A green synthesized medicine residue carbon-based iron composite for the removal of chromium (VI) and cadmium (II): Performance, kinetics and mechanism.

Nowadays, clean-up of heavy metals from wastewaters using waste residue carbon-based material has received increasing attention. In this work, a novel Chinese medicine residue carbon-based nano zero-valent iron composite (CM-nZVI) had been successfully prepared using the combined Chinese medicine residue, FeCl3 and green tea extract. Cr(VI) and/ or Cd(II) removal in water by the CM-nZVI were systematacially investigated with a series of batch experiments. The most relevant findings indicated the adsorption efficiecy and capacity of Cr(VI) by CM-nZVI were respecitvely nearly 98% and 26 mg/g under optimized reaction conditions. The negative influences of the cations on the Cr(VI) removal followed the order of Al3+ > Ca2+ > Mg2+ Na+ > K+, but the anions followed the order of HCO3- > PO43- > NO3- > Cl- > SO42-. Humic acid (HA) and ionic strength with high concentrations severely inhibited Cr(VI) removal. The Cr(VI) adsorption on CM-nZVI fitted well by the pseudo-second-order kinetic and Langmuir models. A monolayer endothermic chemisorption occurred on Cr(VI) adsorption over CM-nZVI, and Cr(VI) removal by CM-nZVI primarily involved in the absorption, reduction, precipitation and complexation processes. Both Cr(VI) and Cd(II) removals had been achieved by CM-nZVI at their low concentrations. This CM-nZVI showed a better reusability proprity for Cr(VI) and Cd(II) removal with the regeneration of CM-nZVI through simple pickling. The outcomes of this work show that CM-nZVI could be used an effective material for heavy metals removal from water.

Identifying clinical risk factors correlate with suicide attempts in patients with first episode major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is the most common mental disorder associated with suicide attempts. When a patient first visits the clinic, clinicians are often expected to make concrete diagnose about acute suicidal risk. However, the timeliness of suicide attempts correlates with patients with MDD has not been tested. METHODS: We divided 1718 first-episode and untreated MDD outpatients into those who did not have suicide attempts (non-attempts), recent suicide attempters (≤14 days before assessment) and long - dated suicide attempters (> 30 days before assessment). Positive Symptom Scale of Positive and Negative Syndrome Scale (PANSS), the 17-item Hamilton Depression Scale, 14 - item Hamilton Anxiety Scale, and clinical global impression of severity scale (CGI-S) was assessed. Body mass index, some glycolipid metabolism and thyroid hormone parameters were measured. A gradient-boosted decision trees statistical model was used to generate equally weighted classification for distinguishing recent and long - dated suicide attempters from non-attempts. RESULTS: The classifier identified higher excitement, hostility, anxiety, depression symptoms and higher free thyroxine (FT4) as risk factors for recent suicide attempters with an estimated accuracy of 87% (sensitivity, 59.1%; specificity, 61.2 %). For long - dated suicide attempters' risk factors, single status, higher anxiety and hostility symptoms, higher LDLC and lower BMI, the estimated accuracy was 88% (sensitivity, 52.8%; specificity, 49.6%). CONCLUSIONS: Risk factors for suicide attempt among patients with MDD can be identified by integrating demographic, clinical, and biological variables as early as possible during the first time see a doctor.

Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.

SHP2 is a nonreceptor protein tyrosine phosphatase encoded by the PTPN11 gene and is involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also plays an important role in the programed cell death pathway (PD-1/PD-L1). As an oncoprotein as well as a potential immunomodulator, controlling SHP2 activity is of high therapeutic interest. As part of our comprehensive program targeting SHP2, we identified multiple allosteric binding modes of inhibition and optimized numerous chemical scaffolds in parallel. In this drug annotation report, we detail the identification and optimization of the pyrazine class of allosteric SHP2 inhibitors. Structure and property based drug design enabled the identification of protein-ligand interactions, potent cellular inhibition, control of physicochemical, pharmaceutical and selectivity properties, and potent in vivo antitumor activity. These studies culminated in the discovery of TNO155, (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (1), a highly potent, selective, orally efficacious, and first-in-class SHP2 inhibitor currently in clinical trials for cancer.

Assessing IRAK4 Functions in ABC DLBCL by IRAK4 Kinase Inhibition and Protein Degradation.

The interleukin-1 receptor-activated kinase 4 (IRAK4) belongs to the IRAK family of serine/threonine kinases and plays a central role in the innate immune response. However, the function of IRAK4 in tumor growth and progression remains elusive. Here we sought to determine the enzymatic and scaffolding functions of IRAK4 in activated B-cell-like diffuse large B cell lymphoma (ABC DLBCL). We chose a highly selective IRAK4 kinase inhibitor to probe the biological effects of kinase inhibition and developed a series of IRAK4 degraders to evaluate the effects of protein degradation in ABC DLBCL cells. Interestingly, the results demonstrated that neither IRAK4 kinase inhibition nor protein degradation led to cell death or growth inhibition, suggesting a redundant role for IRAK4 in ABC DLBCL cell survival. IRAK4 degraders characterized in this study provide useful tools for understanding IRAK4 protein scaffolding function, which was previously unachievable using pharmacological perturbation.

[Application of CRISPR/Cas9 mediated gene editing in trees].

The CRISPR/Cas9 system, which can induce precise modifications at a target gene, has been recognized as the most promising gene editing technology, and has played an important role in precision crop breeding. It also provides a new strategy for fundamental researches and molecular breeding of forest trees. Recently, CRISPR/Cas9-mediated gene editing has been applied more extensively in tree genetic studies. It has not only succeeded in developing new drought- resistance or disease-resistant cultivars, but also shows a great potential in regulating lignin biosynthesis and shortening the breeding cycle of forest trees. In this review, we summarize the application and advance of CRISPR/Cas9 in gene function identification and genetic improvement of forest plants. We also discuss the related problems and future perspectives. This review aims to provide a useful reference for tree functional genomics and genetic engineering breeding.

Pollen Typhae Total Flavone Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis in Human Aortic-Vascular Smooth Muscle Cells through Down-Regulating PERK-eIF2α-ATF4-CHOP Pathway.

OBJECTIVE: To test the hypothesis that the inhibition of endoplasmic reticulum (ER) stress-induced apoptosis in oxidized low-density lipoproteins (ox-LDL)-induced human aortic-vascular smooth muscle cells (HA-VSMCs) was associated with suppression of the protein kinase RNA-like ER kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-activating transcription factor 4 (ATF4)-CCAAT/enhancer binding protein homologous protein (CHOP) signaling pathway by Pollen Typhae total flavone (PTF). METHODS: Primary HA-VSMCs were cultured and identified. The cultured HA-VSMCs were randomized into 5 groups, including a normal control group, an ox-LDL group (70 µg/mL high ox-LDL), an HPTF group (70 µg/mL high ox-LDL+500 µg/mL PTF), an MPTF group (70 µg/mL high ox-LDL+250 µg/mL PTF), and a LPTF group (70 µg/mL high ox-LDL+100 µg/mL PTF) in the first part; and a normal control group, an ox-LDL group (70 µg/mL high ox-LDL), an MPTF group (70 µg/mL high ox-LDL+250 µg/mL PTF), a shRNA group (transducted with PERK shRNA lentiviral particles), a scramble shRNA group (transducted with control shRNA lentiviral particles), an MPTF+ox-LDL+shRNA group (250 µg/mL PTF+70 µg/mL high ox-LDL+PERK shRNA lentiviral particles) and an ox-LDL+shRNA group (70 µg/mL high ox-LDL+PERK shRNA lentiviral particles) in the second part. The protein expression levels of ER-associated apoptosis proteins were detected by Western blot, and their mRNA expression levels were detected by quantitative real-time reverse transcription-polymerase chain reaction. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was applied to test cell viability, and the level of apoptosis was monitored by flow cytometry. RESULTS: The MTT assay and flow cytometry showed that the ox-LDL group had a significant increase in apoptosis, which was attenuated in PTF treatment groups and shRNA groups. Moreover, the ox-LDL group had increased protein and mRNA levels of binding immunoglobulin protein and ER-associated apoptosis proteins, such as PERK, eIF2α, ATF4 and CHOP, which were attenuated in PTF treatment groups and shRNA groups. CONCLUSIONS: The apoptosis induced by ox-LDL had a strong relation to ER stress. The protective effect of PTF on ER stressinduced apoptosis was associated with inhibition of the PERK-eIF2α-ATF4-CHOP pathway, which might be a potential therapeutic strategy for enhancing the stability of atherosclerotic plaques.

6-Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors.

Protein tyrosine phosphatase SHP2 is an oncoprotein associated with cancer as well as a potential immune modulator because of its role in the programmed cell death PD-L1/PD-1 pathway. In the preceding manuscript, we described the optimization of a fused, bicyclic screening hit for potency, selectivity, and physicochemical properties in order to further expand the chemical diversity of allosteric SHP2 inhibitors. In this manuscript, we describe the further expansion of our approach, morphing the fused, bicyclic system into a novel monocyclic pyrimidinone scaffold through our understanding of SAR and use of structure-based design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic efficiency, improved potency, and enhanced pharmacokinetic properties. We also report other pyrimidinone analogues with favorable pharmacokinetic and potency profiles. Overall, this work improves upon our previously described allosteric inhibitors and exemplifies and extends the range of permissible chemical templates that inhibit SHP2 via the allosteric mechanism.

Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors.

SHP2 is a nonreceptor protein tyrosine phosphatase within the mitogen-activated protein kinase (MAPK) pathway controlling cell growth, differentiation, and oncogenic transformation. SHP2 also participates in the programed cell death pathway (PD-1/PD-L1) governing immune surveillance. Small-molecule inhibition of SHP2 has been widely investigated, including in our previous reports describing SHP099 (2), which binds to a tunnel-like allosteric binding site. To broaden our approach to allosteric inhibition of SHP2, we conducted additional hit finding, evaluation, and structure-based scaffold morphing. These studies, reported here in the first of two papers, led to the identification of multiple 5,6-fused bicyclic scaffolds that bind to the same allosteric tunnel as 2. We demonstrate the structural diversity permitted by the tunnel pharmacophore and culminated in the identification of pyrazolopyrimidinones (e.g., SHP389, 1) that modulate MAPK signaling in vivo. These studies also served as the basis for further scaffold morphing and optimization, detailed in the following manuscript.

Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.

The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS­ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 µM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS­ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.

Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor.

SHP2 is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell growth and differentiation via the MAPK signaling pathway. SHP2 also purportedly plays an important role in the programmed cell death pathway (PD-1/PD-L1). Because it is an oncoprotein associated with multiple cancer-related diseases, as well as a potential immunomodulator, controlling SHP2 activity is of significant therapeutic interest. Recently in our laboratories, a small molecule inhibitor of SHP2 was identified as an allosteric modulator that stabilizes the autoinhibited conformation of SHP2. A high throughput screen was performed to identify progressable chemical matter, and X-ray crystallography revealed the location of binding in a previously undisclosed allosteric binding pocket. Structure-based drug design was employed to optimize for SHP2 inhibition, and several new protein-ligand interactions were characterized. These studies culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine (SHP099, 1), a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor.

The effect of banana (Musa acuminata) peels hot-water extract on the immunity and resistance of giant freshwater prawn, Macrobrachium rosenbergii via dietary administration for a long term: Activity and gene transcription.

The non-specific immune parameters, disease resistance and immune genes expressions in Macrobrachium rosenbergii were evaluated at 120 days of post feeding the diets containing the extracts of banana, Musa acuminate, fruit's peel (banana peels extract, BPE) at 0, 1.0, 3.0 and 6.0 g kg(-1). Results showed that prawns fed with a diet containing BPE at the level of 1.0, 3.0 and 6.0 g kg(-1) for 120 days had a significantly higher survival rate (30.0%, 40.0% and 56.7%, respectively) than those fed with the control diet after challenge with Lactococcus garvieae for 144 h, and the respective relative survival percentages were 22.2%, 33.3%, and 51.9%, respectively. Dietary BPE supplementation at 3.0 and/or 6.0 g kg(-1) for 120 days showed a significant increase total haemocyte count (THC), granular cell (GC), superoxide dismutase (SOD) activity, phenoloxidase (PO) activity, transglutaminase (TG) activity, and phagocytic activity and clearance efficiency to L. garvieae infection, and meanwhile, the significant decrease in haemolymph clotting times and respiratory bursts (RBs) per haemocyte of prawns were revealed. Furthermore, the mRNA expressions of prophenoloxidase (proPO), lipopolysaccharide and ß-1,3-glucan binding protein (LGBP), peroxinectin (PE), transglutaminase (TG), and crustin (CT) were significantly increased. We therefore recommend that BPE can be used as an immunomodulator for prawns through dietary administration at 6.0 g kg(-1) for a long term (over 120 days) to modify immune responses and genes expression following the enhanced resistance against pathogens.

Synthesis, characterization and luminescent properties of europium complexes with 2,4,6-tris-(2-pyridyl)-s-triazine as highly efficient sensitizers.

Using 2,4,6-tris-(2-pyridyl)-s-triazine (TPTZ) as a neutral ligand, and p-hydroxybenzoic acid, terephthalic acid and nitrate as anion ligands, five novel europium complexes have been synthesized. These complexes were characterized using elemental analysis, rare earth coordination titrations, UV/vis absorption spectroscopy and infrared spectroscopy. Luminescence spectra, luminescence lifetime and quantum efficiency were investigated and the mechanism discussed in depth. The results show that the complexes have excellent emission intensities, long emission lifetimes and high quantum efficiencies. The superior luminescent properties of the complexes may be because the triplet energy level of the ligands matches well with the lowest excitation state energy level of Eu(3+). Moreover, changing the ratio of the ligands and metal ions leads to different luminescent properties. Among the complexes, Eu2(TPTZ)2(C8H4O4)(NO3)4(C2H5OH)·H2O shows the strongest luminescence intensity, longest emission lifetime and highest quantum efficiency.

Synthesis of A83586C analogs with potent anticancer and beta-catenin/ TCF4/osteopontin inhibitory effects and insights into how A83586C modulates E2Fs and pRb.

The synthesis of three potent new antitumor agents is described: the A83586C-citropeptin hybrid (1), the A83586C-GE3 hybrid (2), and l-Pro-A83586C (3). Significantly, compounds 1 and 2 function as highly potent inhibitors of beta-catenin/TCF4 signaling within cancer cells, while simultaneously downregulating osteopontin (Opn) expression. A83586C antitumor cyclodepsipeptides also inhibit E2F-mediated transcription by downregulating E2F1 expression and inducing dephosphorylation of the oncogenic hyperphosphorylated retinoblastoma protein (pRb).

Immune response of white shrimp, Litopenaeus vannamei, after a concurrent infection with white spot syndrome virus and infectious hypodermal and hematopoietic necrosis virus.

In the present study, we investigated immunological changes in viral-infected white shrimp, Litopenaeus vannamei. White shrimp were infected with white spot syndrome virus (WSSV) or co-infected with WSSV and infectious hypodermal and hematopoietic necrosis virus (IHHNV) as detected by polymerase chain reaction (PCR). The complete (100%) mortality rate of shrimp was caused by viral infection due to immune parameters being suppressed including decreases in phenoloxidase activity, total hemocyte counts, differential hemocyte counts, and the gene expressions of prophenoloxidase and peroxinectin. In addition, increases in lipopolysaccharide and beta-1,3-glucan-binding protein of hemocytes and the hepatopancreas, and respiratory bursts per cell, and a decrease in superoxide dismutase were found in viral-infected shrimp, which may have been related to the defense against viral infection.

Validating cancer drug targets.

A cancer drug target is only truly validated by demonstrating that a given therapeutic agent is clinically effective and acts through the target against which it was designed. Nevertheless, it is desirable to declare an early-stage drug target as 'validated' before investing in a full-scale drug discovery programme dedicated to it. Although the outcome of validation studies can guide cancer research programmes, strictly defined universal validation criteria have not been established.

[Clinical and pathological characteristics of focal segmental glomerulosclerosis in children].

OBJECTIVE: To investigate the clinical and pathological characteristics of focal segmental glomerulosclerosis (FSGS) in children. METHODS: The data of 38 children,aged from one and half to 15 years, 25 boys and 13 girls, with primary FSGS were studied retrospectively. RESULTS: Majority of the cases in this study were school-aged children. The average age of initial onset was 8.9 +/- 3.68 years. The ratio of boys to girls was 1.92. The clinical manifestation included isolated proteinuria in 3 cases, proteinuria and hematuria in 1 and nephrotic syndrome in 34 (simple type in 16 and nephritic type in 18). Of 38 cases, 24 (63%) presented with hematuria, 11 (29%) with hypertension and 7 (18%) with decreased creatinine clearance. The pathologic classification included perihilar variant in 17 cases, peripheral variant in 14 and tip variant in 7. The predominant clinical feature of children with tip variant was simple type of nephrotic syndrome (86%). Microscopic hematuria was not common (29%). Blood pressure and renal function were normal. The children with diffuse mesangial hypercellularity superimposed on changes of FSGS (in 21 of 38 cases) were more likely to have hematuria (76%) and less simple nephrotic syndrome (30%). The initial treatment response to prednisone in 34 cases with nephrotic syndrome showed sensitive in 12 cases, resistant in 21 and unknown in 1. Transition from sensitive to resistant occurred in six of 12 children. Three of 4 cases with non-nephrotic syndrome showed no response and the remaining one had unknown response. It was found that 44% of children who received cyclophosphamide and 83% of children who received pulse methylprednisolone and pulse cyclophosphamide or cyclosporin A in addition to oral steroids had complete or partial remission. Correlation analysis showed that the level of proteinuria after treatment was correlated directly with renal tubulointerstitial lesion and renal function (Pr = 0.48, P < 0.05; Pr = 0.45, P < 0.05). CONCLUSION: FSGS was common in school-aged children. The predominant presenting feature was nephrotic syndrome. Hematuria was common. Hypertension and renal insufficiency were less frequently seen. The renal biopsy showed multiple variants. Pulse methylprednisolone and pulse cyclophosphamide or cyclosporin A treatments showed relatively good response.

[Antineutrophil cytoplasmic autoantibody positive vasculitis induced by propylthiouracil: a case report].

OBJECTIVE: Propylthiouracil (PTU) as a drug used during the treatment of hyperthyroidism could induce antineutrophil cytoplasmic autoantibody-positive vasculitis. Here the author reported a childhood case of antineutrophil cytoplasmic autoantibody-positive vasculitis induced by PTU, which is rarely described. METHODS: The diagnosis was made according to the symptoms, signs, serum markers and renal biopsy, and the relevant literature was reviewed. RESULTS: The 12-year-old girl presented with gross hematuria, proteinuria, renal function damage [Ccr 52.46 ml/(min. 1.73 m(2))], positive antineutrophil cytoplasmic autoantibody (ANCA-MPO) (MPO ELISA 140%) and a vasculitis lesion in the renal biopsy sample. She had been treated with PTU for 5 years because of Graves disease. After the diagnosis, the PTU was withdrawn, and prednisone (40 mg/d) and cyclophosphamide (25 mg, Bid) were applied. Three weeks after the therapy with prednisone and cyclophosphamide the gross hematuria disappeared. Three months after the treatment the renal function returned to normal [Ccr 124 mg/(min.1.73 m(2))], and the titer of ANCA-MPO decreased from 140% to 57%. CONCLUSION: PTU may induce antineutrophil cytoplasmic autoantibody positive vasculitis. A right diagnosis and treatment can improve its prognosis of the disease.

Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex.

Key molecular lesions in colorectal and other cancers cause beta-catenin-dependent transactivation of T cell factor (Tcf)-dependent genes. Disruption of this signal represents an opportunity for rational cancer therapy. To identify compounds that inhibit association between Tcf4 and beta-catenin, we screened libraries of natural compounds in a high-throughput assay for immunoenzymatic detection of the protein-protein interaction. Selected compounds disrupt Tcf/beta-catenin complexes in several independent in vitro assays and potently antagonize cellular effects of beta-catenin-dependent activities, including reporter gene activation, c-myc or cyclin D1 expression, cell proliferation, and duplication of the Xenopus embryonic dorsal axis. These compounds thus meet predicted criteria for disrupting Tcf/beta-catenin complexes and define a general standard to establish mechanism-based activity of small molecule inhibitors of this pathogenic protein-protein interaction.