Identification of QTL regions for seedling root traits and their effect on nitrogen use efficiency in wheat (Triticum aestivum L.).

KEY MESSAGE: QTL for a wheat ideotype root system and its plasticity to nitrogen deficiency were characterized. Root system architecture-related traits (RRTs) and their plasticity to nitrogen availability are important for nitrogen acquisition and yield formation in wheat (Triticum aestivum L.). In this study, quantitative trait loci (QTL) analysis was conducted under different nitrogen conditions, using the seedlings of 188 recombinant inbred lines derived from a cross between Kenong 9204 and Jing 411. Fifty-three QTL for seven RRTs and fourteen QTL for the plasticity of these RRTs to nitrogen deficiency were detected. Thirty of these QTL were mapped in nine clusters on chromosomes 2B, 2D, 3A, 3D, 6B, 6D, 7A and 7B. Six of these nine clusters were also colocated with loci for nitrogen use efficiency (NUE)-related traits (NRTs). Among them, three QTL clusters (C2B, C6D and C7B) were highlighted, considering that they individually harbored three stable robust QTL (i.e., QMrl-2B.1, QdRs-6D and QMrl-7B). C2B and C7B stably contributed to the optimal root system, and C6D greatly affected the plasticity of RRTs in response to nitrogen deficiency. However, strong artificial selection was only observed for C7B in 574 derivatives of Kenong 9204. Covariance analysis identified QMrl-7B as the major contributor in C7B that affected the investigated NRTs in mature plants. Phenotypic analysis indicated that thousand kernel weight might represent a "concomitant" above-ground trait of the "hidden" RRTs controlled by C7B, which are used for breeding selection. Dissecting these QTL regions with potential breeding value will ultimately facilitate the selection of donor lines with both high yield and NUE in wheat breeding programs.

In Vitro Immunomodulatory Effects of Inonotus obliquus Extracts on Resting M0 Macrophages and LPS-Induced M1 Macrophages.

Background: Inonotus obliquus (Chaga) is a parasitic fungus that is distributed mainly in northeast China. Our literature research showed chaga polysaccharides have bilateral effects on tumor necrosis factor (TNF)-α and interleukin (IL)-1ß levels when they exert antitumor and antidiabetic activities. The current research tried to explore the influence of chaga extracts on inflammatory factors via macrophage polarization which has bilateral immune-regulation not only on healthy tissue homeostasis but also on pathologies. Methods: Chaga was extracted with 100°C water and precipitated with 80% ethanol. The extracts were studied on RAW264.7 macrophage at resting condition (M0) and lipopolysaccharide (LPS)-activated subtype (classic activated macrophage, M1). The IL-1ß, TNF-α, nitric oxide (NO) level, and the protein expressions of M1 and alternative activated macrophage (M2) markers including IL-1ß, inducible NO synthase (iNOS), mannose receptor (CD206), and arginase (Arg)-1 were compared. Results: The 100 g extracts contained 13.7 g polysaccharides and 1.9 g polyphenols. Compared with M0, the 50 µg/mL extracts increased NO level (P < 0.05) and decreased CD206 and Arg-1 expression significantly (P < 0.05). The extracts at 100-200 µg/mL increased NO and TNF-α level (P < 0.05), but increased iNOS and IL-1ß expression significantly (P < 0.05). Compared with M1, the extracts decreased NO level at 25, 50, 100, and 200 µg/mL and decreased IL-1ß and TNF-α level at 100-200 µg/mL significantly (P < 0.05). At 25-200 µg/mL, the extracts significantly increased CD206 and Arg-1 expression and decreased IL-1ß and iNOS expression separately (P < 0.05). Conclusions: Our research suggested that the bilateral effects of the chaga extracts on iNOS, IL-1ß, and NO level on M0/M1 macrophages might be related with chaga polysaccharides and chaga polyphenols. Some in vivo anticancer and antidiabetic research of purified chaga polysaccharides related to macrophage differentiation should be conducted further.

Antiosteoporosis Studies of 20 Medicine Food Homology Plants Containing Quercetin, Rutin, and Kaempferol: TCM Characteristics, In Vivo and In Vitro Activities, Potential Mechanisms, and Food Functions.

Dietary nutraceutical compounds have been evidenced as backbone for bone health in recent years. It is reported that medicine food homology (MFH) plants have multiple nutraceutical compounds. Based on our literature research, 20 MFH plants caught our attention because they contain three popular antiosteoporosis compounds simultaneously: quercetin, rutin, and kaempferol. According to traditional Chinese medicine (TCM), their characteristics including natures, flavors, attributive to meridian tropism, and efficacies were listed. The relationships between TCM efficacies, such as "heat clearing," "tonic," and "the interior warming," and antiosteoporosis pharmacological actions such as antioxidant and immune regulation were discussed. The in vivo antiosteoporosis effects of the 20 MFH plants were summarized. The in vitro antiosteoporosis activities and related mechanisms of the 20 plants and quercetin, rutin, kaempferol were detailed. The TGF-ß-Smad signaling, fibroblast growth factor, and Wnt/ß-catenin signaling on bone formation and the RANKL signaling, NF-κB signaling, and macrophage-colony-stimulating factor on bone resorption were identified. From food point, these 20 MFH plants could be classified as condiment, vegetable, fruit, tea and related products, beverage, etc. Based on the above discussion, these 20 MFH plants could be used as daily food supplements for the prevention and treatment against osteoporosis.

Protective effects of budesonide on LPS-induced podocyte injury by modulating macrophage M1/M2 polarization: Evidence from in vitro and in silico studies.

Budesonide (Bud), one of the most widely used lung medicines, is currently used as a repurposing medicine for immunoglobulin A nephropathy (IgAN) treatment. The progression of IgAN is related to inflammation involving macrophages and podocytes. The present study aimed to explore the effects of Bud on classically activated (M1)/alternatively activated (M2) macrophage polarization and podocyte injury under lipopolysaccharide (LPS)-induced inflammatory stress in vitro. Anti-inflammatory bioinformation of Bud was identified based on the Gene Expression Omnibus database. RAW264.7 cells were treated with normal medium, LPS, curcumin (Cur, positive control), or Bud 5, 10, or 20 µM. The expression levels of inducible nitric oxide synthase (iNOS), TNF-α, mannose receptor (CD206) and arginase (Arg)-1 were quantified by western blotting. The collected supernatants from macrophages were termed (Nor)MS, (LPS)MS, (Cur)MS and (Bud)MS. The TNF-α, IL-1ß and nitric oxide (NO) levels in the supernatants were evaluated by ELISA and Griess assay. The podocytes were cultured in different supernatants and their survival rates were assessed by bromodeoxyuridine assay. TNF signaling is an important pathway by which Bud exerts anti-inflammatory activities. Compared with the LPS group, 5, 10 and 20 µM Bud significantly increased Arg-1 and decreased iNOS expression (Six: P<0.05) and 20 µM Bud significantly increased Arg-1 and CD206 and decreased iNOS and TNF-α expression (Four: P<0.05). Cur significantly decreased iNOS and TNF-α expression (Two: P<0.05). Compared with LPS, 5, 10 and 20 µM Bud and Cur significantly decreased TNF-α, IL-1ß and NO levels (All: P<0.05). The podocyte survival rates of (Bud)MS and (Cur)MS were significantly higher than those of (LPS)MS (Four: P<0.05). The protective effect of Bud on podocyte injury is related to its modulation of M1/M2 polarization.

Triple Combination Therapy With PD-1/PD-L1, BRAF, and MEK Inhibitor for Stage III-IV Melanoma: A Systematic Review and Meta-Analysis.

Triple combination of anti-PD-1/PD-L1 immunotherapy and anti-BRAF plus anti-MEK targeted therapy is a promising antitumor strategy and is increasingly being used in clinical trials. To evaluate the safety and efficacy of triple combination of PD-1/PD-L1, BRAF, and MEK inhibition in patients diagnosed with stage III-IV melanoma, we performed a systematic review and meta-analysis of randomized controlled trials (RCTs). The PubMed, EMBASE, and Cochrane Library were searched for all studies published from inception to January 2021. The progression free survival (PFS), overall survival (OS), overall response rate (ORR), and risk of adverse events (AEs) were extracted by two independent investigators and pooled hazard ratio (HR) or risk ratio (RR) with 95% CI were determined using the random-effects model for data synthesis. Overall, five randomized controlled trials encompassing 1,266 patients with stage III-IV melanoma were selected. Triple combination therapy significantly improved PFS (HR = 0.71; 95% CI = 0.59 to 0.86; P = 0.0005) and 2-year OS (RR = 1.12; 95% CI = 1.03 to 1.23; P = 0.01), but had no impact on ORR (RR = 1.09; 95% CI = 0.91 to 1.30; P = 0.37) when compared with controlled treatment group. In addition, triple combination therapy was associated with increased risks of hypothyroidism, arthralgia, myalgia, ALT increased, AST increased, asthenia, and pyrexia compared with control group. Triple combination therapy of PD-1/PD-L1, BRAF, and MEK inhibition achieved better survival benefits but had higher incidence of some adverse events over two-drug combination or monotherapy. Further randomized controlled clinical trials are needed to verify our results. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2021 CRD42021235845 Available from https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021235845.

Study on diagnostic values and pathological conditions of serum HGF and CA199 in endometriosis.

OBJECTIVE: This study aimed at exploring the diagnostic values and pathological conditions of serum HGF and CA199 in endometriosis (EMT). METHODS: From May 2017 to January 2019, 86 patients with EMT, who were admitted to our hospital, were grouped as Group B, whereas 78 healthy women undergoing physical examinations during the same period were grouped as Group A. Serum HGF and CA199 levels in both groups were detected to analyze their diagnostic values for EMT and their relationships with clinical data. RESULTS: Compared with those in Group A, both serum HGF and CA199 expression elevated significantly in Group B (P<0.05). Their expression was correlated with the age, course of disease, number of nodules and infiltration depth of the patients (P<0.05). Besides, their expression was remarkably higher in patients with stages III ± IV than that in patients with stages I ± II (P<0.05). According to the Kaplan-Meier curves for tumor-free survival, the high expression of HGF and CA199 was related to the poor prognosis of the patients (P<0.05). According to the COX regression analysis for risk factors, the number of nodules, infiltration depth, American Fertility Society (AFS) staging, HGF and CA199 were the independent risk factors of EMT recurrence (P<0.05). CONCLUSION: HGF and CA199 increase in patients with EMT, and can be used as the biomarkers for diagnosing the disease and predicting its prognosis.

Pharmacological Actions, Molecular Mechanisms, Pharmacokinetic Progressions, and Clinical Applications of Hydroxysafflor Yellow A in Antidiabetic Research.

Hydroxysafflor yellow A (HSYA), a nutraceutical compound derived from safflower (Carthamus tinctorius), has been shown as an effective therapeutic agent in cardiovascular diseases, cancer, and diabetes. Our previous study showed that the effect of HSYA on high-glucose-induced podocyte injury is related to its anti-inflammatory activities via macrophage polarization. Based on the information provided on PubMed, Scopus and Wanfang database, we currently aim to provide an updated overview of the role of HSYA in antidiabetic research from the following points: pharmacological actions, molecular mechanisms, pharmacokinetic progressions, and clinical applications. The pharmacokinetic research of HSYA has laid foundations for the clinical applications of HSYA injection in diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. The application of HSYA as an antidiabetic oral medicament has been investigated based on its recent oral delivery system research. In vivo and in vitro pharmacological research indicated that the antidiabetic activities of HSYA were based mainly on its antioxidant and anti-inflammatory mechanisms via JNK/c-jun pathway, NOX4 pathway, and macrophage differentiation. Further anti-inflammatory exploration related to NF-κB signaling, MAPK pathway, and PI3K/Akt/mTOR pathway might deserve attention in the future. The anti-inflammatory activities of HSYA related to diabetes and diabetic complications will be a highlight in our following research.

Comparison of critical biomarkers in 2 erectile dysfunction models based on GEO and NOS-cGMP-PDE5 pathway.

BACKGROUND: Erectile dysfunction is a disease commonly caused by diabetes mellitus (DMED) and cavernous nerve injury (CNIED). Bioinformatics analyses including differentially expressed genes (DEGs), enriched functions and pathways (EFPs), and protein-protein interaction (PPI) networks were carried out in DMED and CNIED rats in this study. The critical biomarkers that may intervene in nitric oxide synthase (NOS, predominantly nNOS, ancillary eNOS, and iNOS)-cyclic guanosine monophosphate (cGMP)-phosphodiesterase 5 enzyme (PDE5) pathway, an important mechanism in erectile dysfunction treatment, were then explored for potential clinical applications. METHODS: GSE2457 and GSE31247 were downloaded. Their DEGs with a |logFC (fold change)| > 0 were screened out. Database for Annotation, Visualization and Integrated Discovery (DAVID) online database was used to analyze the EFPs in Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes networks based on down-regulated and up-regulated DEGs respectively. PPI analysis of 2 datasets was performed in Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and Cytoscape. Interactions with an average score greater than 0.9 were chosen as the cutoff for statistical significance. RESULTS: From a total of 1710 DEGs in GSE2457, 772 were down-regulated and 938 were up-regulated, in contrast to the 836 DEGs in GSE31247, from which 508 were down-regulated and 328 were up-regulated. The 25 common EFPs such as aging and response to hormone were identified in both models. PPI results showed that the first 10 hub genes in DMED were all different from those in CNIED. CONCLUSIONS: The intervention of iNOS with the hub gene complement component 3 in DMED and the aging process in both DMED and CNIED deserves attention.

Renal Protective Effects of Inonotus obliquus on High-Fat Diet/Streptozotocin-Induced Diabetic Kidney Disease Rats: Biochemical, Color Doppler Ultrasound and Histopathological Evidence.

Diabetic kidney disease (DKD) is the current leading cause of end-stage renal disease. Inonotus obliquus (chaga), a medicinal fungus, has been used in treatment of diabetes. Here, we aim to identify the renal protective effects of chaga extracts on a DKD rat model which was induced by a high-fat diet and streptozotocin injection. During the total 17-weeks experiment, the biological parameters of serum and urine were examined, and the color Doppler ultrasound of renal artery, the periodic acid-Schiff staining, and electron microscopy of kidney tissue were performed. The compositions of chaga extracts were analyzed and the intervention effects of the extracts were also observed. Compared with the normal control group, the biochemical research showed that insulin resistance was developed, blood glucose and total cholesterol were elevated, urinary protein excretion and serum creatinine levels were significantly increased in the DKD model. The ultrasound examinations confirmed the deteriorated blood flow parameters of the left renal interlobar artery in the rat models. Finally, histopathological data supported renal injury on the thickened glomerular basement membrane and fusion of the foot processes. 8 weeks intervention of chaga improved the above changes significantly, and the 100 mg/kg/d chaga group experienced significant effects compared with the 50 mg/kg/d in some parameters. Our findings suggested that Doppler ultrasound examinations guided with biochemical indicators played important roles in evaluating the renal injury as an effective, noninvasive, and repeatable method in rats. Based on biochemical, ultrasound, and histopathological evidence, we confirmed that chaga had pharmacodynamic effects on diabetes-induced kidney injury and the aforementioned effects may be related to delaying the progression of DKD.

Protective Effects of Thalidomide on High-Glucose-Induced Podocyte Injury through In Vitro Modulation of Macrophage M1/M2 Differentiation.

Objective. It has been shown that podocyte injury represents an important pathological basis that contributes to proteinuria and eventually leads to kidney failure. High glucose (HG) activates macrophage polarization, further exacerbating HG-induced podocyte injury. Our previous study on diabetic nephropathy rats indicated that thalidomide (Tha) has renoprotective properties. The present study explored the effects of Tha on mRNA and protein expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor- (TNF-) α, mannose receptor (CD206), and arginase- (Arg-) 1 in HG-activated macrophages. iNOS and TNF-α are established as markers of classically activated macrophage (M1). CD206 and Arg-1 are regarded as markers of alternatively activated macrophages (M2). During the experiment, the supernatants of (HG)-treated and (Tha)-treated macrophages, designated as (HG) MS and (Tha) MS, were simultaneously collected and processed. TNF-α and interleukin- (IL-) 1ß levels as well as protein expressions of nephrin and podocin in HG, (HG) MS, and (Tha) MS-cultured podocytes were evaluated. The results showed that compared to the 11.1 mM normal glucose (NG), the 33.3 mM HG-cultured RAW 264.7 cells exhibited upregulated iNOS and TNF-α mRNAs and protein expressions, and downregulated CD206 and Arg-1 expressions significantly (p < 0.05). Tha 200 µg/ml suppressed iNOS and TNF-α, and promoted CD206 and Arg-1 expressions significantly compared to the HG group (p < 0.05). Furthermore, (HG) MS-treated podocytes showed an increase in TNF-α and IL-1ß levels and a downregulation in nephrin and podocin expression significantly compared to NG-treated and HG-treated podocytes (p < 0.05). The (Tha 200 µg/ml) MS group exhibited a decrease in TNF-α and IL-1ß level, and an upregulation in nephrin and podocin expressions significantly compared to the (HG) MS group (p < 0.05). Our research confirmed that HG-activated macrophage differentiation aggravates HG-induced podocyte injury in vitro and the protective effects of Tha might be related to its actions on TNF-α and IL-1ß levels via its modulation on M1/M2 differentiation.

Protective Effects of Two Safflower Derived Compounds, Kaempferol and Hydroxysafflor Yellow A, on Hyperglycaemic Stress-Induced Podocyte Apoptosis via Modulating of Macrophage M1/M2 Polarization.

OBJECTIVE: The primary initiating mechanism in diabetes nephropathy (DN) is hyperglycemia-induced inflammation in which macrophage and podocyte play important roles. The present research is aimed at exploring the effects of kaempferol (Ka) and hydroxysafflor yellow A (HSYA) on classically activated (M1)/alternatively activated (M2) macrophage polarization and podocyte apoptosis under hyperglycaemic conditions in vitro. METHODS: (1) RAW264.7 cells were treated with 11.1 mM glucose (NG), 33.3 mM glucose (HG), Ka 4-8 µM, and HSYA 100-200 µM separately. The expressions of inducible nitric oxide synthase (iNOS), tumor necrosis factor- (TNF-) α, mannose receptor (CD206), and arginase- (Arg-) 1 were quantified by Western blotting and real-time quantitative PCR. The collected supernatants from macrophage were named as (NG) MS, (HG) MS, (Ka) MS, and (HSYA) MS. (2) The podocyte survival rate was assessed by Bromodeoxyuridine assay, while TNF-α and interleukin- (IL-) 1ß levels were evaluated by Elisa. RESULTS: (1) Compared to the HG group, the Ka and HSYA 100 µM groups decreased iNOS and TNF-α levels and increased Arg-1 and CD206 expressions significantly (protein and mRNA: p < 0.05, respectively). (2) The podocyte survival rate of Ka 8 µM was higher than that of HG, and the rates of (Ka) MS and (HSYA 100 µM) MS were higher than that of (HG) MS significantly (all: p < 0.05). (3) TNF-α and IL-1ß levels of Ka and HSYA 100 µM were significantly lower than those of the HG group, and both levels in the (Ka) MS and (HSYA) MS were lower than those in the (HG) MS group significantly (p < 0.05, respectively). CONCLUSION: The protective effects of Ka and HSYA on podocyte apoptosis under hyperglycemic stress are related to their modulation on M1/M2 polarization and the lowering effects on TNF-α and IL-1ß levels.

Mesocrystalline Ta3N5 superstructures with long-lived charges for improved visible light photocatalytic hydrogen production.

Highly ordered mesocrystalline semiconductors often indicate tremendous prospects in the clean energy production and environmental photocatalysis mainly because of their unique superstructure for efficient charge transport pathways and long-lived charges. Here, superstructure Ta3N5 mesocrystals with the high-energy surface {2 0 0} planes exposed were the first time to be successfully fabricated by topological transformation of Ta2O5 mesocrystals. The prepared Ta3N5 mesocrystals showed enhanced visible-light photocatalytic hydrogen production activity of 98.67 µmol g-1 for 180 min irradiation, which was approximately 5.28 times that of comm-Ta3N5 prepared with commercial Ta2O5 as the starting material, mainly due to the formation of long-distance electron conduction pathways and long-lived charges. The detailed electronic band structures of the prepared Ta3N5 mesocrystals were also investigated by electrochemical method. Finally, possible visible-light photocatalytic mechanisms of Ta3N5 mesocrystals for enhanced hydrogen production was also proposed in detail. Current work also indicates that tantalum-based mesocrystals show great potential to enhance the charge separation for efficient photocatalytic water splitting.

QTL Detection for Kernel Size and Weight in Bread Wheat (Triticum aestivum L.) Using a High-Density SNP and SSR-Based Linkage Map.

High-density genetic linkage maps are essential for precise mapping quantitative trait loci (QTL) in wheat (Triticum aestivum L.). In this study, a high-density genetic linkage map consisted of 6312 SNP and SSR markers was developed to identify QTL controlling kernel size and weight, based on a recombinant inbred line (RIL) population derived from the cross of Shixin828 and Kenong2007. Seventy-eight putative QTL for kernel length (KL), kernel width (KW), kernel diameter ratio (KDR), and thousand kernel weight (TKW) were detected over eight environments by inclusive composite interval mapping (ICIM). Of these, six stable QTL were identified in more than four environments, including two for KL (qKL-2D and qKL-6B.2), one for KW (qKW-2D.1), one for KDR (qKDR-2D.1) and two for TKW (qTKW-5A and qTKW-5B.2). Unconditional and multivariable conditional QTL mapping for TKW with respect to TKW component (TKWC) revealed that kernel dimensions played an important role in regulating the kernel weight. Seven QTL-rich genetic regions including seventeen QTL were found on chromosomes 1A (2), 2D, 3A, 4B and 5B (2) exhibiting pleiotropic effects. In particular, clusters on chromosomes 2D and 5B possessing significant QTL for kernel-related traits were highlighted. Markers tightly linked to these QTL or clusters will eventually facilitate further studies for fine mapping, candidate gene discovery and marker-assisted selection (MAS) in wheat breeding.