Mulberry biomass-derived nanomedicines mitigate colitis through improved inflamed mucosa accumulation and intestinal microenvironment modulation

The therapeutic outcomes of conventional oral medications against ulcerative colitis (UC) are restricted by inefficient drug delivery to the colitis mucosa and weak capacity to modulate the inflammatory microenvironment. Herein, a fluorinated pluronic (FP127) was synthesized and employed to functionalize the surface of mulberry leaf-derived nanoparticles (MLNs) loading with resveratrol nanocrystals (RNs). The obtained FP127@RN-MLNs possessed exosome-like morphologies, desirable particle sizes (around 171.4 nm), and negatively charged surfaces (â 14.8 mV). The introduction of FP127 to RN-MLNs greatly improved their stability in the colon and promoted their mucus infiltration and mucosal penetration capacities due to the unique fluorine effect. These MLNs could efficiently be internalized by colon epithelial cells and macrophages, reconstruct disrupted epithelial barriers, alleviate oxidative stress, provoke macrophage polarization to M2 phenotype, and down-regulate inflammatory responses. Importantly, in vivo studies based on chronic and acute UC mouse models demonstrated that oral administration of chitosan/alginate hydrogel-embedding FP127@RN-MLNs achieved substantially improved therapeutic efficacies compared with nonfluorinated MLNs and a first-line UC drug (dexamethasone), as evidenced by decreased colonic and systemic inflammation, integrated colonic tight junctions, and intestinal microbiota balance. This study brings new insights into the facile construction of a natural, versatile nanoplatform for oral treatment of UC without adverse effects.We are grateful to Dr. J. Sun from University of Oxford for his corrections and improvement of this manuscript. Funding: This study was supported by the National Natural Science Foundation of China (82072060 and 22008201), the Fundamental Research Funds for the Central Universities (SWU-XDPY22006), the Venture & Innovation Support Program for Chongqing Overseas Returnees (2205012980212766), the Natural Science Foundation Project of Chongqing (cstc2020jcyj-msxmX0292), and the Natural Science Foundation Project of Chongqing for Distinguished Young Scholar. Author contributions: W.Y., M.W., X.S., and B.X. designed experiments, supervised the project, and wrote the manuscript draft. W.Y., Y.M., H.X., Z.Z., J.W., C.X., W.S., and E.Z. performed the experiments. R.L.R., S.C.K., M.W., X.S., and B.X. edited and revised the manuscript. All authors have approved the final version of the manuscript. Competing interests: The authors declare that there is no con flict of interest regarding the publication of this article

Dynamic changes of soil microorganisms in rotation farmland at the western foot of the Greater Khingan range

Crop rotation and other tillage systems can affect soil microbial communities and functions. Few studies have reported the response of soil spatial microbial communities to rotation under drought stress. Therefore, the purpose of our study was to explore the dynamic changes of the soil space microbial community under different drought stress-rotation patterns. In this study, two water treatments were set up, control W1 (mass water content 25%–28%), and drought W2 (mass water content 9%–12%). Four crop rotation patterns were set in each water content, spring wheat continuous (R1), spring wheat-potato (R2), spring wheat-potato-rape (R3) and spring wheat-rape (R4), for a total of eight treatments (W1R1, W1R2, W1R3, W1R4, W2R1, W2R2, W2R3, W2R4). Endosphere, rhizosphere and bulk soil of spring wheat in each treatment were collected, and root space microbial community data were generated. The soil microbial community changed under different treatments and their relationship with soil factors were analyzed using a co-occurrence network, mantel test, and other methods. The results revealed that the alpha diversity of microorganisms in the rhizosphere and bulk soil did not differ significantly, but it was significantly greater than in the endosphere. The bacteria community structure was more stable, fungi alpha-diversity significant changes (p < 0.05), that were more sensitive to the response of various treatments than bacteria. The co-occurrence network between fungal species was stable under rotation patterns (R2, R3, R4), while the community stability was poor under continuous cropping pattern (R1), and interactions were strengthened. Soil organic matter (SOM), microbial biomass carbon (MBC), and pH value were the most important factors dominating the bacteria community structural changed in the endosphere, rhizosphere, and bulk soil. The dominant factor that affected the fungal community structural changed in the endosphere, rhizosphere, and bulk soil was SOM. Therefore, we conclude that soil microbial community changes under the drought stress-rotation patterns are mainly influenced by soil SOM and microbial biomass content

Structural Pharmacology of Cation-Chloride Cotransporters

Loop and thiazide diuretics have been cornerstones of clinical management of hypertension and fluid overload conditions for more than five decades. The hunt for their molecular targets led to the discovery of cation-chloride cotransporters (CCCs) that catalyze electroneutral movement of Cl− together with Na+ and/or K+. CCCs consist of two 1 Na+-1 K+-2 Cl− (NKCC1-2), one 1 Na+-1 Cl− (NCC), and four 1 K+-1 Cl− (KCC1-4) transporters in human. CCCs are fundamental in trans-epithelia ion secretion and absorption, homeostasis of intracellular Cl− concentration and cell volume, and regulation of neuronal excitability. Malfunction of NKCC2 and NCC leads to abnormal salt and water retention in the kidney and, consequently, imbalance in electrolytes and blood pressure. Mutations in KCC2 and KCC3 are associated with brain disorders due to impairments in regulation of excitability and possibly cell volume of neurons. A recent surge of structures of CCCs have defined their dimeric architecture, their ion binding sites, their conformational changes associated with ion translocation, and the mechanisms of action of loop diuretics and small molecule inhibitors. These breakthroughs now set the stage to expand CCC pharmacology beyond loop and thiazide diuretics, developing the next generation of diuretics with improved potency and specificity. Beyond drugging renal-specific CCCs, brain-penetrable therapeutics are sorely needed to target CCCs in the nervous system for the treatment of neurological disorders and psychiatric conditions

Bombyx mori Dihydroorotate Dehydrogenase: Knockdown Inhibits Cell Growth and Proliferation via Inducing Cell Cycle Arrest

Dihydroorotate dehydrogenase (DHODH), in the de novo pyrimidine biosynthetic pathway, is the fourth enzyme of pyrimidine synthesis and is used to oxidize dihydroorotate and hence to orotat. We cloned and characterized here the dhod of silkworms, Bombyx mori. The full-length cDNA sequence of dhod is 1339 bp, including an open reading frame (ORF) of 1173 bp that encoded a 390 amino acid protein. And two domains were involved in the Dihydroorotate dehydrogenase amino acid sequence of silkworms, Bombyx mori (BmDHODH), namely a DHO_dh domain and a transmembrane domain in N-termina. The silkworm dhod is expressed throughout development and in nine tissues. Moreover, knockdown of the silkworm dhod gene reduced cell growth and proliferation through G2/M phase cell cycle arrest. Similarly, DHODH inhibitor (leflunomide) also reduced cell growth and proliferation, with a significant decrease of cyclin B and cdk2. DHODH is the fourth enzyme of pyrimidine synthesis, so we also found that leflunomide can inhibit, at least in part, the endomitotic DNA replication in silk glands cells. These findings demonstrate that downregulation of BmDHODH inhibits cell growth and proliferation in silkworm cells, and the endomitotic DNA replication in silk gland cells

Inside vesicle adhesion between two vesicles in 2-D case

A theoretic model is proposed to study the adhesion behavior of a vesicle adhering inside another vesicle in 2-D case. The equilibrium shape equations and boundary conditions are investigated. With zero pressure, the integral case of the shape equations with dimensionless parameters is derived. When a soft vesicle adheres inside a rigid ring, the bifurcation between two phases is revealed, the critical adhesion condition and phase diagram are obtained. The finite element method (FEM) is used to study the deformation processes induced by the change of work of adhesion and bending rigidity. The relationships between the energy, adhesion length, cell volume, bending rigidity and work of adhesion are obtained

The Prognostic Role of Glasgow Prognostic Score and C-reactive Protein to Albumin Ratio for Sarcoma: A System Review and Meta-Analysis

Backgrounds. Both pretreatment serum CRP (C-reactive protein) level and ALB (albumin) level have been found to be predictive of survival for multiple malignancies including sarcoma. Since both of the GPS (Glasgow prognostic score) and CAR (C-reactive protein to albumin ratio) are based on the combination of CRP and ALB, we conducted a meta-analysis to evaluate the prognostic role of these two parameters for sarcoma patients. Methods. A detailed literature search was conducted in MEDLINE, Embase, and Cochrane Library for relevant research publications written in English. Patients’ clinical characteristics, outcomes of overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were extracted. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were combined to evaluate the prognostic role of GPS or CAR. Results. Twelve articles containing 2695 patients were identified as eligible studies. The results showed that an elevated GPS was significantly correlated with poor OS (HR=2.42; 95% CI: 1.98-2.94; p<0.001; fixed-effects model), DSS (HR=2.28; 95% CI: 1.75-2.97; p<0.001; fixed-effects model), and DFS (HR=2.05; 95% CI: 1.62-2.60; p<0.001; fixed-effects model). A higher CAR also was shown to be significantly correlated with poor OS (HR=2.23; 95% CI: 1.70-2.92; p<0.001; fixed-effects model) and DFS (HR=1.81; 95% CI: 1.7-2.58; p=0.001; fixed-effects model). Conclusion. An elevated GPS is predictive of poor survival in patients with sarcomas and is promising to be used as a factor for risk stratification. A higher CAR value is also predictive of poor survival; however, the optimal CAR cut-off value is still to be determined

The value of C-reactive protein as an independent prognostic indicator for disease-specific survival in patients with soft tissue sarcoma: A meta-analysis.

BACKGROUNDS:Serum C-reactive protein (CRP) level has been shown to be a predictor of survival for multiple cancer types. The aim of this study was to evaluate whether pretreatment serum CRP level could serve as a reliable independent prognostic indicator for survival in patients with soft tissue sarcoma (STS). METHODS:A detailed literature search was conducted in Medline, Embase and Cochrane for relevant research publications written in English. Patients' clinical characteristics, outcomes of disease-specific survival (DSS) and disease/recurrence free survival (DFS/RFS) were extracted. Only the results of multivariate survival analysis were recruited in our analysis. Pooled hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated to evaluate the prognostic role of CRP. This study was registered on PROPERO and the registration number is CRD42018104802. RESULTS:Nine articles containing 1655 patients were identified as eligible studies. The random effects model showed that elevated CRP level was significantly correlated with poor DSS (HR = 2.08; 95% CI: 1.33-3.24; p < 0.001). After excluding the heterogeneous study, the fixed effects model showed that elevated CRP level was firmly correlated with poor DSS (HR = 2.36; 95% CI: 1.84-3.03; p < 0.001). The fixed effects model revealed that elevated CRP level was significantly correlated with poor DFS (HR = 1.78; 95% CI: 1.39-2.30; p < 0.001) among studies have more than 100 samples. CONCLUSION:The results of this meta-analysis suggest that elevated pretreatment serum CRP level could serve as an independent risk factor for poor DSS and DFS/RFS in STS patents

Simulation of Fracture Morphology during Sequential Fracturing

During hydraulic fracturing, the aperture of hydraulic fractures will shrink by the in-situ stress, but will not fully close because of the existence of proppant inside the fracture. In previous studies, few people noticed the existence of proppant, which has resulted in the inaccuracy of simulation results. In this study, based on the boundary element method, a numerical simulation model for sequential fracturing was established, which respectively considered the influence of proppant in staged fracturing and zipper fracturing. In addition, the influence mechanism of proppant on fracture morphology is then revealed. Simulation results show that the residual aperture of the previous hydraulic fracture, which was produced by proppant, may increase with the increase of proppant stiffness and fracture spacing and may also be shrunk by the dynamic propagation of subsequent hydraulic fracture. However, the residual aperture will rebound after hydraulic fracturing construction is finished. The shrinkage and rebound values of residual aperture of hydraulic fracture are usually less than 1 mm. In addition, at the same time, the residual aperture of previous hydraulic fracture may also influence the propagation of subsequent hydraulic fracture. These influences are represented by the bend of fractures in multistage fracturing and the intersection in zipper fracturing. With the increase of well spacing, the influence degree of residual aperture on subsequent fracture propagation is reduced. The previous hydraulic fracture cannot have a significant effect on the deflection of subsequent hydraulic fracture when fracture spacing is between 10 and 30 m. The above research has important guiding significance for controlling fracture morphology in hydraulic fracturing