Obinutuzumab may be an effective and safe option for adult minimal change disease and focal segmental glomerulosclerosis patients after multitarget therapy including rituximab.

INTRODUCTION: Rituximab has proven effective and safe in pediatric and adult minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) patients with frequently relapsing nephrotic syndrome (FRNS). However, its efficacy diminishes in several patients who experience nephrotic syndrome relapsing in short durations or failing to achieve remission. We aimed to explore the efficacy and safety of obinutuzumab, a novel anti-CD20 antibody, in these patients. METHODS: A retrospective case series study at our center included 11 adult MCD or FSGS patients who presented with nephrotic syndrome characterized by short-duration relapses or lack of remission after multitarget therapy, including rituximab. Primary outcomes included the first relapse-free time, relapse rate during follow-up, and the use of immunosuppressants after obinutuzumab. All adverse events were recorded. RESULTS: Eleven adult patients (median age 26.0 years, 81.9% males) received an average obinutuzumab dose of 2.0 (1.0, 2.0) g during a median follow-up period of 17.0 (12.0, 22.0) months. The first relapse-free time was 12.1 (10.8, 18.9) months. Two patients with FSGS experienced relapses, while the remaining maintained remission by the end of follow-up. Six patients (54.5%) achieved cessation of corticosteroids and immunosuppressants within three months after obinutuzumab. Adverse events were mostly mild. CONCLUSION: Obinutuzumab may be an efficient and safe option for inducing remission in adult MCD and FSGS patients who presented with nephrotic syndrome relapsing in short durations or failed to achieve remission after multitarget therapy, including rituximab. It was effective in maintaining remission in MCD patients, while its efficacy in maintaining remission in FSGS patients remained uncertain.

Distinct DNA conformations during forward and backward translocations through a conical nanopore.

DNA conformations, which encompass the three-dimensional structures of the DNA strand, play a crucial role in genome regulation. During DNA translocation in a nanopore, various conformations occur due to interactions among force fields, the fluidic environment, and polymer features. The most common conformation is folding, where DNA moves through the nanopore in a two-strand or multi-strand manner, influencing the current signature. Factors such as hydrodynamic drag, ionic environments, and DNA length significantly affect these conformations. Notably, conical nanopores, with their asymmetrical geometry, impose unique constraints on DNA translocation. Our findings reveal that during forward translocation, from the narrow (cis) end to the wide (trans) end, DNA experiences less resistance, resulting in shorter translocation times and higher blockade currents. Conversely, backward translocation, from the wide (trans) end to the narrow (cis) end, leads to longer translocation times and more complex conformations due to increased hydrodynamic drag and geometric constraints. This study employs molecular ping-pong methods to confine DNA, further highlighting the intricate dynamics of DNA folding within nanopores. These insights enhance the understanding of DNA behavior in confined environments, contributing to advancements in nanopore-based sensing and sequencing technologies, with implications for genome regulation and biomedical applications.

Deciphering the Roles of Extracellular Polymeric Substances (EPS) in Shaping Disinfection Kinetics through Permanent Removal via Genetic Disruption.

Extracellular polymeric substances (EPS) ubiquitously encapsulate microbes and play crucial roles in various environmental processes. However, understanding their complex interactions with dynamic bacterial behaviors, especially during the disinfection process, remains very limited. In this work, we investigated the impact of EPS on bacterial disinfection kinetics by developing a permanent EPS removal strategy. We genetically disrupted the synthesis of exopolysaccharides, the structural components of EPS, in Pseudomonas aeruginosa, a well-known EPS-producing opportunistic pathogen found in diverse environments, creating an EPS-deficient strain. This method ensured a lasting absence of EPS while maintaining bacterial integrity and viability, allowing for real-time in situ investigations of the roles of EPS in disinfection. Our findings indicate that removing EPS from bacteria substantially lowered their susceptibility threshold to disinfectants such as ozone, chloramine B, and free chlorine. This removal also substantially accelerated disinfection kinetics, shortened the resistance time, and increased disinfection efficiency, thereby enhancing the overall bactericidal effect. The absence of EPS was found to enhance bacterial motility and increase bacterial cell vulnerability to disinfectants, resulting in greater membrane damage and intensified reactive oxygen species (ROS) production upon exposure to disinfectants. These insights highlight the central role of EPS in bacterial defenses and offer promising implications for developing more effective disinfection strategies.

Effects of Dietary Protein-to-Energy Ratios on Growth, Immune Response, Antioxidative Capacity, Liver and Intestinal Histology, and Growth-Related Gene Expression in Hybrid Yellow Catfish (Pelteobagrus fulvidraco ♀ × Pelteobagrus vachelli ♂).

This study is aimed at evaluating the effects of dietary protein-to-energy ratios on the growth, immunological response, antioxidative capacity, liver and intestinal histology, and growth-related gene expression of hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × Pelteobagrus vachelli ♂). Eight diets were formulated to form different protein/energy ratios of 84, 88, 90, 93, 95, 96, 99, and 103 mg/kcal (P/E84, P/E88, P/E90, P/E93, P/E95, P/E96, P/E99, and P/E103), respectively. These diets contain different levels of gross energy (GE), ranging from 4.13 to 4.76 kcal g-1. Seven hundred and twenty healthy fish (17.15 ± 0.02 g) were randomly dispersed into 24 rectangular fiberglass tanks with 8 treatments in triplicate groups. The fish fed a P/E ratio of 95 mg/kcal demonstrated the best growth and feed utilization. A significant (P < 0.05) increase in percent weight gain (WG%) and specific growth rate (SGR) was seen as the dietary P/E ratio ameliorated from P/E84 to P/E95, followed by a decreased pattern in these parameters. Feed conversion ratio (FCR) and daily feed intake (DFI) were significantly impacted by dietary P/E ratios (P < 0.05). Additionally, an optimum P/E ratio improved intestinal morphology. However, low or high P/E ratio diets can cause oxidative stress, impaired liver function, and significantly reduced nonspecific immunity. The expression of target of rapamycin (TOR) and insulin-like growth factor-1 (IGF1) genes in the liver was considerably influenced by dietary protein-to-energy ratios (P < 0.05). Based on the statistical analysis of WG% against the dietary P/E ratio, the optimal P/E ratio for the studied species was estimated to be 92.92 mg/kcal.

Hemodiafiltration improves red blood cell lifespan in patients with end-stage renal disease.

INTRODUCTION: Uremic toxin-induced shortening of red blood cell (RBC) lifespan is an important mechanism of anemia in end-stage renal disease (ESRD). Conventional hemodialysis does not improve RBC lifespan; the efficacy of hemodiafiltration (HDF) for alleviating RBC lifespan has not yet been evaluated in patients with ESRD. METHODS: Twenty-three patients with ESRD in maintenance hemodialysis were enrolled. Baseline data for sex, age, dialysis vintage, pre-dialysis hemoglobin (Hb), blood urea nitrogen (BUN), intact parathyroid hormone (iPTH), single pool Kt/V (spKt/V), and plasma indophenol sulfate (IS) were collected. RBC lifespans before and after one session of HDF were compared. The resultant differences were subjected to correlational analyses with baseline data. RESULTS: RBC lifespan increased from 73 (66, 89) days at baseline to 77 (71, 102) days after a single HDF treatment (p = 0.034). Meanwhile, plasma IS concentration decreased from 113.05 (80.67, 133.05) mg/L to 83.87 (62.98, 96.78) mg/L (p < 0.001). RBC lifespan increases correlated negatively with Hb levels. CONCLUSIONS: A single HDF treatment improved RBC lifespan in ESRD patients on maintenance hemodialysis, with more severe pre-HDF anemia at baseline being associated with greater increases in RBC lifespan.

Evaluating the influence of different environmental water allocation schemes on the water level of a typical shallow lake in semiarid regions: From the perspective of an integrated modeling approach.

Many lakes in semiarid regions around the world rely on environmental water allocation to maintain the health of the lake ecosystem. However, under changing environments, the competition for water resources between human society and natural ecosystems has intensified. How to manage environmental water allocation more reasonably and precisely has become an important issue. The largest lake on the North China Plain, Baiyangdian Lake (BYDL), is a typical lake facing such challenges. To provide feasible strategies for sustainable water allocation to BYDL, with the proper parameterization of hydrological processes, this study developed a 10-day temporal scale lake water level prediction model to quantify how environmental water allocation regulates the BYDL water level under different hydroclimatic conditions. Evaluation of model performance revealed that environmental water allocation rather than natural climatic periodicity dominates the variation in the BYDL water level. The model structure could be further improved with consideration of more detailed observations of both the surface runoff entering BYDL and the water area beneath the canopy of the reeds in BYDL. Analysis of 72 model simulation scenarios indicated that water allocations from multiple sources are indispensable and that the water resources that guarantee maintaining the BYDL water level within the ecologically suitable range vary substantially under different hydroclimatic conditions. More elaborate allocation plans are required both to improve the water quality and health of the aquatic ecosystem of BYDL and to reduce the risk of flooding. The findings from this study are valuable for guiding the implementation of environmental water allocations to lakes in semiarid regions worldwide.

Assessing alterations of water level due to environmental water allocation at multiple temporal scales and its impact on water quality in Baiyangdian Lake, China.

Lakes in arid/semiarid regions face problems of insufficient inflow and degradation of water quality, which threaten the health of the lake ecosystem. Baiyangdian Lake (BYDL), the largest lake in the North China Plain, is confronted with such challenges. The objective of this study was to improve understanding of how changes in water level influence water quality in the BYDL at different temporal scales, especially related to implementations of intermittent environmental water allocation activities in the past two decades, by using data on monthly lake water level, climate factors of precipitation and temperature, and lake water quality. The Mann-Kendall method and continuous wavelet analysis revealed that the lake water level shows a significant decreasing trend after 1967, and the period of 16-year was identified as the principal period for 1950-2018. Based on cross-wavelet transform and wavelet coherence analysis, the periodic agreement and coherence between water level and climatic factors decreased after 1997, when environmental water allocations started, indicating that the influences of climatic factors, i.e., precipitation and temperature, became weak. By utilizing the cross-wavelet transform and wavelet coherence analysis methods, the relationships between lake water level and water quality parameters of chemical oxygen demand, ammonia nitrogen, total nitrogen, and total phosphorus were investigated. We found that the change in source and amount of environmental water allocation is one possible reason for the temporal evolution in joint variability between lake water level and water quality. Meanwhile, a dilution effect of freshwater allocated to BYDL was detected in the time-frequency domain. However, the result also indicates that the driving mechanism of water quality is complex due to the combined impacts of water allocation, nonpoint source pollution in the rainy season, and nutrient release from lake sediment. Our findings improve the general understanding of changes in water level in lakes located in arid and semiarid regions under climate change and intensive human activities, and also provide valuable knowledge for decision making in aquatic ecosystem restoration of BYDL and other similar lakes.

Determination of Ultra-Trace Cobalt in Water Samples Using Dispersive Liquid-Liquid Microextraction Followed by Graphite Furnace Atomic Absorption Spectrometry.

A novel method for the determination of ultra-trace cobalt by dispersive liquid-liquid microextraction (DLLME) coupled with graphite furnace atomic absorption spectrometry has been developed. It is based on the color reaction of Co2+ with 2-(5-bromo-2-pyridylazo)-5-dimethylaminoaniline (5-Br-PADMA) in a Britton-Robinson buffer solution at pH 6.0 to form stable hydrophobic chelates, which were separated and enriched by DLLME with 1,2-dichloroethane (CH2ClCH2Cl) as extraction and acetonitrile (CH3CN) as a dispersive solvent. The sedimented phase containing the chelates is then determined with GFAAS. Parameters that affect extraction efficiency, such as types and volumes of extraction and disperser solvents, pH of sample solution, extraction time, concentration of the chelating agent 5-Br-PADMA, and salt effect, were investigated. Under optimal conditions, the calibration graph was linear over the range 0.05-1.0 ng/mL, with a correlation coefficient of 0.9922 and a detection limit of 0.03 ng/mL. Preconcentration factor (PF) is calculated as the ratio of the aqueous solution volume (5 mL) to that of the organic phase volume (40 µL), and enrichment factor (EF) is calculated as the ratio of the slopes of the calibration graphs obtained with and without DLLME for 5.0 mL of sample solution, which were 120 and 112.5, respectively. The extraction efficiency, calculated by EF/PF·100, was 93.8%. The relative standard deviation (RSD) at the 0.5 ng/mL Co2+ level was 3.8% (n = 6). The method has been applied to the determination of trace cobalt in water samples with satisfactory results.

Qualitative and Quantitative Analysis of Edible Bird's Nest Based on Peptide Markers by LC-QTOF-MS/MS.

Edible bird's nest (EBN) is an expensive health food. There are many adulterants in the market. It remains challenging to discriminate EBN from its adulterants due to a lack of high-specificity markers. Besides, the current markers are confined to soluble fraction of EBN. Here, both soluble and insoluble fractions were analyzed by LC-QTOF-MS/MS. A total of 26 high-specificity peptides that were specific to EBN were selected as qualitative authentication markers. Among them, 10 markers can discriminate EBN from common adulterants, 13 markers discriminate white EBN from grass EBN/common adulterants, and 3 markers discriminate grass EBN from white EBN/common adulterants. Three of them, which showed high signal abundance (Peak area ≥ 106) and satisfactory linearity (R2 ≥ 0.995) with EBN references, were selected as the assay marker; and their peptide sequences were confidently identified by searching database/de novo sequencing. Based on these markers, a qualitative and quantitative analytical method was successfully developed and well-validated in terms of linearity, precision, repeatability, and accuracy. The method was subsequently applied to detect EBN products on the market. The results indicated that more than half of EBN products were not consistent with what the merchants claimed.

Qualitative and Quantitative Analysis of Ejiao-Related Animal Gelatins through Peptide Markers Using LC-QTOF-MS/MS and Scheduled Multiple Reaction Monitoring (MRM) by LC-QQQ-MS/MS.

Donkey-hide gelatin, also called Ejiao (colla corii asini), is commonly used as a food health supplement and valuable Chinese medicine. Its growing popular demand and short supply make it a target for fraud, and many other animal gelatins can be found as adulterants. Authentication remains a quality concern. Peptide markers were developed by searching the protein database. However, donkeys and horses share the same database, and there is no specific marker for donkeys. Here, solutions are sought following a database-independent strategy. The peptide profiles of authentic samples of different animal gelatins were compared using LC-QTOF-MS/MS. Fourteen specific markers, including four donkey-specific, one horse-specific, three cattle-specific, and six pig-specific peptides, were successfully found. As these donkey-specific peptides are not included in the current proteomics database, their sequences were determined by de novo sequencing. A quantitative LC-QQQ multiple reaction monitoring (MRM) method was further developed to achieve highly sensitive and selective analysis. The specificity and applicability of these markers were confirmed by testing multiple authentic samples and 110 batches of commercial Ejiao products, 57 of which were found to be unqualified. These results suggest that these markers are specific and accurate for authentication purposes.

A rare complication of pelvic perforation by an excessive medial slide of the helical blade after treatment of an intertrochanteric fracture with proximal femoral nail anti-rotation: A case report and literature review.

Intertrochanteric fractures have become a severe public health problem in elderly patients. Proximal femoral nail anti-rotation (PFNA) is a commonly used intramedullary fixation device for unstable intertrochanteric fractures. Pelvic perforation by cephalic screw is a rare complication. We reported an 84-year-old female who fell at home and sustained an intertrochanteric fracture. The patient underwent surgery with PFNA as the intramedullary fixation device. Routine postoperative examination revealed medial migration of the helical blade that eventually caused pelvic perforation. We performed a cemented total hip arthroplasty as the savage procedure. At the latest follow-up of 12 months after total hip arthroplasty, the patient had no pain or loosening of the prosthesis in the left hip. Pelvic perforation should be considered when choosing PFNA as the intramedullary fixation device, especially in patients with severe osteoporosis wherein the helical blade can be easily inserted during the operation. The lack of devices to avoid oversliding of the helical blade in PFNA is an unreported cause of this complication and should be considered in such cases.

An optimized BRD4 inhibitor effectively eliminates NF-κB-driven triple-negative breast cancer cells.

Acetylation of NF-κB's RelA subunit at lysine-310 (AcLys310) helps to maintain constitutive NF-κB activity in cancers such as triple-negative breast cancer (TNBC). Bromodomain-containing factor BRD4 binds to acetylated RelA to promote the activity of NF-κB. Hence, interfering with the acetylated RelA-BRD4 interaction is a potential strategy for treating NF-κB-driven TNBC. Here, a new compound 13a was obtained by structural optimization and modification of our previously reported compound. In comparison with the well-known BRD4 inhibitor (+)-JQ1, 13a showed more potent anticancer activity in NF-κB-active MDA-MB-231 cells. Mechanistically, 13a antagonized the protein-protein interaction (PPI) between BRD4 and acetylated RelA, decreased levels of IL-6, IL-8, Snail, Vimentin, and ZEB1, induced cell senescence and DNA damage, and weakened the adhesion, metastasis, and invasion ability of TNBC cells. Our results provide insights into avenues for the further development of potent BRD4-acetylated RelA PPI inhibitors. Moreover, our findings highlight the effectiveness and feasibility of blocking the interaction between BRD4 and acetylated RelA against NF-κB-active cancers, and of screening antagonists of this PPI.

Accelerated start-up for photo-fermentative hydrogen production in biofilm reactor by adding waste effluent.

The difficulty and long duration of start-up wastes numerous costs, labors and time and a little fluctuate during the process might fail it. However, studies dealing with the problem hindering accelerated start-up are still insufficient. Current research focused to develop a method for accelerated start-up in an efficient way. This work outlined a novel alternative for accelerated start-up. This joint method, adding waste effluent with applying biofilm reactor, could successfully start up hydrogen production in the first 24 h via increasing ability of hydrogen producers while the control group produced little hydrogen. The two factors, biofilm formation and addition of waste effluent, expressed the combined effects on accelerated start-up. This study suggested that little molecules like quorum sensing system factors and indoles might be the crucial regulating and stimulating factors and express the accelerated start-up ability only in biofilm reactors.

Rubinoboletus ballouii polysaccharides exhibited immunostimulatory activities through toll-like receptor-4 via NF-κB pathway.

The biological activities of water-soluble components of edible mushroom Rubinoboletus ballouii (RB) were seldom reported. Polysaccharides of RB (RBP) were prepared and well-characterized using chemical analyses. The immunomodulatory properties of RBP were investigated using human monocyte-derived dendritic cells (moDC) in vitro, and cyclophosphamide (CTX)-induced immunosuppressive mouse model. Results showed that RBP was found to contain 80.6% (w/w) of neutral sugars including D-fucose, D-mannose, D-glucose and D-galactose (1.7:1.4:1.0:1.8), and 12.5% (w/w) of proteins, which composed of glutamine, threonine, serine, etc. RBP could promote the maturation of moDC and increase the secretion of IL-12p40, IL-10, and TNF-α. Furthermore, the stimulation of IL-12p40 production was inhibited by pretreatment with toll-like receptor (TLR)-4 blocker or NF-κB pathway blocker, suggesting that the activation of moDC by RBP was mediated through NF-κB pathway via TLR-4 receptor. On the other hand, in CTX-treated mice, RBP restored the loss of CD34bright CD45dim hematopoietic stem cells and increased IL-2 production in sera and splenocytes culture supernatant, as well as up-regulated the percentage of CD4+ T helper lymphocyte in mice splenocytes. These findings strongly suggested that RBP are the active ingredients of RB responsible for its immunostimulatory actions and deserved to be further investigated as cancer supplements.

Oncogene PLCE1 may be a diagnostic biomarker and prognostic biomarker by influencing cell cycle, proliferation, migration, and invasion ability in hepatocellular carcinoma cell lines.

Hepatocellular carcinoma (HCC) is a lethal malignancy worldwide. HCC has traits of late diagnosis and high recurrence. This study explored potential diagnosis and prognosis significance of phospholipase C epsilon 1 (PLCE1) in HCC. The messenger RNA (mRNA) levels and diagnostic value of PLCE1 were determined by real-time polymerase chain reaction and online databases GEPIA, oncomine, and GSE14520 data set. Survival analysis used the Kaplan-Meier Plotter website. Cell cycle, proliferation, migration, and invasion assays were performed with downregulated PLCE1 expression in HCC-M and HepG2 cell lines. PLCE1 was differentially expressed and highly expressed in tumors and had low expression in nontumor tissues (all p < .05). The diagnostic value of PLCE1 was validated with the datasets (all p < .01, all areas under curves > 0.7). PLCE1 mRNA expression was associated with the overall and relapse-free survival (both p < .05). Functional experiments indicated that downregulation of PLCE1 expression led to increased G1 stage in cell cycle and decreased cell proliferation, migration, and invasion compared with a negative control group (all p ≤ .05). The oncogene PLCE1 was differentially expressed in HCC and non-HCC tissues. It is a candidate for diagnosis and serves as prognosis biomarker. PLCE1 influenced survival by affecting the cell cycle, proliferation, migration, and invasion ability.

Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms.

BACKGROUND: This study explored the prognostic significance of Glypican (GPC) family genes in patients with pancreatic ductal adenocarcinoma (PDAC) after pancreaticoduodenectomy using data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). METHODS: A total of 112 PDAC patients from TCGA and 48 patients from GEO were included in the analysis. The relationship between overall survival and the expression of GPC family genes as well as basic clinical characteristics was analyzed using the Kaplan-Meier method with the log-rank test. Joint effects survival analysis was performed to further examine the relationship between GPC genes and prognosis. A prognosis nomogram was established based on clinical characteristics and prognosis-related genes. Prognosis-related genes were investigated by genome-wide co-expression analysis and gene set enrichment analysis (GSEA) was carried out to identify potential mechanisms of these genes affecting prognosis. RESULTS: In TCGA database, high expression of GPC2, GPC3, and GPC5 was significantly associated with favorable survival (log-rank P = 0.031, 0.021, and 0.028, respectively; adjusted P value = 0.005, 0.022, and 0.020, respectively), and joint effects analysis of these genes was effective for prognosis prediction. The prognosis nomogram was applied to predict the survival probability using the total scores calculated. Genome-wide co-expression and GSEA analysis suggested that the GPC2 may affect prognosis through sequence-specific DNA binding, protein transport, cell differentiation and oncogenic signatures (KRAS, RAF, STK33, and VEGFA). GPC3 may be related to cell adhesion, angiogenesis, inflammatory response, signaling pathways like Ras, Rap1, PI3K-Akt, chemokine, GPCR, and signatures like cyclin D1, p53, PTEN. GPC5 may be involved in transcription factor complex, TFRC1, oncogenic signatures (HOXA9 and BMI1), gene methylation, phospholipid metabolic process, glycerophospholipid metabolism, cell cycle, and EGFR pathway. CONCLUSION: GPC2, GPC3, and GPC5 expression may serve as prognostic indicators in PDAC, and combination of these genes showed a higher efficiency for prognosis prediction.

Iridium(III)-based chemosensors for the detection of metal ions.

In recent years, transition metal complexes with their prominent photophysical properties have emerged as versatile chemosensors to probe different target analytes, including metal ions. By incorporating specific metal ion receptors, various iridium(III) complex-based cation sensors have been developed using different mechanisms. In this review, we survey examples of iridium(III) complex-based metal ion chemosensors that have been reported in the literature. Their design, mechanism and outlook will also be discussed.

Development of Natural Product-Conjugated Metal Complexes as Cancer Therapies.

Platinum-based drugs have revolutionized cancer care, but are unfortunately associated with various adverse effects. Meanwhile, natural product scaffolds exhibit multifarious bioactivities and serve as an attractive resource for cancer therapy development. Thus, the conjugation of natural product scaffolds to metal complexes becomes an attractive strategy to reduce the severe side effects arising from the use of metal bearing drugs. This review aims to highlight the recent examples of natural product-conjugated metal complexes as cancer therapies with enhanced selectivity and efficacy. We discuss the mechanisms and features of different conjugate complexes and present an outlook and perspective for the future of this field.

Emerging Screening Approaches in the Development of Nrf2-Keap1 Protein-Protein Interaction Inhibitors.

Due to role of the Keap1-Nrf2 protein-protein interaction (PPI) in protecting cells from oxidative stress, the development of small molecule inhibitors that inhibit this interaction has arisen as a viable approach to combat maladies caused by oxidative stress, such as cancers, neurodegenerative disease and diabetes. To obtain specific and genuine Keap1-Nrf2 inhibitors, many efforts have been made towards developing new screening approaches. However, there is no inhibitor for this target entering the clinic for the treatment of human diseases. New strategies to identify novel bioactive compounds from large molecular databases and accelerate the developmental process of the clinical application of Keap1-Nrf2 protein-protein interaction inhibitors are greatly needed. In this review, we have summarized virtual screening and other methods for discovering new lead compounds against the Keap1-Nrf2 protein-protein interaction. We also discuss the advantages and limitations of different strategies, and the potential of this PPI as a drug target in disease therapy.

Astragalus Polysaccharide RAP Induces Macrophage Phenotype Polarization to M1 via the Notch Signaling Pathway.

Macrophages occur in polarized phenotypes, whose characteristics determine the role they play in tumor growth. The M1 phenotype macrophages promote tumoricidal responses and suppress tumor growth. Our previous study showed that a polysaccharide isolated from Radix Astragali, named RAP, was itself non-cytotoxic but induced RAW264.7 cells' cytotoxicity against cancer cells. The current study was undertaken to determine its mechanism. Series studies was conducted to show that RAP is able to induce much higher gene expression of M1 markers, including iNOS, IL-6, TNF-a, and CXCL10, compared with the control group. When RAP-induced BMDMs were transplanted together with 4T1 tumor cells in BALB/c mice, both tumor volume and tumor weight decreased. Further studies indicated that RAP induces the Notch signaling pathway in RAW264.7 cells. The function of Notch signaling in macrophage polarization was confirmed by using γ-secretase inhibitor. These results suggested that Astragalus polysaccharide RAP induces macrophage's polarization to M1 phenotype via the Notch signaling pathway.