Role of gut microbiota in doxorubicin-induced cardiotoxicity: from pathogenesis to related interventions.

Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.

Mechanical behaviors of a new elliptical valve stent in bicuspid aortic valve.

BACKGROUND AND OBJECTIVE: The conventional valve stents that are cylindrical in shape will become elliptical when implanted in bicuspid aortic valve, thereby reducing the durability of the artificial valve. In this study, a new design of valve stent is presented where valve stents have elliptical cross-section at the annulus and it is expected to have better expandability and circle shape during the interaction between the stent and bicuspid aortic valve, thereby extending the durability of artificial valve. METHODS: Finite element method (FEM) is used to study the mechanical behavior of the novel valve stent in the bicuspid aortic valve. The effects of three matching relationship between the ellipticity of the stents and the ellipticity of the annulus (i.e., the ellipticity of the stent is greater than, equal to and less than the annulus ellipticity, respectively) on the mechanical behavior of stent expansion are studied. In addition, the expansion mechanical behavior of the novel valve stent at different implantation depths is also compared. RESULTS: Results indicate that novel valve stent implantation with elliptical features is superior to conventional circular valve stent. When the novel valve stent ellipticity is less than the annulus ellipticity, the ellipticity of the novel valve stent after implantation is smaller than that of the conventional circular valve stent. This indicated that the novel valve stent has better expandability and post-expansion shape, making artificial valve to have better durability. The risk of paravalvular leak after implantation is lowest when the novel valve stent ellipticity is less than annulus ellipticity. When the novel valve stent ellipticity coincides with annulus ellipticity, the aortic wall is subjected to greatest stress. With the increase of implantation depth, the stress on the novel valve stent decrease. CONCLUSIONS: This study might provide insights for improving stent design for bicuspid aortic valve.

Contribution of Immune Responses to the Cardiotoxicity and Hepatotoxicity of Deltamethrin in Early Life Stage Zebrafish (Danio rerio).

Deltamethrin (DM) is a widely used insecticide that has demonstrated developmental toxicity in the early life stages of fish. To better characterize the underlying mechanisms, embryos from Tg(cmlc2:RFP), Tg(apo14:GFP), and Tg(mpx:GFP) transgenic strains of zebrafish were exposed to nominal DM concentrations of 0.1, 1, 10, 25, and 50 µg/L until 120 h post-fertilization (hpf). Heart size increased 56.7%, and liver size was reduced by 17.1% in zebrafish exposed to 22.7 and 24.2 µg/L DM, respectively. RNA sequencing and bioinformatic analyses predicted that key biological processes affected by DM exposure were related to inflammatory responses. Expression of IL-1 protein was increased by 69.0% in the 24.4 µg/L DM treatment, and aggregation of neutrophils in cardiac and hepatic histologic sections was also observed. Coexposure to resatorvid, an anti-inflammatory agent, mitigated inflammatory responses and cardiac toxicity induced by DM and also restored liver biomass. Our data indicated a complex proinflammatory mechanism underlying DM-induced cardiotoxicity and hepatotoxicity which may be important for key events of adverse outcomes and associated risks of DM to early life stages of fish.

Molecular Insights into Water-Chloride and Water-Water Interactions in the Supramolecular Architecture of Aconine Hydrochloride Dihydrate.

Despite the previous preparation of aconine hydrochloride monohydrate (AHM), accurate determination of the crystal's composition was hindered by severely disordered water molecules within the crystal. In this study, we successfully prepared a new dihydrate form of the aconine hydrochloride [C25H42NO9+Cl-·2(H2O), aconine hydrochloride dihydrate (AHD)] and accurately refined all water molecules within the AHD crystal. Our objective is to elucidate both water-chloride and water-water interactions in the AHD crystal. The crystal structure of AHD was determined at 136 K using X-ray diffraction and a multipolar atom model was constructed by transferring charge-density parameters to explore the topological features of key short contacts. By comparing the crystal structures of dihydrate and monohydrate forms, we have observed that both AHD and AHM exhibit identical aconine cations, except for variations in the number of water molecules present. In the AHD crystal, chloride anions and water molecules serve as pivotal connecting hubs to establish three-dimensional hydrogen bonding networks and one-dimensional hydrogen bonding chain; both water-chloride and water-water interactions assemble supramolecular architectures. The crystal packing of AHD exhibits a complete reversal in the stacking order compared to AHM, thereby emphasizing distinct disparities between them. Hirshfeld surface analysis reveals that H···Cl- and H···O contacts play a significant role in constructing the hydrogen bonding network and chain within these supramolecular architectures. Furthermore, topological analysis and electrostatic interaction energy confirm that both water-chloride and water-water interactions stabilize supramolecular architectures through electrostatic attraction facilitated by H···Cl- and H···O contacts. Importantly, these findings are strongly supported by the existing literature evidence. Consequently, navigating these water-chloride and water-water interactions is imperative for ensuring storage and safe processing of this pharmaceutical compound.

The effect of selenium on the proliferation of bovine endometrial epithelial cells in a lipopolysaccharide-induced damage model.

BACKGROUND: Endometritis is a common bovine postpartum disease. Rapid endometrial repair is beneficial for forming natural defense barriers and lets cows enter the next breeding cycle as soon as possible. Selenium (Se) is an essential trace element closely related to growth and development in animals. This study aims to observe the effect of Se on the proliferation of bovine endometrial epithelial cells (BEECs) induced by lipopolysaccharide (LPS) and to elucidate the possible underlying mechanism. RESULTS: In this study, we developed a BEECs damage model using LPS. Flow cytometry, cell scratch test and EdU proliferation assay were used to evaluate the cell cycle, migration and proliferation. The mRNA transcriptions of growth factors were detected by quantitative reverse transcription-polymerase chain reaction. The activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/ß-catenin pathways were detected by Western blotting and immunofluorescence. The results showed that the cell viability and BCL-2/BAX protein ratio were significantly decreased, and the cell apoptosis rate was significantly increased in the LPS group. Compared with the LPS group, Se promoted cell cycle progression, increased cell migration and proliferation, and significantly increased the gene expressions of TGFB1, TGFB3 and VEGFA. Se decreased the BCL-2/BAX protein ratio, promoted ß-catenin translocation from the cytoplasm to the nucleus and activated the Wnt/ß-catenin and PI3K/AKT signaling pathways inhibited by LPS. CONCLUSIONS: In conclusion, Se can attenuate LPS-induced damage to BEECs and promote cell proliferation and migration in vitro by enhancing growth factors gene expression and activating the PI3K/AKT and Wnt/ß-catenin signaling pathways.

Rhein alleviates myocardial ischemic injury by inhibiting mitochondrial division, activating mitochondrial autophagy and suppressing myocardial cell apoptosis through the Drp1/Pink1/Parkin pathway.

BACKGROUND: Rhein, which has antioxidant and anti-inflammatory response properties, is a beneficial treatment for different pathologies. However, the mechanism by which rhein protects against myocardial ischemic injury is poorly understood. METHODS AND RESULTS: To establish an acute myocardial infarction (AMI) rat model, we performed left anterior descending (LAD) ligation. Sprague‒Dawley rats were randomly divided into four groups: sham, AMI, AMI + rhein (AMI + R), and AMI + mitochondrial fission inhibitor (AMI + M). The extent of myocardial injury was evaluated by TTC staining, serum myocardial injury markers, and HE and Masson staining. Cardiac mitochondria ultrastructure was visualized by transmission electron microscopy. TUNEL assay and flow cytometry analysis were used to estimate cell apoptosis. Protein expression levels were measured by Western blotting. In vitro, the efficacy of rhein was assessed in H9c2 cells under hypoxic condition. Our results revealed that rats with AMI exhibited increased infarct size and indicators of myocardial damage, along with activation of Drp1-dependent mitochondrial fission, decreased mitophagy and increased apoptosis rates. However, pretreatment with rhein significantly reversed these effects and demonstrated similar efficacy to Mdivi-1. Furthermore, rhein pretreatment protected against myocardial ischemic injury by inhibiting mitochondrial fission, as evidenced by decreased Drp1 expression. It also enhanced mitophagy, as indicated by increased expression of Beclin1, Pink1 and Parkin, an increased LC3-II/LC3-I ratio and increased formation of autolysosomes. Additionally, rhein pretreatment mitigated apoptosis in AMI. These results were also confirmed in vitro in H9c2 cells. CONCLUSION: Our results demonstrate that rhein pretreatment exerts cardioprotective effects against myocardial ischemic injury via the Drp1/Pink1/Parkin pathway.

Metabolomics unveils the exacerbating role of arachidonic acid metabolism in atherosclerosis.

Atherosclerosis is a complex vascular disorder characterized by the deposition of lipids, inflammatory cascades, and plaque formation in arterial walls. A thorough understanding of its causes and progression is necessary to develop effective diagnostic and therapeutic strategies. Recent breakthroughs in metabolomics have provided valuable insights into the molecular mechanisms and genetic factors involved in atherosclerosis, leading to innovative approaches for preventing and treating the disease. In our study, we analyzed clinical serum samples from both atherosclerosis patients and animal models using laser desorption ionization mass spectrometry. By employing methods such as orthogonal partial least-squares discrimination analysis (OPLS-DA), heatmaps, and volcano plots, we can accurately classify atherosclerosis (AUC = 0.892) and identify key molecules associated with the disease. Specifically, we observed elevated levels of arachidonic acid and its metabolite, leukotriene B4, in atherosclerosis. By inhibiting arachidonic acid and monitoring its downstream metabolites, we discovered the crucial role of this metabolic pathway in regulating atherosclerosis. Metabolomic research provides detailed insights into the metabolic networks involved in atherosclerosis development and reveals the close connection between abnormal metabolism and the disease. These studies offer new possibilities for precise diagnosis, treatment, and monitoring of disease progression, as well as evaluating the effectiveness of therapeutic interventions.

Herbal Products-Powered Thermosensitive Hydrogel with Phototherapy and Microenvironment Reconstruction for Accelerating Multidrug-Resistant Bacteria-Infected Wound Healing.

Wound healing and infection remain significant challenges due to the ineffectiveness against multidrug-resistant (MDR) bacteria and the complex oxidative wound microenvironments. To address these issues, thymoquinone-reinforced injectable and thermosensitive TQ@PEG-PAF-Cur hydrogels with dual functions of microenvironment reshaping and photodynamic therapy are developed. The hydrogel comprises natural compound thymoquinone (TQ) and poly (ethylene glycol)-block-poly (alanine-co-phenyl alanine) copolymers (PEG-PAF) conjugated with natural photosensitizer curcumin (Cur). The incorporation of TQ and Cur reduces the sol-to-gel transition temperature of TQ@PEG-PAF-Cur to 30°C, compared to PEG-PAF hydrogel (37°C), due to the formation of strong hydrogen bonding, matching the wound microenvironment temperature. Under blue light excitation, TQ@PEG-PAF-Cur generates significant amounts of reactive oxygen species such as H2 O2 , 1O2 , and ·OH, exhibiting rapid and efficient bactericidal capacities against methicillin-resistant Staphylococcus aureus and broad spectrum ß-lactamases Escherichia coli via photodynamic therapy (PDT). Additionally, Cur effectively inhibits the expressions of proinflammatory cytokines in skin tissue-forming cells. As a result, the composite hydrogel can rapidly transform into a gel to cover the wound, reshape the wound microenvironment, and accelerate wound healing in vivo. This collaborative antibacterial strategy provides valuable insights to guide the development of multifunctional materials for efficient wound healing.

The effect and mechanism of selenium supplementation on the proliferation capacity of bovine endometrial epithelial cells exposed to lipopolysaccharide in vitro under high cortisol background.

Bovine endometritis severely inhibits uterine repair and causes considerable economic loss. Besides, parturition-induced high cortisol levels inhibit immune function, reduce cell proliferation, and further inhibit tissue repair. Selenium (Se) is an essential trace element for animals to maintain normal physiological function and has powerful antioxidant functions. This study investigated whether Se supplementation reduces endometrial damage and promotes tissue repair in cows with endometritis under stress and explored the underlying mechanism. Primary bovine endometrial epithelial cells were isolated and purified from healthy cows. The cells were treated with different combinations of lipopolysaccharide (LPS), cortisol, and various concentrations of Se. Data showed that LPS stimulation inhibited cell proliferation and increased cell apoptosis. High levels of cortisol further exacerbated these effects. Flow cytometry, scratch wound healing tests, and 5-ethynyl-2'-deoxyuridine (EdU) proliferation assays showed that Se supplementation promoted cell cycle progression, cell migration, and cell proliferation in the presence of LPS and cortisol. The quantitative PCR results showed that the expression of related growth factors was increased after Se supplementation. After administering various inhibitors, we further demonstrated that Se supplementation decreased the activity of glycogen synthetase kinase 3ß (GSK-3ß) through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway to reduce the degradation of ß-catenin except the Wnt signal to promote cell proliferation. In conclusion, Se supplementation attenuated the cell damage induced by LPS at high cortisol levels and increased cell proliferation to promote uterine repair by elevating the mRNA expression of TGFB3 and VEGFA and activating the PI3K/AKT/GSK-3ß/ß-catenin signaling pathway.

After parturition, endometritis is a common bovine disease, which hinders endometrial repair and reduces bovine economic value. Besides, parturition-induced high cortisol levels cause immunosuppression, aggravate infection, and further inhibit cell proliferation and tissue repair. As an essential trace element, adding selenium to feed helps to maintain the normal physiological function of animals. This study developed a cellular model using lipopolysaccharide (LPS) and cortisol to simulate cows with endometritis in stress conditions. The results showed that Se supplementation attenuated bovine endometrial epithelial cell damage and promoted their proliferation in the presence of LPS and high cortisol levels, which are positively correlated with the concentration of Se. Besides, this study proved another molecular mechanism for Se to regulate ß-catenin except for the Wnt signal by affecting the ß-catenin degradation pathway.

Injectable Nano-Micro Composites with Anti-bacterial and Osteogenic Capabilities for Minimally Invasive Treatment of Osteomyelitis.

The effective management of osteomyelitis remains extremely challenging due to the difficulty associated with treating bone defects, the high probability of recurrence, the requirement of secondary surgery or multiple surgeries, and the difficulty in eradicating infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Hence, smart biodegradable biomaterials that provide effective and precise local anti-infection effects and can promote the repair of bone defects are actively being developed. Here, a novel nano-micro composite is fabricated by combining calcium phosphate (CaP) nanosheets with drug-loaded GelMA microspheres via microfluidic technology. The microspheres are covalently linked with vancomycin (Van) through an oligonucleotide (oligo) linker using an EDC/NHS carboxyl activator. Accordingly, a smart nano-micro composite called "CaP@MS-Oligo-Van" is synthesized. The porous CaP@MS-Oligo-Van composites can target and capture bacteria. They can also release Van in response to the presence of bacterial micrococcal nuclease and Ca2+, exerting additional antibacterial effects and inhibiting the inflammatory response. Finally, the released CaP nanosheets can promote bone tissue repair. Overall, the findings show that a rapid, targeted drug release system based on CaP@MS-Oligo-Van can effectively target bone tissue infections. Hence, this agent holds potential in the clinical treatment of osteomyelitis caused by MRSA.

Bio-Responsive Sliver Peroxide-Nanocarrier Serves as Broad-Spectrum Metallo-ß-lactamase Inhibitor for Combating Severe Pneumonia.

Metallo-ß-lactamases (MBLs) represent a prevalent resistance mechanism in Gram-negative bacteria, rendering last-line carbapenem-related antibiotics ineffective. Here, a bioresponsive sliver peroxide (Ag2 O2 )-based nanovesicle, named Ag2 O2 @BP-MT@MM, is developed as a broad-spectrum MBL inhibitor for combating MBL-producing bacterial pneumonia. Ag2 O2 nanoparticle is first orderly modified with bovine serum albumin and polydopamine to co-load meropenem (MER) and [5-(p-fluorophenyl)-2-ureido]-thiophene-3-carboxamide (TPCA-1) and then encapsulated with macrophage membrane (MM) aimed to target inflammatory lung tissue specifically. The resultant Ag2 O2 @BP-MT@MM effectively abrogates MBL activity by displacing the Zn2+ cofactor in MBLs with Ag+ and displays potent bactericidal and anti-inflammatory properties, specific targeting abilities, and great bioresponsive characteristics. After intravenous injection, the nanoparticles accumulate prominently at infection sites through MM-mediated targeting . Ag+ released from Ag2 O2 decomposition at the infection sites effectively inhibits MBL activity and overcomes the resistance of MBL-producing bacteria to MER, resulting in synergistic elimination of bacteria in conjunction with MER. In two murine infection models of NDM-1+ Klebsiella pneumoniae-induced severe pneumonia and NDM-1+ Escherichia coli-induced sepsis-related bacterial pneumonia, the nanoparticles significantly reduce bacterial loading, pro-inflammatory cytokine levels locally and systemically, and the recruitment and activation of neutrophils and macrophages. This innovative approach presents a promising new strategy for combating infections caused by MBL-producing carbapenem-resistant bacteria.

A practical nomogram included hyperlipidemia for predicting lymph node metastasis in patients with superficial esophageal squamous cell carcinoma.

To select an optimal treatment, it is crucial to evaluate the risk of lymph node metastasis (LNM) in patients with superficial esophageal squamous cell carcinoma (SESCC). The research aimed to explore more risk factors than before and construct a practical nomogram to predict LNM in patients with SESCC. We retrospectively reviewed 1080 patients diagnosed with esophageal cancer who underwent esophagectomy with lymphadenectomy between January 2013 and October 2021 at the Affiliated Hospital of Qingdao University. The clinical parameters, endoscopic features, and pathological characteristics of the 123 patients that were finally enrolled in this study were collected. The independent risk factors for LNM were determined using univariate and multivariate analyses. Using these factors, a nomogram was constructed to predict LNM. LNM was observed in 21 patients. Univariate analysis showed that the absence or presence of hypertriglyceridemia, tumor location, lesion size, macroscopic type, invasion depth, differentiation, absence or presence of lymphovascular invasion (LVI), and perineural invasion were significantly associated with LNM. According to the multivariate analysis, hypertriglyceridemia, tumors located in the lower thoracic esophagus, lesion size > 20 mm, submucosal invasion, and LVI were independent risk factors for LNM. A nomogram was established using these 5 factors. It showed good calibration and discrimination. Hypertriglyceridemia, tumors located in the lower thoracic esophagus, lesion size > 20 mm, submucosal invasion, and LVI were independent risk factors for LNM. A nomogram was constructed using these 5 factors. This model can help clinicians assess the risk of LNM in patients with SESCC for optimal treatment selection.

Correlation between cognitive impairment and serum markers in patients with obstructive sleep apnea-hypopnea syndrome.

BACKGROUND: Previous studies have revealed that sleep structure and hypoxemia are two important environmental factors for cognitive impairment in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). We hypothesized that the pathophysiological mechanisms between these two factors may also be involved in cognitive impairment in patients with OSAHS. Previous studies have suggested that alterations in serum glucose and lipid metabolism, inflammatory responses, and astrocyte markers not only contribute to sleep structural disorders in OSAHS but also affect the occurrence and development of this disease. Therefore, we hypothesized that alterations in the abovementioned indicators may be involved in cognitive impairment in OSAHS. Additionally, obesity is an important risk factor for OSAHS. This study therefore aimed to explore the correlation between serum indicators and cognitive impairment in patients with OSAHS. METHODS: Patients with OSAHS who underwent polysomnography in our hospital were recruited in this study. The overall cognitive function of patients were evaluated using the Mini mental State Examination (MMSE). Blood biochemical indicators such as glucose (GLU), triglycerides (TG), and triglyceride glucose (TyG) index were measured. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of serum glucagon-like peptide-1 receptor (GLP-1R), fibroblast growth factor 21 (FGF21), S100 calcium binding protein B (S100B), brain derived neurotrophic factor (BDNF), inflammatory factors such as C-reactive protein (CRP), tumor necrosis factor-α (TNFα), interleukin-4 (IL-4), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Spearman correlation analysis was used to determine if the indicator was related to cognitive function, and backward linear regression analysis was used to identify the main risk factors for cognitive impairment in non-obese and obese patients with OSAHS. RESULTS: Among 34 patients, 19 were non-obese and 15 were obese. Obese patients exhibited higher AHI compared to non-obese individuals, and the difference was statistically significant (p < 0.05). In non-obese patients, Spearman correlation analysis revealed a negative correlation between serum GLU, IL-4, and MMSE scores (p < 0.05); IL-6 was positively correlated with MMSE (p < 0.05). In addition, GLU and IL-6 were independently correlated with MMSE in non-obese patients (p < 0.05). In obese patients, serum TG and TyG were positively correlated with MMSE scores (p < 0.05); age, BMI, and IL-4 were negatively correlated with MMSE scores (p < 0.05). In addition, age and IL-4 were independently correlated with MMSE in obese patients (p < 0.05). CONCLUSIONS: Our data suggested that GLU and IL-6 were independently correlated with cognitive impairment in non-obese patients with OSAHS; age and IL-4 were independently correlated with cognitive impairment in obese patients. Early detection of this difference in heterogeneity may provide theoretical support for future investigations in prevention and treatment of cognitive impairment in patients with OSAHS.

The Effect of Selenium on Endometrial Repair in Goats with Endometritis at High Cortisol Levels.

Endometritis is a common postpartum disease of female animals that causes significant losses to the goat industry. High levels of cortisol induced by various stresses after delivery severely inhibit innate immunity and tissue repair. The repair ability of the endometrium is closely related to the reproductive performance of goats. Selenium (Se) is an essential trace element in animals that has powerful antioxidant and immunity-enhancing functions. In this study, we established a goat model of endometritis at high cortisol (Hydrocortisone) levels to investigate the effect of Se (supplement additive) on endometrial repair. The results showed that the clinical symptoms, %PMN in uterine secretions, morphological endometrial damage, and the gene expression of BAX were reduced in the goats with Se supplementation compared with those in the model group. Se increased the gene expression of BCL2, VEGFA, TGFB1, and PCNA and activated the PI3K/AKT and Wnt/ß-catenin signaling pathways in goats with Se supplementation. In conclusion, Se reduced the inflammatory response, increased the proliferation, and decreased the apoptosis of endometrial cells to promote endometrial tissue repair in goats with endometritis at high cortisol levels. It probably achieved this effect of promoting repair by activating the Wnt/ß-catenin and PI3K/AKT pathways and affecting the gene expression of VEGFA, TGFB1, PCNA, BCL2, and BAX.

Developing and validating a nomogram for cognitive impairment in the older people based on the NHANES.

Objective: To use the United States National Health and Nutrition Examination Study (NHANES) to develop and validate a risk-prediction nomogram for cognitive impairment in people aged over 60 years. Methods: A total of 2,802 participants (aged ≥ 60 years) from NHANES were analyzed. The least absolute shrinkage and selection operator (LASSO) regression model and multivariable logistic regression analysis were used for variable selection and model development. ROC-AUC, calibration curve, and decision curve analysis (DCA) were used to evaluate the nomogram's performance. Results: The nomogram included five predictors, namely sex, moderate activity, taste problem, age, and education. It demonstrated satisfying discrimination with a AUC of 0.744 (95% confidence interval, 0.696-0.791). The nomogram was well-calibrated according to the calibration curve. The DCA demonstrated that the nomogram was clinically useful. Conclusion: The risk-prediction nomogram for cognitive impairment in people aged over 60 years was effective. All predictors included in this nomogram can be easily accessed from its' user.

Tumor-associated macrophages confer colorectal cancer 5-fluorouracil resistance by promoting MRP1 membrane translocation via an intercellular CXCL17/CXCL22-CCR4-ATF6-GRP78 axis.

Chemotherapy represents a major type of clinical treatment against colorectal cancer (CRC). Aberrant drug efflux mediated by transporters acts as a key approach for tumor cells to acquire chemotherapy resistance. Increasing evidence implies that tumor-associated macrophages (TAMs) play a pivotal role in both tumorigenesis and drug resistance. Nevertheless, the specific mechanism through which TAMs regulate drug efflux remains elusive. Here, we discovered that TAMs endow CRC cells with resistance to 5-fluorouracil (5-FU) treatment via a cell-cell interaction-mediated MRP1-dependent drug efflux process. Mechanistically, TAM-secreted C-C motif chemokine ligand 17 (CCL17) and CCL22, via membrane receptor CCR4, activated the PI3K/AKT pathway in CRC tumor cells. Specifically, phosphorylation of AKT inactivated IP3R and induced calcium aggregation in the ER, resulting in the activation of ATF6 and upregulation of GRP78. Accordingly, excessive GRP78 can interact with MRP1 and promote its translocation to the cell membrane, causing TAM-induced 5-FU efflux. Taken together, our results demonstrated that TAMs promote CRC chemotherapy resistance via elevating the expression of GRP78 to promote the membrane translocation of MRP1 and drug efflux, providing direct proof for TAM-induced drug resistance.

Structural optimization method of rice precision direct seed-metering device based on multi-index orthogonal experimental.

Introduction: To improve the mechanization level of rice planting, a new type of direct seeding device for rice was designed. The device's structural properties will be crucial in determining its seeding performance. Structure optimization in the current seed metering device design process focuses on a single or few indexes, resulting in improved individual performance but imbalanced overall performance. Therefore, a structure optimization method of the direct seeding device based on a multi-index orthogonal experiment was proposed in this study. Methods: First, the DEM-MBD coupling method observed the factors and levels that affected the performance overall. Second, a test platform based on the electric drive control model was constructed, and a multi-index orthogonal test was devised. Finally, the structural parameters of the seed metering devices were optimized based on matrix analysis. Results: From the results, the primary and secondary levels of significance of factors were just as follows: hole diameter > hole number > adjustment angle. The following are the optimal parameters found by optimization analysis: the diameter of the hole was 12 mm, the number of holes was 10, and the adjustment angle was 80°. Validation tests were carried out and analyzed based on the optimal structural parameter combination. The qualification rate of seeds per hole, empty hole rate, average seed number, coefficient of variation of seed number, average hole spacing, and the variance coefficient of hole spacing are 93.07%, 0%, 9.39,14.04%, 22.84 cm, and 9.14%, respectively. Discussion: In comparison to traditional design and structural parameter optimization methods for rice precision seed metering device, this study not just to provides an optimization scheme for improving the overall performance of rice precision seed metering device, but also serves as a technical reference for the development and design of new rice precision seed metering device.

Preparation and evaluation of recombinant pyolysin, fimbriae E and HtaA based protein vaccines against Trueperella pyogenes.

Trueperella pyogenes (T. pyogenes) could cause zoonotic disease in various mammals, resulting in significant economic losses. Due to the lack of effective vaccine and the emergence of bacterial resistance, there is a big need for new and improved vaccines. In this study, the non-hemolytic pyolysin mutant (PLOW497F), fimbriae E (FimE) and a truncated cell wall protein (HtaA-2) were selected to generate single or multivalent protein vaccines and their efficacies against lethal T. pyogenes challenge were evaluated in a mouse model. The results showed that the levels of specific antibody were significantly higher than the PBS control group after the booster vaccination. Compared to PBS treated mice, vaccinated mice had upregulated expressions of the inflammatory cytokine genes after the first vaccination. There was a downward trend thereafter, but return to the similar or even higher levels after challenge. Furthermore, co-immunization with rFimE or rHtaA-2 could significantly enhance the anti-hemolysis antibodies induced by rPLOW497F. The supplement of rHtaA-2 induced higher agglutinating antibodies compared with single administration with rPLOW497F or rFimE. Apart from these, the pathological lesions of lung were alleviated in rHtaA-2, rPLOW497F or their combinations immunized mice. Notably, immunization with rPLOW497F, rHtaA-2, combinations of rPLOW497F and rHtaA-2 or rHtaA-2 and rFimE completely protected mice from challenge, whereas the PBS immunized mice could not survive past 1 day post challenge. Thus, PLOW497F and HtaA-2 might be useful in developing efficient vaccines to prevent T. pyogenes infection.

The bound polyphenols of foxtail millet (Setaria italica) inner shell inhibit breast cancer by promoting lipid accumulation-induced autophagic death.

Foxtail millet is a traditional excellent crop with high nutritional value in the world, belong to cereals. The bran of foxtail millet is rich in polyphenol that has antioxidant, anti-inflammatory, and anti-tumorigenic effects. Previously, we extracted bound polyphenols from the inner shell of foxtail millet bran (BPIS). Here, we report that BPIS specifically induced breast cancer cell death and elevated the autophagy level simultaneously. The addition of an autophagy inhibitor blocked BPIS-induced breast cancer cell death, indicating that excessive autophagy induced cell death. Furthermore, oil red O and BODIPY staining also confirmed that lipids, which are important inducers of autophagy, accumulated in breast cancer cells treated with BPIS. Lipidomics research revealed that glycerophospholipids were the main accumulated lipids induced by BPIS. Further study showed that elevated PCYT1A expression was responsible for glycerophospholipid accumulation, and BPIS contained ferulic acid and p-coumaric acid, which induced PCYT1A expression and breast cancer cell death. Collectively, our results revealed that BPIS resulted in autophagic death by enhancing lipid accumulation in breast cancer cells, and BPIS contains ferulic acid and p-coumaric acid, which provided new insights into developing nutraceuticals and drugs for breast cancer patients.

Protective effect of sodium butyrate on intestinal barrier damage and uric acid reduction in hyperuricemia mice.

PURPOSE: The goal of this study was to examine the role of sodium butyrate in preserving the intestinal mucosal barrier and reducing hyperuricemia (HUA). METHODS: First, we established a mouse model of HUA via intraperitoneal injection of potassium oxonate together with a yeast-rich diet to detect the levels of serum uric acid (UA) and fecal short-chain fatty acids (SCFAs). Then, in vitro, different concentrations of UA and sodium butyrate (NaB) were used to treat LS174T and Caco2 cells. The effects of UA and NaB on the gut barrier were determined based on the expression levels of MUC2, ZO-1, and Occludin.Finally, C57BL/6 mice were used to model HUA, and these mice were administered 200 mg·kg-1·d-1 NaB by gavage to counter the HUA. The effect of NaB on HUA in the intestinal tract was elucidated by determining serum UA levels, inflammatory parameters, epithelial barrier integrity, and via histological analysis. RESULTS: The data showed that the content of fecal SCFAs in HUA mice decreased. Additionally, in LS174T and Caco2 cells, NaB reversed the decrease of ZO-1, Occludin, and MUC2 protein expression caused by high UA levels. Furthermore, NaB decreased serum UA of HUA mice, and reversed both the decreased expression of MUC2, ZO-1, Occludin, and ABCG2 proteins and the increased level of inflammatory factors in the intestinal tissues of these mice. CONCLUSION: The HUA mouse model showed intestinal barrier damage. NaB protected the intestinal barrier of HUA mice and reduced the serum UA level.