Effects of the combined regulation of nitrogen, phosphorus, and potassium nutrients on the migration and transformation of arsenic species in paddy soil.

Nitrogen (N), phosphorus (P) and potassium (K) are three macroelements in agriculture production, but their combined effects on arsenic (As) toxicity and its translocation in rice plants are not clear. In this study, an orthogonal rotation combination based on different N, P and K (NPK) concentration was first designed to examine their combined effect on the As toxicity, its transformation and migration in rice plants based on the hydroponic culture and pot soil culture. The results showed that 2.0 mg/L arsenite (As(III)) had obvious toxicity on the growth of indica LuYouMingZhan (LYMZ) and the optimal NPK concentration was 28.41, 6 and 50 mg/L based on the quadratic regression of the recovery rate of chlorophyll SPAD value of indica LYMZ. The optimal NPK combination significantly alleviated the physiological toxicity of As(III) on indica LYMZ rice seedling and decreased the accumulation of inorganic As in their roots and shoots by 23.8±1.8 % and 33.4±2.4 % respectively; further pot culture from different As(III) polluted soil showed that the optimal NPK combination significantly increased the dry weight of roots, stems, sheaths and leaves of indica LYMZ rice plants as well as yield indicators by 6.4 %-61.7 % and 7.1 %-89.8 % respectively, decreased the accumulation of As(III) and arsenate by 6.25 %-100 % and 12.36 %-100 % respectively in their roots, stems, sheaths, leaves, brans and kernels except As(III) concentration in their sheaths, decreased the accumulation of dimethylarsenate in their sheaths, leaves, brans and kernels, and had the best repair effect on the translocation of As species in 50 mg/kg As(III)-added soil. Our study provided a desirable strategy for alleviating As toxicity in paddy soil and reducing As pollution in rice plants.

Novel Amphiphilic PROTAC with Enhanced Pharmacokinetic Properties for ALK Protein Degradation.

Advancements in anticancer strategies spotlight proteolysis targeting chimera (PROTAC) technology, yet it is hindered by poor water solubility and bioavailability. This study introduces a novel amphiphilic PROTAC, B1-PEG, synthesized through PEGylation of an optimized PROTAC molecule, B1, to enhance its properties. B1-PEG is engineered to self-organize into micelles in water and releases its active form in response to the tumor-specific high GSH environment. Comparative pharmacokinetic analysis revealed B1-PEG's superior bioavailability at 84.8%, outperforming the unmodified PROTAC molecule B1. When tested in a H3122 xenograft mouse model, B1-PEG significantly regressed tumors, underscoring its potential as a formidable candidate in targeted cancer therapy. Our findings offer a promising direction for overcoming bioavailability limitations in PROTAC drug design.

Effect of inorganic arsenic in paddy soil on the migration and transformation of selenium species in rice plants.

Selenium (Se) in paddy rice is one of the significant sources of human Se nutrition. However, the effect of arsenic (As) pollution in soil on the translocation of Se species in rice plants is unclear. In this research, a pot experiment was designed to examine the effect of the addition of 50 mg As/kg soil as arsenite or arsenate on the migration of Se species from soil to indica Minghui 63 and Luyoumingzhan. The results showed that the antagonism between inorganic As and Se was closely related to the rice cultivar and Se oxidation state in soil. Relative to the standalone selenate treatment, arsenite significantly (p < 0.05) decreased the accumulation of selenocystine, selenomethionine and selenate in the roots, stems, sheaths, leaves, brans and kernels of both cultivars by 21.4%-100.0%, 40.0%-100.0%, 41.0%-100%, 5.4%-96.3%, 11.3%-100.0% and 26.2%-39.7% respectively, except for selenocystine in the kernels of indica Minghui 63 and selenomethionine in the leaves of indica Minghui 63 and the stems of indica Luyoumingzhan. Arsenate also decreased (p < 0.05) the accumulation of selenocystine, selenomethionine and selenate in the roots, stems, brans and kernels of both cultivars by 34.9%-100.0%, 30.2%-100.0%, 11.3%-100.0% and 5.6%-39.6% respectively, except for selenate in the stems of indica Minghui 63. However, relative to the standalone selenite treatment, arsenite and arsenate decreased (p < 0.05) the accumulation of selenocystine, selenomethionine and selenite only in the roots of indica Minghui 63 by 45.5%-100.0%. Our results suggested that arsenite and arsenate had better antagonism toward Se species in selenate-added soil than that in selenite-added soil; moreover, arsenite had a higher inhibiting effect on the accumulation of Se species than arsenate.

Exposure to polystyrene nanoplastics induces abnormal activation of innate immunity via the cGAS-STING pathway.

Endogenous immune defenses provide an intrinsic barrier against external entity invasion. Microplastics in the environment, especially those at the nanoscale (nanoplastics or NPs), may pose latent health risks through direct exposure. While links between nanoplastics and inflammatory processes have been established, detailed insights into how they may perturb the innate immune mechanisms remain uncharted. Employing murine and macrophage (RAW264.7) cellular models subjected to polystyrene nanoplastics (PS-NPs), our investigative approach encompassed an array of techniques: Cell Counting Kit-8 assays, flow cytometric analysis, acridine orange/ethidium bromide (AO/EB) fluorescence staining, cell transfection, cell cycle scrutiny, genetic manipulation, messenger RNA expression profiling via quantitative real-time PCR, and protein expression evaluation through western blotting. The results showed that PS-NPs caused RAW264.7 cell apoptosis, leading to cell cycle arrest, and activated the cGAS-STING pathway. This resulted in NF-κB signaling activation and increased pro-inflammatory mediator expression. Importantly, PS-NPs-induced activation of NF-κB and its downstream inflammatory cascade were markedly diminished after the silencing of the STING gene. Our findings highlight the critical role of the cGAS-STING pathway in the immunotoxic effects induced by PS-NPs. We outline a new mechanism whereby nanoplastics may trigger dysregulated innate immune and inflammatory responses via the cGAS/STING pathway.

Unlocking the hidden potential: Enhancing the utilization of stems and leaves through metabolite analysis and toxicity assessment of various parts of Aconitum carmichaelii.

ETHNOPHARMACOLOGICAL RELEVANCE: Aconitum carmichaelii is widely used in traditional Chinese medicine clinics as a bulk medicinal material. It has been used in China for more than two thousand years. Nevertheless, the stems and leaves of this plant are usually discarded as non-medicinal parts, even though they have a large biomass and exhibit therapeutic properties. Thus, it is crucial to investigate metabolites of different parts of Aconitum carmichaelii and explore the relationship between metabolites and toxicity to unleash the utilization potential of the stems and leaves. AIM OF THE STUDY: Using plant metabolomics, we aim to correlate different metabolites in various parts of Aconitum carmichaelii with toxicity, thereby screening for toxicity markers. This endeavor seeks to offer valuable insights for the development of Aconitum carmichaelii stem and leaf-based applications. MATERIALS AND METHODS: UHPLC-Q-Orbitrap MS/MS-based plant metabolomics was employed to analyze metabolites of the different parts of Aconitum carmichaelii. The cardiotoxicity and hepatotoxicity of the extracts from different parts of Aconitum carmichaelii were also investigated using zebrafish as animal model. Toxicity markers were subsequently identified by correlating toxicity with metabolites. RESULTS: A total of 113 alkaloids were identified from the extracts of various parts of Aconitum carmichaelii, with 64 different metabolites in stems and leaves compared to daughter root (Fuzi), and 21 different metabolites in stems and leaves compared to mother root (Wutou). The content of aporphine alkaloids in the stems and leaves of Aconitum carmichaelii is higher than that in the medicinal parts, while the content of the diester-diterpenoid alkaloids is lower. Additionally, the medicinal parts of Aconitum carmichaelii exhibited cardiotoxicity and hepatotoxicity, while the stems and leaves have no obvious toxicity. Finally, through correlation analysis and animal experimental verification, mesaconitine, deoxyaconitine, and hypaconitine were used as toxicity markers. CONCLUSION: Given the low toxicity of the stems and leaves and the potential efficacy of aporphine alkaloids, the stems and leaves of Aconitum carmichaelii hold promise as a valuable medicinal resource warranting further development.

Predictive metabolomic signatures for safety assessment of three plastic nanoparticles using intestinal organoids.

Nanoplastic particles are pervasive environmental contaminants with potential health risks, while mouse intestinal organoids provide accurate in vitro models for studying these interactions. Metabolomics, especially through LC-MS, enables detailed cellular response studies, and there's a novel interest in comparing metabolic changes across nanoparticle species using gut organoids. This study used a mouse intestinal organoid combined with cell model to explore the differences in metabolites and toxicity mechanisms induced by exposure to three nanoplastics (PS, PTFE, and PMMA). The results showed that PS, PTFE, and PMMA exposure reduced mitochondrial membrane potential, intracellular ROS accumulation and oxidative stress, and inhibited the AKT/mTOR signaling pathway. Non-targeted metabolomics results confirmed that three types of nanoplastic particles regulate cellular status by regulating fatty acid metabolism, nucleotide metabolism, necroptosis and autophagy pathways. More importantly, these representative metabolites were further validated in model groups after mouse intestinal organoids and HCT116 cells were exposed to the respective NPs, indicating that organoid metabolomics results can be used to effectively predict toxicity. Untargeted metabolomics is sensitive enough to detect subtle metabolomic changes when functional cellular analysis shows no significant differences. Overall, our study reveals the underlying metabolic mechanism of NPs-induced intestinal organoid toxicity and provides new insights into the possible adverse consequences of NPs.

Association of Perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposures and the risk of systemic lupus erythematosus: a case-control study in China.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) may have a role in impaired health. However, the data on the association between PFASs and Systemic lupus erythematosus (SLE) have been limited. We designed a population-based case-control study in China and evaluated the association. 100 normal persons (Control) and 100 SLE patients (Case) were obtained from 113 controls and 125 cases according to matching conditions. Serum samples were collected by venipuncture for UHPLC-MRM-MS Analysis to obtain the concentration of five PFASs in participants. Demographic characterization description was performed for the two groups of participants, the PFASs concentration distribution of the two groups was described and compared, then divided into three tiers (< 50th, 50th ~ 75th, > 75th) for subsequent analysis. Conditional logistic regression models were utilized to calculate the odds ratios (ORs) and 95% CIs for SLE. Relationship between changes in the concentration of PFASs and the risk of SLE assessed by restricted cubic spline. As the highest serum levels of the five PFASs tested in this study population, the highest perfluoroundecanoic acid (PFUnA) quartile had a 2.78-fold (95%CI: 1.270, 6.10) compared with the lowest quartile of PFUnA exposure, other types of PFASs also showed high association with SLE as well as PFASs mixture. Additionally, the exposure of PFASs exist a dose-response relationship (ptrend < 0.05). This risk association remained be found after adjusting the covariates in model 1 (adjustment of BMI) and in model 2(adjustment of BMI, smoking, drinking, hypertension and leukocyte). The restricted cubic spline illustrated a gradual increase in the possible risk of SLE with the increasing exposure of PFASs components levels. Our study firstly revealed that PFASs are risk factors for SLE and PFASs exposures are associated with SLE risk in a dose - response manner. Evidence from larger and more adequately powered cohort studies is needed to confirm our results.

Lactate exacerbates lung damage induced by nanomicroplastic through the gut microbiota-HIF1a/PTBP1 pathway.

Exposure to nanomicroplastics (nano-MPs) can induce lung damage. The gut microbiota is a critical modulator of the gut-lung axis. However, the mechanisms underlying these interactions have not been elucidated. This study explored the role of lactate, a key metabolite of the microbiota, in the development of lung damage induced by nano-MPs (LDMP). After 28 days of exposure to nano-MPs (50-100 nm), mice mainly exhibited damage to the lungs and intestinal mucosa and dysbiosis of the gut microbiota. Lactate accumulation was observed in the lungs, intestines and serum and was strongly associated with the imbalance in lactic acid bacteria in the gut. Furthermore, no lactate accumulation was observed in germ-free mice, while the depletion of the gut microbiota using a cocktail of antibiotics produced similar results, suggesting that lactate accumulation in the lungs may have been due to changes in the gut microbiota components. Mechanistically, elevated lactate triggers activation of the HIF1a/PTBP1 pathway, exacerbating nano-MP-induced lung damage through modulation of the epithelial-mesenchymal transition (EMT). Conversely, mice with conditional knockout of Ptbp1 in the lungs (Ptbp1flfl) and PTBP1-knockout (PTBP1-KO) human bronchial epithelial (HBE) cells showed reversal of the effects of lactate through modulation of the HIF1a/PTBP1 signaling pathway. These findings indicate that lactate is a potential target for preventing and treating LDMP.

Deficiency of S100A8/A9 attenuates pulmonary microvascular leakage in septic mice.

BACKGROUND: We have reported a positive correlation between S100 calcium-binding protein (S100) A8/S100A9 and sepsis-induced lung damage before. However, limited knowledge exists concerning the biological role of S100A8/A9 in pulmonary vascular endothelial barrier dysfunction, as well as the diagnostic value of S100A8/A9 in sepsis. METHODS: Sepsis was induced in C57BL/6J mice and S100A9-knockout (KO) mice through the cecal ligation and puncture (CLP). Pulmonary vascular leakage was determined by measuring extravasated Evans blue (EB). Reverse transcription polymerase chain reaction and the histological score were used to evaluate inflammation and lung injury, respectively. Recombinant S100A8/A9 (rhS100A8/A9) was used to identify the effects of S100A8/A9 on endothelial barrier dysfunction in human umbilical vein endothelial cells (HUVECs). Additionally, the diagnostic value of S100A8/A9 in sepsis was assessed using receiver operating characteristic. RESULTS: S100A8/A9 expression was up-regulated in the lungs of CLP-operated mice. S100A9 KO significantly reversed CLP-induced hypothermia and hypotension, resulting in an improved survival rate. S100A9 KO also decreased the inflammatory response, EB leakage, and histological scores in the lungs of CLP-operated mice. Occludin and VE-cadherin expressions were decreased in the lungs of CLP-operated mice; However, S100A9 KO attenuated this decrease. Moreover, CLP-induced signal transducer and activator of transcription 3 (STAT3) and p38/extracellular signal-regulated kinase (ERK) signalling activation and apoptosis were mitigated by S100A9 KO in lungs. In addition, rhS100A8/A9 administration significantly decreased occludin and VE-cadherin expressions, increased the phosphorylated (p)-ERK/ERK, p-p38/p38, and B-cell leukaemia/lymphoma 2 protein (Bcl-2)-associated X protein/Bcl-2 ratios in HUVECs. CONCLUSION: The present study demonstrated S100A8/A9 aggravated sepsis-induced pulmonary inflammation, vascular permeability, and lung injury. This was achieved, at least partially, by activating the P38/STAT3/ERK signalling pathways. Moreover, S100A8/A9 showed the potential as a biomarker for sepsis diagnosis.

Metabolomics reveals that PS-NPs promote lung injury by regulating prostaglandin B1 through the cGAS-STING pathway.

Nanoplastics have been widely studied as environmental pollutants, which can accumulate in the human body through the food chain or direct contact. Research has shown that nanoplastics can affect the immune system and mitochondrial function, but the underlying mechanisms are unclear. Lungs and macrophages have important immune and metabolic functions. This study explored the effects of 100 nm PS-NPs on innate immunity, mitochondrial function, and cellular metabolism-related pathways in lung (BEAS-2B) cells and macrophages (RAW264.7). The results had shown that PS-NPs exposure caused a decrease in mitochondrial membrane potential, intracellular ROS accumulation, and Ca2+ overload, and activated the cGAS-STING signaling pathway related to innate immunity. These changes had been observed at concentrations of PS-NPs as low as 60 µg/mL, which might have been comparable to environmental levels. Non-target metabolomics and Western Blotting results confirmed that PS-NPs regulated prostaglandin B1 and other metabolites to cause cell damage through the cGAS-STING pathway. Supplementation of prostaglandin B1 alleviated the immune activation and metabolic disturbance caused by PS-NPs exposure. This study identified PS-NPs-induced innate immune activation, mitochondrial dysfunction, and metabolic toxicity pathways, providing new insights into the potential for adverse outcomes of NPs in human life.

Deficiency of S100 calcium binding protein A9 attenuates vascular dysfunction in aged mice.

BACKGROUND: S100 calcium-binding protein A9 (S100A9) is a danger-associated molecular pattern molecule that mediates the inflammatory response. Inflammation is essential in aging-related cardiovascular diseases. However, less is known regarding the role of S100A9 in vascular aging. METHODS: S100A9 null mice were used to investigate the role of S100A9 in aging-related pathologies. Artery rings were used to measure the functional characteristics of vascular with a pressurized myograph. Telomere length, Sirtuin activity, oxidative stress, and endothelial nitric oxide synthetase (eNOS) activity were used to elevate vascular senescence. Intraperitoneal glucose tolerance (IPGTT) and insulin sensitivity test (IST) were employed to investigate the effects of S100A9 on insulin resistance. Inflammation response was reflected by the concentration of inflammatory cytokines. The Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) inhibitors were used to identify the downstream molecular mechanisms of S100A9 in aging-induced senescence in endothelial cells. RESULTS: S100A9 expression in vascular increased with aging in mice and humans. Deficiency of S100A9 alleviated vascular senescence in aged mice, as evidenced by increased telomere length, Sirtuin activity, and eNOS activity. Meanwhile, S100A9 knockout improved endothelium-dependent vasodilatation and endothelial continuity in aged mice. Moreover, the increased insulin resistance, oxidative stress, and inflammation were mitigated by S100A9 deletion in aged mice. In vitro, S100A9 induced senescence in endothelial cells, and that effect was blunted by TLR4 but not RAGE inhibitors. CONCLUSION: The present study suggested that S100A9 may contribute to aging-related pathologies and endothelial dysfunction via the TLR4 pathway. Therefore, targeting S100A9/TLR4 signaling pathway may represent a crucial therapeutic strategy to prevent age-related cardiovascular diseases.

Lactobacillus rhamnosus GG ameliorates radiation-induced lung fibrosis via lncRNASNHG17/PTBP1/NICD axis modulation.

Radiation-induced pulmonary fibrosis (RIPF) is a major side effect experienced for patients with thoracic cancers after radiotherapy. RIPF is poor prognosis and limited therapeutic options available in clinic. Lactobacillus rhamnosus GG (LGG) is advantaged and widely used for health promotion. However. Whether LGG is applicable for prevention of RIPF and relative underlying mechanism is poorly understood. Here, we reported a unique comprehensive analysis of the impact of LGG and its' derived lncRNA SNHG17 on radiation-induced epithelial-mesenchymal transition (EMT) in vitro and RIPF in vivo. As revealed by high-throughput sequencing, SNHG17 expression was decreased by LGG treatment in A549 cells post radiation and markedly attenuated the radiation-induced EMT progression (p < 0.01). SNHG17 overexpression correlated with poor overall survival in patients with lung cancer. Mechanistically, SNHG17 can stabilize PTBP1 expression through binding to its 3'UTR, whereas the activated PTBP1 can bind with the NICD part of Notch1 to upregulate Notch1 expression and aggravated EMT and lung fibrosis post radiation. However, SNHG17 knockdown inhibited PTBP1 and Notch1 expression and produced the opposite results. Notably, A549 cells treated with LGG also promoted cell apoptosis and increased cell G2/M arrest post radiation. Mice of RIPF treated with LGG decreased SNHG17 expression and attenuated lung fibrosis. Altogether, these data reveal that modulation of radiation-induced EMT and lung fibrosis by treatment with LGG associates with a decrease in SNHG17 expression and the inhibition of SNHG17/PTBP1/Nothch1 axis. Collectively, our results indicate that LGG exerts protective effects in RIPF and SNHG17 holds a potential marker of RIPF recovery in patients with thoracic cancers.

iNOS contributes to heart failure with preserved ejection fraction through mitochondrial dysfunction and Akt S-nitrosylation.

INTRODUCTION: Despite the high morbidity and mortality of heart failure with preserved fraction (HFpEF), there are currently no effective therapies for this condition. Moreover, the pathophysiological basis of HFpEF remains poorly understood. OBJECTIVE: The aim of the present study was to investigate the role of inducible nitric oxide synthase (iNOS) and its underlying mechanism in a high-fat diet and Nω-nitro-L-arginine methyl ester-induced HFpEF mouse model. METHODS: The selective iNOS inhibitor L-NIL was used to examine the effects of short-term iNOS inhibition, whereas the long-term effects of iNOS deficiency were evaluated using iNOS-null mice. Cardiac and mitochondrial function, oxidative stress and Akt S-nitrosylation were then measured. RESULTS: The results demonstrated that both pharmacological inhibition and iNOS knockout mitigated mitochondrial dysfunction, oxidative stress and Akt S-nitrosylation, leading to an ameliorated HFpEF phenotype in mice. In vitro, iNOS directly induced Akt S-nitrosylation at cysteine 224 residues , leading to oxidative stress, while inhibiting insulin-mediated glucose uptake in myocytes. CONCLUSION: Altogether, the present findings suggested an important role for iNOS in the pathophysiological development of HFpEF, indicating that iNOS inhibition may represent a potential therapeutic strategy for HFpEF.

Linking the Low-Density Lipoprotein-Cholesterol (LDL) Level to Arsenic Acid, Dimethylarsinic, and Monomethylarsonic: Results from a National Population-Based Study from the NHANES, 2003-2020.

Arsenic (As) contamination is a global public health problem. Elevated total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) are risk factors for cardiovascular diseases, but data on the association of urinary arsenic species' level and LDL-C are limited. We performed an association analysis based on urinary arsenic species and blood TC and LDL-C in US adults. Methods: Urinary arsenic, arsenic acid (AA), dimethylarsinic (DMA), monomethylarsonic (MMA), TC, LDL-C, and other key covariates were obtained from the available National Health and Nutrition Examination Survey (NHANES) data from 2003 to 2020. Multiple linear regression analysis and generalized linear model are used to analyze linear and nonlinear relationships, respectively. Results: In total, 6633 adults aged 20 years were enrolled into the analysis. The median total urinary arsenic level was 7.86 µg/L. A positive association of urinary arsenic concentration quartiles was observed with TC (ß: 2.42 95% CI 1.48, 3.36). The OR for TC of participants in the 80th versus 20th percentiles of urinary total arsenic was 1.34 (95% CI 1.13, 1.59). The OR for LDL-C of participants in the 80th versus 20th percentiles of urinary total arsenic was 1.36 (95% CI 1.15, 1.62). For speciated arsenics analysis, the OR for arsenic acid and TC was 1.35 (95% CI 1.02, 1.79), whereas the OR for DMA and LDL-L was 1.20 (95% CI 1.03, 1.41), and the OR for MMA and LDL-L was 1.30 (95% CI 1.11, 1.52). Conclusions: Urinary arsenic and arsenic species were positively associated with increased LDL-C concentration. Prevention of exposure to arsenic and arsenic species maybe helpful for the control of TC and LDL-C level in adults.

Esomeprazole inhibits endoplasmic reticulum stress and ameliorates myocardial ischemia-reperfusion injury.

Proton pump inhibitors (PPIs) are often prescribed in association with clopidogrel and aspirin to patients with myocardial infraction (MI), but their effects on heart is controversial. The purpose of this study was to investigate the effects and potential mechanism of omeprazole (OME) and esomeprazole (ESO) in myocardial ischemia reperfusion (I/R) injury. In the present study, mice were treated with OME, ESO or vehicle for 3 weeks and then subjected to myocardial I/R or sham surgery. At 1 day after surgery, echocardiography was performed to access cardiac injury. Hematoxylin and eosin (H&E) staining was performed to evaluate cardiomyocyte morphology. The IL1ß was evaluated by Immunohistochemistry (IHC). Elisa was used to detect cTnt content in serum. The expression of CD86, CD206, CHOP, ATF6, eIF2α and p eIF2α were determined by Western blot (WB). The result showed that ESO markedly improved the left ventricular ejection fraction (LVEF), shortening fraction (FS), suppressed inflammatory infiltration, endoplasmic reticulum stress (ERS) and decreased proinflammatory macrophages in I/R hearts, while OME had no significant effects on cardiac function, inflammation and ERS in the I/R heart. In conclusion, ESO but not OME pretreatment reduces the proportion of proinflammatory macrophages, inhibits endoplasmic reticulum stress, and alleviates I/R injury in mice, indicating that ESO maybe a more proper PPI than OME for application in I/R injury.

Helicobacter pylori and Alzheimer's Disease-Related Metabolic Dysfunction: Activation of TLR4/Myd88 Inflammation Pathway from p53 Perspective and a Case Study of Low-Dose Radiation Intervention.

Gut dysbiosis is observed in Alzheimer's disease (AD) and is frequently associated with AD-induced metabolic dysfunction. However, the extent and specific underlying molecular mechanisms triggered by alterations of gut microbiota composition and function mediating AD-induced metabolic dysfunction in AD remain incompletely uncovered. Here, we indicate that Helicobacter pylori (H. pylori) is abundant in AD patients with relative metabolic dysfunction. Fecal microbiota transplantation from the AD patients promoted metabolic dysfunction in mice and increased gut permeability. H. pylori increased gut permeability through activation of the TLR4/Myd88 inflammation pathway in a p53-dependent manner, leading to metabolic dysfunction. Moreover, p53 deficiency reduced bile acid concentration, leading to an increased abundance of H. pylori colonization. Overall, these data identify H. pylori as a key promoter of AD-induced metabolic dysfunction.

Potential role of PRKCSH in lung cancer: bioinformatics analysis and a case study of Nano ZnO.

PRKCSH, also known as glucosidase II beta, functions as a contributor to lung tumorigenesis by regulating the cell cycle in a p53-dependent manner under severe environmental stress. However, the prognostic value and molecular mechanisms by which the level of PRKCSH is significantly increased in cancer cells are not clearly understood. Here, we first generated a biological profile of PRKCSH expression changes in cancers by analysing bioinformatic data from cancer databases. We found that higher PRKCSH expression was correlated with a poorer prognosis and greater infiltration of most immune cell types in patients with lung cancer. In particular, PRKCSH expression showed significant negative correlations with the level of STAT6 (r = -0.31, p < 0.001) in lung cancer tissues. We further found that PRKCSH deficiency promoted G2/M arrest in response to zinc oxide nanoparticle (Nano ZnO) treatment in A549 cells. With regard to the mechanism, PRKCSH deficiency may induce STAT6 translocation to the nucleus to activate p53 expression through binding to the p53 promoter region from -365 bp to +126 bp. Eventually, activated p53 contributed to Nano-ZnO-induced G2/M arrest in lung cancer cells. Taken together, our data provide new insights into immunotherapy target choices and the prognostic value of PRKCSH. Since the G2/M cell cycle checkpoint is crucial for lung cancer prognosis, targeting PRKCSH expression to suppress the activation of the STAT6/p53 pathway is a potential therapeutic strategy for managing lung cancer.

Drug-Related Problems among Hospitalized Surgical Elderly Patients in China.

There is a lack of data on drug-related problems (DRPs) among elderly patients from surgical departments. The current study is aimed at identifying and categorizing types of DRPs and assessing the severities of the DRPs. Medication orders for hospitalized patients aged ≥65 years from six surgery departments were reviewed to determine DRPs over 6 months in a tertiary teaching hospital of Chongqing, China. DRPs were classified based on the Pharmaceutical Care Network Europe classification V8.02. The severity ratings of the DRPs were assessed using the National Coordinating Council for Medication Error Reporting and Prevention classification. A total of 53,231 medication orders from 1,707 elderly patients were reviewed, and 1,061 DRPs were identified. Treatment safety (44.9%) was the most common DRP type. Drug selection (43.1%) and dose selection (43.1%) were the major causes of DRPs. A total of 75.1% of the DRPs were classified into severity categories B to D (causing no or potential harm), and 24.9% were classified as categories E to H (causing actual harm). DRPs are common in hospitalized elderly surgical patients. Pharmacists should provide medication order reviews in this vulnerable patient population.

Osteomorphological features of the hind limb bones of Saiga antelope (Saiga tatarica).

The intralimb indices and calcaneal linear metrics are known as the reliable predictors of locomotor adaptation in artiodactyls. The osteological features of hindlimb in adult Saiga (Saiga tatarica) were described, and its correlation with cursoriality and habitat adaptation was discussed. Gross anatomy data showed Saiga owned the deep acetabulum as a broad lunate surface, the large acetabular anteversion, the well-developed ischiatic tuberosity and the prominent gluteal lines. It also presented the robust rough line and the strong gluteal tuberosity. A proximodistally elongated eminence located on the cranially distal tibia, which had not been found in goat. The tibial extensor groove was deep. The calcaneal tuberosity was robust. Digital anatomy data showed Saiga owned the higher metatarsal-femur ratio than forest musk deer and sheep. Comparing with wild bovids and sheep, Saiga presented a transitional variation in calcaneal form. The mean greatest length of the calcaneus (GLC) and the height of the sustentacular facet (HSF) in Saiga were shorter than that in sheep and longer than that in wild bovids respectively (F = 587.492; F = 10.264, p < .05). The wild bovids had longer cubonavicular facets than the other two groups (F = 18.587, p < .05). The great metatarsal-femur ratio of Saiga implied a superior cursorial ability and high conservation confronting the different habitats. The calcaneal linear metrics might shed light on lifestyle-related functional adaptation over decades of short-term evolution in the semi-free range environment.

Identify and categorize drug-related problems in hospitalized surgical patients in China.

Background Data is lacking on types and severities of drug-related problems (DRPs) in hospitalized surgical patients in China. Objective To identify and categorize types and causes of DRPs, and to assess severities of these DRPs. Setting An academic teaching hospital in Chongqing, China. Method We retrospectively reviewed all medication orders for patients in six surgical departments during a six-month period. DRPs were classified using the Pharmaceutical Care Network Europe (PCNE) classification, and the severity ratings of these DRPs were based on the National Coordinating Council for Medication Error Reporting and Prevention (NCCMERP) classification. Main outcome measure The number, types, causes and severities of the DRPs. Results A total of 291,944 medication orders in 10,643 patients were reviewed, and 3548 DRPs were identified. The average DRP number per patient was 0.3. The most common problem was treatment effectiveness (39.9%) and the major cause of the problems was dose selection (47.0%). Total 80.1% of the DRPs were rated at severity categories B to D (causing no or potential harm), whereas 19.9% were rated as categories E to H (causing actual harm). Conclusion DRPs are common in surgical patients, and prospective pharmacist medication order review services are needed to improve patients' pharmaceutical care.