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Guizhi-Shaoyao-Zhimu decoction (GSZD), a classic Chinese herbal formula, can reportedly ameliorate clinical rheumatoid arthritis (RA) symptoms without serious adverse effects. We performed a systematic review and meta-analysis of randomised controlled trials to assess the effect and safety of GSZD for treating RA. We systematically searched for such randomised controlled trials, which compared GSZD with common treatments for RA, in PubMed, Embase, the Cochrane Library, Web of Knowledge, the VIP database, the China National Knowledge Infrastructure, Wanfang, Baidu Scholar, Google Scholar, and the Chinese Biomedical Database. The main index for evaluating the curative effects was the total clinical effective rate; the secondary indicators were sign changes (morning stiffness time, joint swelling index, joint tenderness index, swollen joint count) and laboratory indicators (erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor). We retrieved a total of 708 studies and included 10 in our analysis (n = 792). Compared with conventional drugs, GSZD was more likely to achieve clinical efficacy (relative risk = 1.19; 95% CI: 1.12-1.26) and significantly improve the patient's physical signs. In addition, GSZD exhibited a likelihood of reducing the incidence of adverse events by 73% compared with the control (relative risk = 0.27; 95% CI: 0.09, 0.77). Altogether, we provide evidence that GSZD is an effective and safe drug for treating RA clinically. [ABSTRACT FROM AUTHOR]

Guizhi Shaoyao Zhimu decoction, a traditional Chinese medicine formula used empirically for the treatment of rheumatoid arthritis (RA), has been shown to alleviate bone destruction in rats with collagen-induced arthritis (CIA). The aim of this study is to characterize the effects of Guizhi Shaoyao Zhimu granules (GSZGs) on bone destruction in RA and the underlying mechanism. A CIA arthritis model using DBA/1 mice. The animals were divided into a normal group; CIA model group; low, medium, and high-dose GSZG groups (3, 6, and 9 g/kg/day); and a methotrexate group (1.14 mg/kg/w). In vitro , a cytokine induced osteoclastogenesis model was established. After 28 days of treatment, the paw volume was measured, bone destruction was examined by micro-CT, and the generation of osteoclasts in bone tissue was evaluated via tartrate-resistant acid phosphatase (TRAP) staining. Furthermore, the inhibitory effect and underlying mechanism of action of GSZG on RANKL-induced osteoclastogenesis were investigated in vitro. The in vivo analyses demonstrated that the paw volume and degree of bone erosion of mice in the medium- and high-dose GSZG groups were significantly decreased compared to the CIA model group. In addition, GSZG treatment suppressed the excessive generation of osteoclasts in the bone tissue of CIA mice. In vitro , GSZG inhibited RANKL-induced osteoclastogenesis and osteoclast-mediated bone resorption. Specifically, it only inhibited the generation of osteoclast precursors (OCPs); it had no significant effect on the fusion of OCPs or maturation of osteoclasts. Finally, we showed that the inhibitory effect of GSZG on osteoclastogenesis was related to the promotion of PTEN-induced kinase protein 1 (PINK1)/Parkin pathway-mediated mitophagy of osteoclast precursors, which was verified using a PINK1 knockdown small interfering RNA in OCPs. These findings indicate that GSZG is a candidate for the treatment of bone destruction in RA and provide a more detailed elucidation of the mechanism of GSZG anti-RA bone erosion, i.e. , inhibition of the ROS/NF-κB axis through the PINK1/Parkin-mediated mitochondrial autophagic pathway to inhibit osteoclast precursor production, compared to the published literature. [Display omitted] [ABSTRACT FROM AUTHOR]

Soil organic carbon (SOC) sequestration effectively reduces global CO 2 emissions while ensuring crop production and sustainable agricultural development. Evaluating the effects of straw returning combined with controlled-release nitrogen (N) fertilizer on soil organic carbon (SOC) sequestration is necessary. We conducted a long-term (2013–2018) insitu field trial with six treatments: straw combined with no N and two N fertilizer types [no N fertilizer (CKS), conventional N fertilizer (BBFS) and controlled-release N fertilizer (CRFS)] and their corresponding no N and two N fertilizer treatments (CK, BBF, and CRF), each in three replicates. Overall, straw returning combined with N fertilizer (BBFS and CRFS) improves carbon storage and crop yield by changing aggregate distribution, with the effect of CRFS being more substantial. We further found CRFS treatment significantly increased SOC storage in small macro-aggregates (0.25–2 mm) by 9.2% and 28.4%, respectively, compared to BBFS and CKS treatments, which is mainly due to CRFS treatment increasing the proportion of small macro-aggregates (0.25–2 mm) by 8.1% and 20.1%, respectively, in contrast with BBFS and CKS treatments. Compared to BBFS and CKS treatments, CRFS treatment increased the fluorescence intensity of hydrophobic compounds in humic acid (HA) by 45.0% and 107.6%, respectively. Similarly, in small macro-aggregates (0.2–2.5 mm), CRFS treatment significantly increased the fluorescence intensity of hydrophobic compounds in HA. Lastly, structural equation modeling showed that straw returning treatments promote aggregate formation and carbon sequestration by increasing the fluorescence intensity of hydrophobic compounds in HA, ultimately increasing crop yield. Therefore, CRFS treatment is theoretically an effective method to promote SOC storage and increase crop yield and is a viable practice for sustainable agriculture. [Display omitted] • CRFS treatment enhanced C storage in small macro-aggregates. • In the CRFS treatment, the proportion of small macro-aggregate increased. • Appling CRFS treatment increased the fluorescence intensity of hydrophobic compounds. • CRFS treatment could increase crop yields by increasing organic carbon storage. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A modified drift-flux model was developed to predict “S-shape” relation of the overall gas holdup and gas velocity in JLR. • Gas–liquid co-injection mode results in larger gas holdup and liquid circulation velocity in comparison with gas jet alone mode. • Gas–liquid co-injection promotes the flow development. • JLR shows the largest liquid circulation compared with the BC and ALR. Abstract Hydrodynamics in an up flow jet-loop reactor (JLR) is experimentally investigated. The overall gas holdup, radial and axial distributions of local gas holdup and liquid velocity are presented. A modified drift-flux model was developed for correlating the “S-shape” relationship of overall gas holdup and gas velocity. Experiments show that the gas–liquid co-injection mode results in larger gas holdup and liquid circulation velocity than those of the gas jet alone mode. Liquid velocity distribution is more prone to reach the fully developed regime than the gas holdup, and the gas–liquid co-injection promotes the flow development. Comparison of JLR with the conventional bubble column (BC) and airlift reactor (ALR) shows that the JLR has a largest liquid circulation velocity, which is mostly beneficial to liquid mixing and solid suspension. [ABSTRACT FROM AUTHOR]

Aerogel with ultra-lightweight, special wettability and porous structure played a potential role in the separation of oil layer/water mixture. In this research cost-effective mesoporous three-dimensional (3D) aerogel was designed and fabricated through a simple and green hydrothermal, synthetic method as a sorbent for efficient treatment of emulsified oil. The -prepared grapefruit peel aerogel exhibits mesoporous structures (2–50 nm) with an average pore size/diameter of 10.21 nm, a surface area of 17.31 m2/g and pore volume up to 0.0321 cm3/g. Excellent hydrophobicity of DMS-MGA aerogel with a water contact angle of 143.1° depicting great potential of this material for effective separation of water-oil emulsion. Furthermore, the prepared aerogel displayed excellent regeneration capability of more than 98% after eight cycles of sorption–regeneration. The carbonization process destroyed graphite crystals, and a new peak confirmed the alteration. PDMS raised crystallinity indices to 86%. Raman spectroscopy also revealed two peaks at 1498 and 1588 cm−1 linked with carbon's D and G bands. The effective grafting of dimethyl siloxane on DMS-MGA surface resulted in two new strong bands in the FT-IR spectra at 1254 cm−1 (C-H in Si-CH 3) and 796 cm−1 (Si-O). TGA showed that the total carbon output was 28.5%, which is indicative of its good stability at elevated temperatures. DMS-MGA demonstrated near-complete sorption at a neutral pH of 7 of a crude oil-in-water emulsions. After 15 sorption-regeneration cycles, DMS-MGA still had a sorption efficiency of more than 95% despite being in contact with oil, and its anti-compression stability hadn't changed in the slightest. • Prepared grapefruit peel-modified aerogel (DMS-MGA) with superoleophilic/ hydrophobic properties. • Wettability of DMS-MGA was mostly due to its high porosity and (DMS) coating. • DMS-MGA was able to separate oil-water emulsions with an efficiency higher than 98%. • A green synthesis converts food waste into a novel adsorbent for environmental and oil-water cleanup. [ABSTRACT FROM AUTHOR]

Controlled-release nitrogen (CRN) fertilizers gradually release N in synchronization with root nutrient absorption, increasing wheat productivity and soil fertility. The role of the soil microbial community in wheat productivity and soil fertility, on the other hand, is unknown. Amplicon sequencing and a co-occurrence network were used in this study to investigate the role of microbial symbiosis in controlling wheat productivity and soil fertility in a 12-year (2008–2019) calcareous soil field experiment. Furthermore, the effects of various fertilization models were compared. The soil microbial community was divided into three closely coexisting symbiotic modules (Modules #1, 2, and 3). Module #1 and #2 were dominated by bacteria, while Module #3e was dominated by fungi. Modules #1 and #3 had higher network transmissibility (closeness centrality) and stability (degree) than Module #2, and they had a significant positive correlation with wheat productivity and soil fertility. Then, using random forests analysis, we examined the relationship between the module microorganism and wheat productivity and soil fertility. Module #1 microorganisms contributed more to wheat productivity and soil fertility than Module #3 microorganisms, and the microorganisms with significant relationships had a more complex composition (P < 0.05), primarily composed of Actinobacteria, Chloroflexi, Gemmatimonadetes, and Proteobacteria. Module #3, on the other hand, was primarily composed of Ascomycota. Finally, according to the structural equation model, CRN fertilizers could significantly improve wheat productivity and soil fertility when compared to soluble N (SN) fertilizers by increasing the diversity of the symbiotic module. In conclusion, our study discovered that Modules #1 and 3 are closely related to wheat productivity and soil fertility. The composition of module microorganisms, as well as the role of CRN fertilizer in symbiotic modules, were also investigated. [Display omitted] • Controlled-release nitrogen (CRN) fertilizer improved wheat productivity and soil fertility. • Long-term CRN fertilization altered soil microbial community structure. • Key symbiotic module significantly affected wheat productivity and soil fertility. • CRN increased the diversity of the key symbiotic module. [ABSTRACT FROM AUTHOR]

A novel phase inversion model was developed to describe the hydrodynamics in turbulent fluidized beds. The proposed model was coupled by a bubble–emulsion two phase model and a gas–cluster two phase model, which was derived from the typical mesoscale structures of two coexisting regions in turbulent fluidized beds. In the dense, bubbling region, the bubble-based interphase forces were used, while in the dilute, dispersed region, the cluster-based interphase forces were developed. The criterion of phase inversion, namely bubble-to-gas, emulsion-to-cluster, or vice versa, was also proposed and tested. Simulation results were compared with experimental data under different conditions to validate the model. The interphase forces acting on bubble or cluster were analyzed to study the radial nonuniformity of solid volume fraction. A coarse grid was utilized in this model, showing more capacity for the industrial scale-ups. [ABSTRACT FROM AUTHOR]

Enolase is a highly conserved enzyme that presents in all organisms capable of glycolysis or fermentation. Its immediate product phosphoenolpyruvate is essential for other important processes like peptidoglycan synthesis and the phosphotransferase system in bacteria. Therefore, enolase inhibitors are of great interest. Here, we report that Gp60, a phage-encoded enolase inhibitor protein (PEIP) of bacteriophage SPO1 for Bacillus subtilis , is an enolase inhibitor. PEIP-expressing bacteria exhibit growth attenuation, thinner cell walls, and safranin color in Gram staining owing to impaired peptidoglycan synthesis. We solve the structure of PEIP-enolase tetramer and show that PEIP disassembles enolase by disrupting the basic dimer unit. The structure reveals that PEIP does not compete for substrate binding but induces a cascade of conformational changes that limit accessibility to the enolase catalytic site. This phage-inspired disassembly of enolase represents an alternative strategy for the development of anti-microbial drugs. [Display omitted] • Bacillus subtilis phage SPO1 encodes a bacteriophage enolase inhibitor protein (PEIP) • PEIP disrupts host glycolysis and cell wall synthesis • PEIP inhibits host enolase by dissembling the enolase octamer • PEIP is a cross-species bacterial enolase inhibitor Zhang and Li et al. show that bacteriophage SPO1 encodes a xenogeneic enolase inhibitor PEIP, which impedes host glycolysis and cell wall synthesis by disrupting the basic dimer unit of enolase. PEIP has a strong cross-species inhibitory effect on bacterial enolase and a much weaker effect on human ENO1. [ABSTRACT FROM AUTHOR]

Evaluation of the effectiveness of best management practices for reducing nitrate leaching in agricultural systems requires detailed water and nitrogen (N) budgets. A 3-year field experiment using 15 auto-weighing lysimeters was set up to quantify nitrate leaching, crop evapotranspiration (ET), and N and water use efficiencies within an intensive wheat-maize rotation system in the Northern China Plain. The lysimeter consists mainly of the following: (1) high-resolution weighing cells; (2) ceramic solution samplers for soil solutions collection; and (3) circular stainless steel leaching trays for collecting seepage water. Two N fertilizer types were applied at two rates (150 and 225 kg N hm−2 for each crop) with no-N applied as the control. The N fertilizer types were monotypic un-coated urea and a blend product with controlled-release urea (CRU) and un-coated urea. The results indicate that when compared with un-coated urea at the same application rate, the blend product greatly improved water and N use efficiencies with significant increase in yields and crop ET as well as reduction of nitrate accumulation and leaching in the soil profile (p < 0.05). This was mostly because the blend product consistently supplied N to meet crop demands over the entire growth season. The study implied that effective best management practices to control nitrate leaching should be based on technically sound fertilization and irrigation schemes in terms of timing, rate, and fertilizer type to suit site specific conditions. Image 1 • Fifteen high-resolution lysimeters were used to develop water and nitrogen budgets. • Nitrogen and water use efficiency of two fertilization methods were compared. • Blending controlled-release urea and uncoated urea reduced nitrate leaching. [ABSTRACT FROM AUTHOR]

Synaptotagmins constitute a family of multifunctional integral membrane proteins found predominantly on vesicles in neural and endocrine tissues. 17 isoforms of synaptotagmin family in mammals have been identified, 7 isoforms among them are known to be able to bind Ca 2+ via their C2 domains. This study presents the crystal structure of the first C2 domain (C2A domain) of synaptotagmin 5 complexed with Ca 2+ at 1.90 Å resolution. Comparison of the Ca 2+ -binding pocket of synaptotagmin 5 C2A domain with other synaptotagmin C2 domains demonstrated that a serine residue locating at Ca 2+ -binding loop probably responsible to the conformational variation of Ca 2+ -binding pocket, and thus impacts the Ca 2+ -binding mechanism of C2 domain, which is verified by structural analysis of the serine mutant and Ca 2+ -binding assays via isothermal titration calorimetry. Alteration of Ca 2+ -binding mechanism might be correlated with different Ca 2+ response rates of synaptotagmins, which is the basis of the functions of synaptotagmins in regulating various types of Ca 2+ -triggered vesicle-membrane fusion processes. [ABSTRACT FROM AUTHOR]

It has been reported that tumor growth and proliferation correspond to mitochondrial dysfunction and that the tumor cellular microenvironment plays a key role in tumor progression, representing an area that might be manipulated to confer therapeutic anti-tumor benefits. In this article, we have identified mitochondrial genes, largely nuclear-encoded genes, which are differentially expressed in breast cancer epithelial and stromal cells compared to cells from normal breast tissues. We determined that gene expression of the mitochondrial membrane respiratory chain complex I and IV and ATP synthesis were reduced in both in epithelial and stromal cancer cells compared to normal breast cells. We also found transport-related genes were significantly more highly expressed in breast cancer epithelial cells. Our data also suggest that mitochondria are likely to proliferate in breast cancer stromal cells, which is supported by the observation that MRPL12, POLG, and RNASEH1 are all up-regulated in cancerous stromal cells. In addition, we present an improved simulated annealing algorithm, SANetWalker, which can be used to detect the functional module. At the same time, this method has a minimal effect on network topology and can be used to identify the highest confidence functional module. Using SANetWalker, we obtained the highest confidence (90%) functional module with a fumarate hydratase (FH)-centered network with 40 nodes and 107 edges. Functional analysis revealed that glutamine metabolism genes were significantly up-regulated in both epithelial and stromal cells from breast cancer tissues, which implicates glutamine metabolism in breast cancer growth and metastasis. [ABSTRACT FROM AUTHOR]

Summary Histone chaperones are critical for guiding specific post-transcriptional modifications of histones, safeguarding the histone deposition (or disassociation) of nucleosome (dis)assembly, and regulating chromatin structures to change gene activities. HAT1-interacting factor 1 (Hif1) has been reported to be an H3-H4 chaperone and to be involved in telomeric silencing and nucleosome (dis)assembly. However, the structural basis for the interaction of Hif1 with histones remains unknown. Here, we report the complex structure of Hif1 binding to H2A-H2B for uncovering the chaperone specificities of Hif1 on binding to both the H2A-H2B dimer and the H3-H4 tetramer. Our findings reveal that Hif1 interacts with the H2A-H2B dimer and the H3-H4 tetramer via distinct mechanisms, suggesting that Hif1 is a pivotal scaffold on alternate binding of H2A-H2B and H3-H4. These specificities are conserved features of the Sim3-Hif1-NASP interrupted tetratricopeptide repeat proteins, which provide clues for investigating their potential roles in nucleosome (dis)assembly. [ABSTRACT FROM AUTHOR]

Cardiac fibrosis is a common precursor of ventricular dysfunction and heart failure. We investigated the role of oxidative stress in myocardial fibrosis and the protective effect of panaxatriol saponin (PTS) against myocardial infarction (MI)-induced cardiac fibrosis and explored the underlying mechanisms. In vitro , cell viability was tested using a cell counting kit. The reactive oxygen species (ROS) levels including hydrogen peroxide (H 2 O 2) and superoxide anion (O 2 •−) were determined. Antioxidant enzyme levels were determined by immunofluorescence and Western blotting. Enzyme-linked immunosorbent assays, echocardiography, histological analysis, immunofluorescence staining, and molecular analysis were performed. Nuclear factor erythroid 2–related factor 2 (Nrf2) activation was evaluated by molecular docking and immunoprecipitation. Finally, the mechanism by which PTS inhibits cardiac fibrosis was investigated using the Nrf2 activator ML334 and a small interfering RNA for Nrf2. Ang II-induced differentiation of cardiac fibroblasts was associated with oxidative stress, characterized by upregulation of α-smooth muscle actin, increased reactive oxygen species production, and inhibition of superoxide dismutase-1 and heme oxygenase expression. In addition, PTS improved cardiac function and ameliorated cardiac fibrosis in MI rats. It also reduced Ang II-induced fibroblast differentiation and proliferation, suppressed oxidative stress, and disrupted the Kelch-like ECH-associated protein 1 (Keap1)–Nrf2 interaction by directly blocking the Nrf2 binding site in Keap1. Overexpression of Nrf2 by ML334 enhanced the antifibrotic effect of PTS. However, genetic ablation of Nrf2 abrogated the antifibrotic effect of PTS in cardiac fibrosis. Taken together, our findings suggest that Nrf2 has promise as a target and PTS as a therapeutic agent for cardiac fibrosis. [Display omitted] • Ang II-induced differentiation of cardiac fibroblasts is associated with enhanced oxidative stress. • PTS is an antioxidant that attenuates Ang II-induced oxidative stress in cardiac fibroblasts. • PTS disrupts the interaction between Nrf2 with Keap1 by binging with the Kelch domain of Keap1. • The antifibrotic effect of PTS depends on its antioxidant activity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Surface spectroscopy reveals the role of hydroxyl groups in the oxidation of aldehyde groups in aqueous phase. • The isotope distinguishes the role of active oxygen species in furfural oxidation. • Experiments were designed to verify the cyclic law of hydroxyl and active oxygen species. • The mechanism of furfural oxidation to furoic acid under base-free conditions was proposed and verified. δ-MnO 2 shows potential application in furfural base-free oxidation to furoic acid. While, its catalytic mechanism was unclear, which limited the further improvement of the catalytic activity. Therefore, three δ crystal MnO 2 with different hydroxyl and active oxygen species concentrations were prepared and applied in the furfural oxidation reaction. IR, Furfural-IR, O 2 -TPD, H 2 O-18O 2 -TPD, and XPS techniques characterized the hydroxyl and active oxygen species. The results show that the hydroxyl group on δ-MnO 2 is important in absorbing and attacking furfural to form geminal diol intermediate. Moreover, two types of oxygen species O -OH and O ads originating from the surface hydroxyl and the strongly adsorbed gas-phase O 2 , respectively, play an essential role in defhydrogenating geminal diol to furoic acid. Most importantly, the hydroxyl, O -OH , and O ads consumed on δ-MnO 2 can be reconstructed under reaction conditions. Among the three δ crystal MnO 2 , δ-MnO 2 , with the most abundant hydroxyl and active oxygen species, exhibited the best catalytic performance with 99.53% furfural conversion and nearly 100% furoic acid selectivity. This work identifies the function of hydroxyl and active oxygen species on δ-MnO 2 in furfural oxidation reaction, guiding the design of a non-noble metal catalyst for furoic acid synthesis under base-free conditions. [ABSTRACT FROM AUTHOR]

Nucleation and growth of droplets onto seed particles and subsequent solidification is an emerging technique for fabrication of complex colloids with controlled particle morphology and chemical makeup. The technique is often implemented at or near equilibrium, where the final composite particle structure is determined by the equilibrium contact angles of the droplets on the seed particles. Here, we apply the technique out of equilibrium, utilizing the rich and intriguing morphologies emerged as a droplet is triggered to dewet on a rod along the free energy minimization pathway. Specifically, 3-trimethoxysilyl propyl methacrylate (TPM) droplets were nucleated and grown onto silica rods. Upon dewetting, the droplets undergo a series of morphology changes, starting from engulfing the rods, contracting to the center, moving sideways to finally being fully separated from the rods. Composite patchy particles of controlled configurations were achieved by stimulating a fast photopolymerization of the TPM droplets at desired stages of the morphology evolution. Through seed surface functionalization, the patches can be decorated by either the hydroxyl or the amine group, which are used to create fluorescently-patterned patchy particles. Combining with surface evolver simulations, we demonstrate that nonequilibrium solidification of droplets on rods can be used to synthesize two-patch particles with a larger range of control over the patch size than its equilibrium counterpart. Image 1 • Non-equilibrium solidification is applied to synthesize two-patch anisotropic colloidal particles. • The nonequilibrium method offers a wider range of control over the patch size than the prevailing equilibrium counterpart. • Patchy particles with controlled fluorescent patterns are created by selectively labelling different parts of the particles. [ABSTRACT FROM AUTHOR]

Bi 5 O 7 I belongs to the family of bismuth oxyhalides (BiOX, X = Cl, Br, I), having a unique layered structure with an internal electrostatic field that promotes the separation and transfer of photo-generated charge carriers. Interestingly, Bi 5 O 7 I exhibits higher thermal stability compared to its other BiOX member compounds and absorption spectrum extended to the visible region. Bi 5 O 7 I has demonstrated applications in diverse fields such as photocatalytic degradation of various organic pollutants, marine antifouling, etc. Unfortunately, owing to its wide band gap of ∼2.9 eV, its absorption lies mainly in the ultraviolet region, and a tiny portion of absorption lies in the visible region. Due to limited absorption, the photocatalytic performance of pure Bi 5 O 7 I is still facing challenges. In order to reduce the band gap and increase the light absorption capability of Bi 5 O 7 I, doping and formation of heterostructure strategies have been employed, which showed promising results in the photocatalytic performance. In addition, the plasmonic heterostructures of Bi 5 O 7 I were also developed to further boost the efficiency of Bi 5 O 7 I as a photocatalyst. Here, in this review article, we present such recent efforts made for the advanced development of Bi 5 O 7 I regarding its synthesis, properties and applications. The strategies for photocatalytic performance enhancement have been discussed in detail. Moreover, in the conclusion section, we have presented the current challenges and discussed possible prospective developments in this field. [Display omitted] • Recent progress in Bi 5 O 7 I-based nanocomposites for degradation of organic pollutants. • Synthesis, properties, and photocatalytic applications of Bi 5 O 7 I. • Unique strategies for enhancing photocatalytic performance. • Current challenges, concluding remarks and prospective developments in this field. [ABSTRACT FROM AUTHOR]

Abstract: Snake venom metalloproteinases (SVMPs) mainly distribute in Crotalid and Viperid snake venom and are classified into the Reprolysin subfamily of the M12 family of metalloproteinases. Previous function investigations have suggested that SVMPs are the key toxins involved in a variety of snake venom-induced pathogenesis including systemic injury, local damage, hemorrhage, edema, hypotension, hypovolemia, inflammation and necrosis. However, up to now, there is no report on ion channels blocking activity about SVMPs. Here, from Trimeresurus stejnegeri venom we purified a component Stejnihagin containing a mixture of Stejnihagin-A and -B, with 86% sequences identity, both as members of SVMPs. In the study, whole-cell patch clamp and vessel tension measurement were employed to identify the effect of Stejnihagin on L-type Ca2+ channels and vessel contraction. The results show that Stejnihagin inhibited L-type Ca2+channels in A7r5 cells with an IC50 about 37nM and simultaneously blocked 60mM K+-induced vessel contraction. Besides, the inhibitory effect of Stejnihagin on L-type Ca2+ channels was also independent of the enzymatic activity. This finding offers new insight into the snake venom metalloproteinase functions and provides a novel pathogenesis of T. stejnegeri venom. Furthermore, it may also provide a clue to study the structure–function relationship of animal toxins and voltage-gated Ca2+ channel. [Copyright &y& Elsevier]

Summary: The Spt4-Spt5 complex is an essential RNA polymerase II elongation factor found in all eukaryotes and important for gene regulation. We report here the crystal structure of Saccharomyces cerevisiae Spt4 bound to the NGN domain of Spt5. This structure reveals that Spt4-Spt5 binding is governed by an acid-dipole interaction between Spt5 and Spt4. Mutations that disrupt this interaction disrupt the complex. Residues forming this pivotal interaction are conserved in the archaeal homologs of Spt4 and Spt5, which we show also form a complex. Even though bacteria lack a Spt4 homolog, the NGN domains of Spt5 and its bacterial homologs are structurally similar. Spt4 is located at a position that may help to maintain the functional conformation of the following KOW domains in Spt5. This structural and evolutionary perspective of the Spt4-Spt5 complex and its homologs suggest that it is an ancient, core component of the transcription elongation machinery. [Copyright &y& Elsevier]

Rheumatoid arthritis (RA) is a known intractable chronic inflammatory disease of synovial joints characterized by hyperplasia and consecutive inflammation with a high prevalence. Guizhi-Shaoyao-Zhimu (GSZD) is the first choice for clinical treatment of RA in Chinese traditional medicine. This study is aimed to explore the possible pharmacological mechanisms of anti-arthritic effect of GSZD. Type II collagen-induced arthritis (CIA) rat model was used to study the anti-arthritic activity of GSZD in vivo , and toe swelling & arthritis score, serum levels of cytokines, and pathological examinations were carried out. In vitro , TNF-α induced MH7A cells were used to study the possible mechanisms of GSZD. The anti-proliferative effects of GSZD were determined by MMT assay, and pro-apoptotic activity of GSZD in MH7A cells was determined by flow cytometry analysis & DAPI staining. Furthermore, the adhesive and invasive abilities of MH7A cells were determined using cell adhesion and transwell assays. MMPs levels were determined by ELISA assays, and mRNA expressions of Caspase-3, -9, Bax, SOCS1, Bcl-2, JAK2, STAT-3 and -5 were determined using qRT-PCR analysis. Besides, the major chemical components in GSZD were analyzed by HPLC-QqQ-MS analysis. Our results showed GSZD reduced the toe swelling & arthritis score, and serum levels of TNF-α, IL-1β, IL-6 & IL-17a in CIA rats; pathological examination results indicated GSZD improved ankle joint injury in CIA rats. In vitro , GSZD showed significant anti-proliferative and pro-apoptotic effects on TNF-α stimulated MH7A cells. After GSZD treatment, the adhesive and invasive abilities of MH7A cells were reduced, and secretions of MMPs, IL-6 and IL-8 were also reduced. GSZD decreased the releases of TNF-α and IL-1β in LPS stimulated RAW 264.7 cells. Further studies showed GSZD up-regulated mRNA expressions of Caspase-3, -9, Bax, and SOCS1, whereas down-regulated mRNA expressions of Bcl-2, JAK2, STAT3 and STAT5. Besides, 13 major chemical components were identified in GSZD extracts through HPLC-QqQ-MS analysis. Our results suggested GSZD possesses an anti-rheumatic effect on CIA rats, and the possible mechanism is related to inhibiting inflammatory response, inhibiting invasion and migration of synovial fibroblasts, and inducing apoptosis in synovial fibroblasts. [ABSTRACT FROM AUTHOR]