH1) used for treatment of acute myeloid leukemia (AML) and cholangiocarcinoma. However, poor solubility, low bioavailability, high dose and side effects limit clinical application of IVO. Methods: Ivosidenib-loaded PLGA nanoparticles (IVO-PLGA-NPs) and Ivosidenib-loaded chitosan coated PLGA nanoparticles (IVO-CS-PLGA-NPs) were prepared using emulsification and solvent evaporation method for the treatment of liver cancer. Results: The developed IVO-PLGA-NPs were evaluated for their particle size (171.7±4.9 nm), PDI (0.333), ZP (-23.0±5.8 mV), EE (96.3±4.3%), and DL (9.66±1.1%); similarly, the IVO-CS-PLGA-NPs were evaluated for their particle size (177.3±5.2 nm), PDI (0.311), ZP +25.9±5.7 mV, EE (90.8±5.7%), and DL (9.42±0.7%). The chitosan coating of IVO-PLGA-NPs was evidenced by an increase in mean particle size and positive ZP value. Because of the chitosan coating, the IVO-CS-PLGA-NPs showed a more stable and prolonged release of IVO than IVO-PLGA-NPs. In comparison to pure-IVO, the IVO-PLGA-NPs and IVO-CS-PLGA-NPs were found to be more effective against HepG2 cells, with IC50 values for the MTT assay being approximately half of those of pure-IVO. In HepG2 cells, the expressions of caspase-3, caspase-9, and p53 were significantly (p < 0.05) elevated. Conclusion: Overall, these findings suggest that chitosan coating of IVO-PLGA-NPs improves the delivery and efficacy of ivosidenib in liver cancer treatment.

Guanidinoacetic acid ameliorates hepatic steatosis and inflammation and promotes white adipose tissue browning in middle-aged mice with high-fat-diet-induced obesity.

Guanidinoacetic acid (GAA) is a naturally occurring amino acid derivative that plays a critical role in energy metabolism. In recent years, a growing body of evidence has emerged supporting the importance of GAA in metabolic dysfunction. Hence, we aimed to investigate the effects of GAA on hepatic and adipose tissue metabolism, as well as systemic inflammatory responses in obese middle-aged mice models and attempted to explore the underlying mechanism. We found that dietary supplementation of GAA inhibited inguinal white adipose tissue (iWAT) hypertrophy in high-fat diet (HFD)-fed mice. In addition, GAA supplementation observably decreased the levels of some systemic inflammatory factors, including IL-4, TNF-α, IL-1ß, and IL-6. Intriguingly, GAA supplementation ameliorated hepatic steatosis and lipid deposition in HFD-fed mice, which was revealed by decreased levels of TG, TC, LDL-C, PPARγ, SREBP-1c, FASN, ACC, FABP1, and APOB and increased levels of HDL-C in the liver. Moreover, GAA supplementation increased the expression of browning markers and mitochondrial-related genes in the iWAT. Further investigation showed that dietary GAA promoted the browning of the iWAT via activating the AMPK/Sirt1 signaling pathway and might be associated with futile creatine cycling in obese mice. These results indicate that GAA has the potential to be used as an effective ingredient in dietary interventions and thus may play an important role in ameliorating and preventing HFD-induced obesity and related metabolic diseases.

[Clinical Efficacy and Safety of Ixazomib-Containing Regimens in the Treatment of Patients with Multiple Myeloma].

OBJECTIVE: To investigate the clinical efficacy and safety of ixazomib-containing regimens in the treatment of patients with multiple myeloma (MM). METHODS: A retrospective analysis was performed on the clinical efficacy and adverse reactions of 32 MM patients treated with a combined regimen containing ixazomib in the Hematology Department of the First People's Hospital of Lianyungang from January 2020 to February 2022. Among the 32 patients, 15 patients were relapsed and refractory multiple myeloma (R/RMM) (R/RMM group), 17 patients who responded to bortezomib induction therapy but converted to ixazomib-containing regimen due to adverse events (AE) or other reasons (conversion treatment group). The treatment included IPD regimen (ixazomib+pomalidomide+dexamethasone), IRD regimen (ixazomib+lenalidomide+dexamethasone), ICD regimen (ixazomib+cyclophosphamide+dexamethasone), ID regimen (ixazomib+dexamethasone). RESULTS: Of 15 R/RMM patients, overall response rate (ORR) was 53.3%(8/15), among them, 1 achieved complete response (CR), 2 achieved very good partial response (VGPR) and 5 achieved partial response (PR). The ORR of the IPD, IRD, ICD and ID regimen group were 100%（3/3）, 42.9%（3/7）, 33.3%（1/3）, 50%（1/2）， respectively， there was no statistically significant difference in ORR between four groups (χ 2=3.375, P =0.452). The ORR of patients was 50% after first-line therapy, 42.9% after second line therapy, 60% after third line therapy or more, with no statistically significant difference among them (χ2=2.164, P =0.730). In conversion treatment group, ORR was 88.2%(15/17), among them, 6 patients achieved CR, 5 patients achieved VGPR and 4 patients achieved PR. There was no statistically significant difference in ORR between the IPD（100%， 3/3）, IRD（100%， 6/6）, ICD（100%， 3/3） and ID（60%， 3/5） regimen groups (χ2=3.737，P =0.184). The median progression-free survival (PFS) time of R/RMM patients was 9 months (95% CI : 6.6-11.4 months), the median overall survival (OS) time was 18 months (95% CI : 11.8-24.4 months). The median PFS time of conversion treatment group was 15 months (95% CI : 7.3-22.7 months), the median OS time not reached. A total of 10 patients suffered grade 3- 4 adverse event (AE). The common hematological toxicities were leukocytopenia, anemia, thrombocytopenia. The common non-hematological toxicities were gastrointestinal symptoms (diarrhea, nausea and vomit), peripheral neuropathy, fatigue and infections. Grade 1-2 peripheral neurotoxicity occurred in 7 patients. CONCLUSION: The ixazomib-based chemotherapy regimens are safe and effective in R/RMM therapy, particularly for conversion patients who are effective for bortezomib therapy. The AE was manageable and safe.

A real-world retrospective-prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience.

INTRODUCTION: Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE-MM1. OBJECTIVES AND METHODS: We conducted a retrospective-prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life. RESULTS: At IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high-risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)-exposed (including both Len-sensitive and Len-refractory pts), and 22% were Len-refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non-hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1-2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow-up of 38 m, median PFS (mPFS) was 16 m and the 1-year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len-naïve (NR), age ≥70 (20 m). In pts exposed to Len, non-refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len-refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31). CONCLUSION: IRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len-sensitive, independent of age, and cytogenetic risk.

Combined pesticides in field doses weaken honey bee (Apis cerana F.) flight ability and analyses of transcriptomics and metabolomics.

Imidacloprid, chlorpyrifos, and glyphosate rank among the most extensively employed pesticides worldwide. The effects of these pesticides and their combined on the flight capability of Apis cerana, and the potential underlying mechanisms remain uncertain. To investigate these effects, we carried out flight mill, transcriptome, and metabolome experiments. Our findings reveal that individual acute oral treatments with pesticides, specifically 20 µL of 10 ng/g imidacloprid (0.2 ng per bee), 30 ng/g chlorpyrifos (0.6 ng per bee), and 60 ng/g glyphosate (1.2 ng per bee), did not impact the flight capability of the bees. However, when bees were exposed to a combination of two or three pesticides, a notable reduction in flight duration and distance was observed. In the transcriptomic and metabolomic analyses, we identified 307 transcripts and 17 metabolites that exhibited differential expression following exposure to combined pesticides, primarily associated with metabolic pathways involved in energy regulation. Our results illuminate the intricate effects and potential hazards posed by combined pesticide exposures on bee behavior. These findings offer valuable insights into the synergistic potential of pesticide combinations and their capacity to impair bee behavior. Understanding these complex interactions is essential for comprehending the broader consequences of pesticide formulations on honey bee populations.

A retrospective study on the efficacy of Roxadustat in peritoneal dialysis patients with erythropoietin hyporesponsiveness.

BACKGROUND/AIMS: Roxadustat, an oral medication for treating renal anemia, is a hypoxia-inducible factor prolyl hydroxylase inhibitor used for regulating iron metabolism and promoting erythropoiesis. To investigate the efficacy and safety of roxadustat in patients undergoing peritoneal dialysis (PD) with erythropoietin hyporesponsiveness. METHODS: Single-center, retrospective study, 81 PD patients (with erythropoietin hyporesponsiveness) were divided into the roxadustat group (n = 61) and erythropoiesis-stimulating agents (ESAs) group (n = 20). Hemoglobin (Hb), total cholesterol, intact parathyroid hormone (iPTH), brain natriuretic peptide (BNP), related indicators of cardiac function and high-sensitivity C-reactive protein (hs-CRP) were collected. Additionally, adverse events were also recorded. The follow-up period was 16 weeks. RESULTS: The two groups exhibited similar baseline demographic and clinical characteristics. At baseline, the roxadustat group had a mean Hb level of 89.8 ± 18.9 g/L, while the ESAs group had a mean Hb level of 95.2 ± 16.0 g/L. By week 16, the Hb levels had increased to 118 ± 19.8 g/L (p < 0.05) in the roxadustat group and 101 ± 19.3 g/L (p > 0.05) in the ESAs group. The efficacy of roxadustat in improving anemia was not influenced by baseline levels of hs-CRP and iPTH. Cholesterol was decreased in the roxadustat group without statin use. An increase in left ventricular ejection fraction and stabilization of BNP were observed in the roxadustat group. CONCLUSION: For PD patients with erythropoietin hyporesponsiveness, roxadustat can significantly improve renal anemia. The efficacy of roxadustat in improving renal anemia was not affected by baseline levels of hs-CRP0 and iPTH.

Glyphosate-based herbicide worsens alterations induced by cafeteria diet on rat uterus.

Exposure to glyphosate-based herbicides (GBH) and consumption of cafeteria (CAF) diet, which are widespread in Western society, seem to be associated with endometrial hyperplasia (EH). Here, we aimed to evaluate the effects of a subchronic low dose of GBH added to the CAF diet on the rat uterus. Female Wistar rats were fed from postnatal day (PND)21 until PND240 with chow (control) or CAF diet. Since PND140, rats also received GBH (2 mg of glyphosate/kg/day) or water through food, yielding four experimental groups: control, CAF, GBH, and CAF+GBH. On PND240, CAF and CAF+GBH animals showed an increased adiposity index. With respect to the control group, no changes in the serum levels of 17ß-estradiol and progesterone were found. However, progesterone levels were higher in the CAF+GBH group than in the CAF and GBH groups. In the uterus, both studied factors alone and in combination induced morphological and molecular changes associated with EH. Furthermore, the addition of GBH provoked an increased thickness of subepithelial stroma in rats fed with the CAF diet. As a consequence of GBH exposure, CAF+GBH rats exhibited an increased density of abnormal gland area, considered preneoplastic lesions, as well as a reduced PTEN and p27 expression, both tumor suppressor molecules that inhibit cell proliferation, with respect to control rats. These results indicate that the addition of GBH exacerbates the CAF effects on uterine lesions and that the PTEN/p27 signaling pathway seems to be involved. Further studies focusing on the interaction between unhealthy diets and environmental chemicals should be encouraged to better understand uterine pathologies.

Conductometric investigation of nano MnSO4 association parameters and complex formation with glycylglycine in aqueous and methanol-water mixtures: Thermodynamic parameters and potential applications.

This study aimed to investigate the ion pair association values and association parameters of nano MnSO4 in water and methanol-water mixtures (20 % and 40 % methanol by mass percentage) at varying temperatures (298.15, 303.15, 308.15, and 313.15 K) using the conductometric technique. Additionally, the parameters for complex formation between nano MnSO4 and glycylglycine as a ligand were determined. The focus was on elucidating the thermodynamic formation parameters for the nano Mn2+-glycylglycine interaction, with particular emphasis on comparing the 1: 1 and 1: 2 (M: L) complexes to understand the complexation behavior more comprehensively. The results indicated that the complexation process was spontaneous, as evidenced by negative ΔGf (formation free energy change) values, which increased with temperature, highlighting the enhanced spontaneity of the process. The findings provide valuable insights into designing new materials and procedures by enhancing our understanding of the complexation behavior of nano MnSO4 with ligands like glycylglycine, thus contributing to advancements in various applications such as chemical synthesis, medicines, and environmental remediation. By elucidating the thermodynamic aspects of these interactions, the study aimed to provide valuable information that could be utilized in practical applications and further research endeavors.