Renoprotective effects of Schoenoplectus tabernaemontani rhizomes aqueous extracts against Adriamycin-induced nephropathy in rats.

In recent years, chronic kidney disease (CKD) has emerged as an increasingly significant issue due to the growing prevalence and high treatment costs. While recorded the positive diuretic effect of Schoenoplectus tabernaemontani, there is a lack of reports on its efficacy in treating CKD. The pharmacological effects and mechanisms of Schoenoplectus tabernaemontani rhizomes aqueous extracts (STE) in CKD were investigated by inducing a rodent model of CKD via injection of Adriamycin (ADR; 7.5 mg/kg) into the tail vein of Wistar rats. In summary, our findings suggest that STE has a beneficial effect on anti-renal fibrosis and can reverse ADR-induced renal injury by suppressing oxidative stress and inflammation. Therefore, STE holds promising potential as a treatment option for CKD.

Discovery of Novel Cholinesterase Inhibitors Easily Crossing the Blood-Brain Barrier via Structure-Property Relationship Investigation: Methylenedioxy-Cinnamicamide Containing Tertiary Amine Side Chain.

In the present investigation, a series of dimethoxy or methylenedioxy substituted-cinnamamide derivatives containing tertiary amine moiety (N. N-Dimethyl, N, N-diethyl, Pyrrolidine, Piperidine, Morpholine) were synthesized and evaluated for cholinesterase inhibition and blood-brain barrier (BBB) permeability. Although their chemical structures are similar, their biological activities exhibit diversity. The results showed that all compounds except for those containing morpholine group exhibited moderate to potent acetylcholinesterase inhibition. Preliminary screening of BBB permeability shows that methylenedioxy substituted compounds have better brain permeability than the others. Compound 10c, containing methylenedioxy and pyrrolidine side chain, showed a better acetylcholinesterase inhibition (IC50: 1.52±0.19 µmol/L) and good blood-brain barrier permeability. Further pharmacokinetic investigation of compound 10c using ultra high performance liquid chromatography-mass/mass spectrometry (UPLC-MS/MS) in mice showed that compound 10c in brain tissue reached its peak concentration (857.72±93.56 ng/g) after dosing 30 min. Its half-life in the serum is 331 min (5.52 h), and the CBrain/CSerum at various sampling points is ranged from 1.65 to 4.71(Mean: 2.76) within 24 hours. This investigation provides valuable information on the chemistry and pharmacological diversity of cinnamic acid derivatives and may be beneficial for the discovery of central nervous system drugs.

Discovery and Biosynthetic Studies of a Highly Reduced Cinnamoyl Lipid, Tripmycin A, from an Endophytic Streptomyces sp.

A Tripterygium wilfordii endophyte, Streptomyces sp. CB04723, was shown to produce an unusually highly reduced cytotoxic cinnamoyl lipid, tripmycin A (1). Structure-activity relationship studies revealed that both the cinnamyl moiety and the saturated fatty acid side chain are indispensable to the over 400-fold cytotoxicity improvement of 1 against the triple-negative breast cancer cell line MDA-MB-231 compared to 5-(2-methylphenyl)-4-pentenoic acid (2). Bioinformatical analysis, gene inactivation, and overexpression revealed that Hxs15 most likely acted as an enoyl reductase and was involved with the side chain reduction of 1, which provides a new insight into the biosynthesis of cinnamoyl lipids.

Design, synthesis and the evaluation of cholinesterase inhibition and blood-brain permeability of daidzein derivatives or analogs.

In the present study, a series of derivatives and analogs of daidzein were designed and synthesized to investigate cholinesterase inhibition and blood-brain barrier permeability. The enzyme assay showed that most of the compounds containing a tertiary amine group exhibit moderate cholinesterase inhibition, 7-hydroxychromone derivatives (absence of B ring of daidzein scaffold) only have a weaker bioactivity, while those compounds without the tertiary amine group have no bioactivity. Among them compound 15a (4'-N,N-dimethylaminoethoxy-7-methoxyisoflavone) appeared the best inhibitory activity (IC50 : 2.14 ± 0.31 µmol/L) and higher selectivity for AChE over BuChE (Ratio: 7.07). It was selected for the further investigation by UPLC-MS/MS. The results show that CBrain/Serum of compound 15a in mice was more than 2.87 within 240 min. This discovery may provide worthy information for the future development of central nervous drugs including but not limited to cholinesterase inhibitors.

Diaporpyrone E, an undescribed α-pyrone from the endophytic fungus Diaporthe sp. CB10100.

An undescribed α-pyrone diaporpyrone E (1), and three known nucleotides, 5'-O-acetyl uridine (2), 5'-O-acetyl thymidine (3), and adenine (4), were identified from Diaporthe sp. CB10100, an endophytic fungus isolated from the medicinal plant Sinomenium acutum. The structure of 1 was determined by extensive analysis of its HRMS, 1D and 2D NMR spectroscopic data, as well as electronic circular dichroism calculations and comparison. The in vitro cytotoxic and antibacterial assays of 1 revealed that it has a 30.2% inhibitory effect on HepG2 cells at 50 µM, while no antibacterial activities against Staphylococcus aureus and Klebsiella pneumoniae at 64 µg/mL.

The Isolation and Structure Elucidation of Spirotetronate Lobophorins A, B, and H8 from Streptomyces sp. CB09030 and Their Biosynthetic Gene Cluster.

Lobophorins (LOBs) are a growing family of spirotetronate natural products with significant cytotoxicity, anti-inflammatory, and antibacterial activities. Herein, we report the transwell-based discovery of Streptomyces sp. CB09030 from a panel of 16 in-house Streptomyces strains, which has significant anti-mycobacterial activity and produces LOB A (1), LOB B (2), and LOB H8 (3). Genome sequencing and bioinformatic analyses revealed the potential biosynthetic gene cluster (BGC) for 1-3, which is highly homologous with the reported BGCs for LOBs. However, the glycosyltransferase LobG1 in S. sp. CB09030 has certain point mutations compared to the reported LobG1. Finally, LOB analogue 4 (O-ß-D-kijanosyl-(1→17)-kijanolide) was obtained through an acid-catalyzed hydrolysis of 2. Compounds 1-4 showed different antibacterial activities against Mycobacterium smegmatis and Bacillus subtilis, which revealed the varying roles of different sugars in their antibacterial activities.

Degradation of mirubactin to multiple siderophores with varying Fe(III) chelation properties.

Three siderophores mirubactins B-D (4-6) were identified as the degradation products of previously isolated mirubactin (1). Their structures were revealed by HR-ESI-MS/MS, NMR analyses, and density functional calculations, among which 4 contains an unusual cyclic amidine functionality. Cyclic voltammetry showed that 5 and 6 have reduced iron complexing capacity. Mirubactin (1) and Fe(III) could also form a stable complex, which may be an ingenious approach to compete for iron acquisition by the producing organisms.

Disrupting the TRIB3-SQSTM1 interaction reduces liver fibrosis by restoring autophagy and suppressing exosome-mediated HSC activation.

Impaired macroautophagy/autophagy is involved in the pathogenesis of hepatic fibrosis. However, how aberrant autophagy promotes fibrosis is far from understood. Here, we aimed to define a previously unrevealed pro-fibrotic mechanism for the stress protein TRIB3 (tribbles pseudokinase 3)-mediated autophagy dysfunction. Human fibrotic liver tissues were obtained from patients with cirrhosis who underwent an open surgical repair process. The functional implications of TRIB3 were evaluated in mouse models of hepatic fibrosis induced by bile duct ligation (BDL) or thioacetamide (TAA) injection. Human fibrotic liver tissues expressed higher levels of TRIB3 and selective autophagic receptor SQSTM1/p62 (sequestosome 1) than nonfibrotic tissues and the elevated expression of TRIB3 and SQSTM1 was positively correlated in the fibrotic tissues. Silencing Trib3 protected against experimentally induced hepatic fibrosis, accompanied by restored autophagy activity in fibrotic liver tissues. Furthermore, TRIB3 interacted with SQSTM1 and hindered its binding to MAP1LC3/LC3, which caused the accumulation of SQSTM1 aggregates and obstructed autophagic flux. The TRIB3-mediated autophagy impairment not only suppressed autophagic degradation of late endosomes but also promoted hepatocellular secretion of INHBA/Activin A-enriched exosomes which caused migration, proliferation and activation of hepatic stellate cells (HSCs), the effector cells of liver fibrosis. Disrupting the TRIB3-SQSTM1 interaction with a specific helical peptide exerted potent protective effects against hepatic fibrosis by restoring autophagic flux in hepatocytes and HSCs. Together, stress-elevated TRIB3 expression promotes hepatic fibrosis by interacting with SQSTM1 and interfering with its functions in liver-parenchymal cells and activating HSCs. Targeting this interaction is a promising strategy for treating fibroproliferative liver diseases.Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; ACTA2/α-SMA: actin, alpha 2, smooth muscle, aorta; BDL: bile duct ligation; BECN1/Beclin 1: beclin 1, autophagy related; CHX: cycloheximide; CQ: chloroquine; Edu: 5-ethynyl-2-deoxyuridine; ESCRT: endosomal sorting complexes required for transport; HSC: hepatic stellate cell; ILV: intralumenal vesicle; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MVB: multivesicular body; PIK3C3: phosphatidylinositol 3-kinase, catalytic subunit type 3; PPI: protein-protein interaction; SQSTM1/p62: sequestosome 1; TAA: thioacetamide; TEM: transmission electron microscopy; TGFB1/TGFß1: transforming growth factor, beta 1; TLR2: toll-like receptor 2; TRIB3: tribbles pseudokinase 3.

[Observation on therapeutic effect of "Tiaoren Tongdu acupuncture" on premature ovarian insufficiency of kidney deficiency].

OBJECTIVE: To observe the clinical efficacy of "Tiaoren Tongdu acupuncture" and oral estradiol and dydrogesterone tablets (femoston) on premature ovarian insufficiency of kidney deficiency. METHODS: A total of 50 patients with premature ovarian insufficiency of kidney deficiency were randomized into an observation group and a control group, 25 cases in each one.In the observation group, "Tiaoren Tongdu acupuncture" was applied at Baihui (GV 20), Zhongwan (CV 12), Guanyuan (CV 4), Qihai (CV 6), Zhongji (CV 3), Yaoyangguan (GV 3), Yaoshu (GV 2), Mingmen (GV 4), etc. once every 2 days, 1 month as a course. In the control group, femoston was prescribed for oral administration, one tablet per time, once a day, 1 month as a course. Both of the two groups were given consecutive treatment for 3 courses. Before and after treatment, the clinical symptoms, menstrual improvement as well as the changes of estradiol (E2), luteotrophic hormone (LH) and follicle-stimulating hormone (FSH) in serum were observed in the two groups. RESULTS: After treatment, the clinical symptoms and menstrual conditions were improved (P<0.01), the levels of FSH and LH were significantly reduced (P<0.01), and the levels of E2 were significantly increased in the two groups (P<0.01). There were no significant difference in menstrual improvement rate and menstrual improvement time between the observation group and the control group (P<0.05), the recurrence rate of menopause and clinical symptom score improvement in the observation group were superior to the control group (P<0.05). In the observation group, the level of E2 in serum was lower and the levels of FSH and LH in serum were significantly lower than those in the control group (P<0.05, P<0.01). In the observation group, the rate of adverse reaction was 4.0% (1/25), which was lower than 36.0% (9/25) in the control group (P<0.05). CONCLUSION: "Tiaoren Tongdu acupuncture" has better therapeutic effect for premature ovarian insufficiency of kidney deficiency. It is superior to femoston in improving clinical symptoms and recurrence rate of menopause as well as reducing the levels of FSH and LH.

Five macrocyclic glycosides from Schoenoplectus tabernaemontani.

Macrocyclic glycosides with unique 22-membered dimeric lactone skeleton, are rare occurring natural products. There are only ten compounds reported so far. Herein we reported the isolation and characterisation of five macrocyclic glycosides from Schoenoplectus tabernaemontani, including three new compounds (Schoenopolide A-C, 1-3) and two known ones, Berchemolide (4) and Clemoarmanoside B (5). Their structures were established on the basis of extensive analysis of spectroscopic data. In addition, the anti-oxidative activity of Berchemolide (4) against H2O2-induced of renal tubular epithelial (HK-2) cells was also evaluated.

Targeting HMGB1 ameliorates cardiac fibrosis through restoring TLR2-mediated autophagy suppression in myocardial fibroblasts.

BACKGROUND: Extracellular high-mobility group box 1 (HMGB1) has been identified as playing a critical role in the pathogenesis of tissue fibrosis. However, the underlying mechanism of its involvement in cardiac fibrosis is still not well-defined. Here, we aim to investigate whether toll-like receptor 2 (TLR2) contributes to the extracellular HMGB1-mediated development and progression of cardiac fibrosis. METHODS: A mouse model of cardiac fibrosis was induced by subcutaneous injection of isoproterenol (ISO). Glycyrrhizic acid (GA), an inhibitor of HMGB1 derived from natural products, was simultaneously administered by intraperitoneal injection. Echocardiography, H&E and Sirius red staining were used to evaluate cardiac function and fibrosis. The myocardial expression of autophagy-associated proteins was examined using immunoblotting. Cardiac fibroblasts were treated with different concentrations of HMGB1 to examine the expression levels of α-SMA, collagen I and autophagy markers. Interactions of HMGB1/TLR2 and α-SMA/p62 were examined by immunoprecipitation and immunofluorescence. RESULTS: ISO-treated mice showed characteristic cardiac fibrosis, increased expression and co-localization of HMGB1 and TLR2, as well as impaired autophagic signals in myocardial tissues, which could be prevented by silencing TLR2. Exogenous administration of HMGB1 blocked the autophagic flux in fibroblasts, which caused extensive accumulation of collagen I and α-SMA. In addition, cardiac fibrosis was alleviated by GA treatment through abrogating the interaction between HMGB1 and TLR2. CONCLUSIONS: Our study suggests that the interaction between TLR2 and HMGB1 contributes to the pathogenesis of cardiac fibrosis via suppressing fibroblast autophagy, and that inhibiting HMGB1 with GA provides therapeutic benefits for the treatment of fibroproliferative heart diseases.

The chemical diversity and structure-based evolution of non-peptide CXCR4 antagonists with diverse therapeutic potential.

The CXC chemokine receptor 4 (CXCR4) is a highly reserved G-protein coupled 7-transmembrane (TM) chemokine receptor which consists of 352 amino acids. CXCR4 has only one endogenous chemokine ligand of CXCL12, besides several other natural nonchemokine ligands such as extracellular ubiquitin and noncognate ligand of MIF. CXCR4 strongly binds to CXCL12 and the resulting CXCLl2/CXCR4 axis is the molecular basis of their various biological functions, which include: (1) mediating immune and inflammatory response; (2) regulation of hematopoietic stem cell migration and homing; (3) an essential co-receptor for HIV entry into host cells; (4) participation in the process of embryonic development; (5) malignant tumor invasion and metastasis; (6) myocardial infarction, ischemic stroke and acute kidney injury. Correspondingly, CXCR4 antagonists find potential therapeutic applications in HIV infection, as well as hematopoietic stem cell migration, inflammation, immune-related diseases, tumor and ischemic diseases. Recently, great achievements have been made and a number of non-peptide CXCR4 antagonists with diversity scaffolds have been discovered. In this review, the discovery of small molecule CXCR4 antagonists focused on the structures, activities, evolution and development of representative CXCR4 antagonists is comprehensively described. The central role of CXCR4 in diverse cellular signaling pathways and its involvement in several diseases progressions are discussed as well.

Evaluation of Adenosine Triphosphate-Binding Cassette Transporter A1 (ABCA1) R219K and C-Reactive Protein Gene (CRP) +1059G/C Gene Polymorphisms in Susceptibility to Coronary Heart Disease.

BACKGROUND This meta-analysis investigated the correlation of ABCA1 R219K and C-Reactive Protein Gene (CRP) +1059G/C gene polymorphisms with susceptibility to coronary heart disease (CHD). MATERIAL AND METHODS We searched PubMed, Springer link, Wiley, EBSCO, Ovid, Wanfang database, VIP database, and China National Knowledge Infrastructure (CNKI) databases to retrieve published studies by keyword. Searches were filtered using our stringent inclusion and exclusion criteria. Resultant high-quality data collected from the final selected studies were analyzed using Comprehensive Meta-analysis 2.0 software. Eleven case-control studies involving 3053 CHD patients and 3403 healthy controls met our inclusion criteria. Seven studies were conducted in Asian populations, 3 studies were done in Caucasian populations, and 1 was in an African population. RESULTS Our major finding was that ABCA1 R219K polymorphism increased susceptibility to CHD in allele model (OR=0.729, 95% CI=0.559~0.949, P=0.019) and dominant model (OR=0.698, 95% CI=0.507~0.961, P=0.027). By contrast, we were unable to find any significant association between the CRP +1059G/C polymorphism and susceptibility to CHD (allele model: OR=1.170, 95% CI=0.782~1.751, P=0.444; dominant model: OR=1.175, 95% CI=0.768~1.797, P=0.457). CONCLUSIONS This meta-analysis provides convincing evidence that polymorphism of ABCA1 R219K is associated with susceptibility to CHD while the CRP +1059G/C polymorphism appears to have no correlation with susceptibility to CHD.

A novel proteolysis-resistant cyclic helix B peptide ameliorates kidney ischemia reperfusion injury.

Helix B surface peptide (HBSP), derived from erythropoietin, displays powerful tissue protection during kidney ischemia reperfusion (IR) injury without erythropoietic side effects. We employed cyclization strategy for the first time, and synthesized thioether-cyclized helix B peptide (CHBP) to improve metabolic stability and renoprotective effect. LC-MS/MS analysis was adopted to examine the stability of CHBP in vitro and in vivo. The renoprotective effect of CHBP in terms of renal function, apoptosis, inflammation, extracellular matrix deposition, and histological injury was also detected in vivo and in vitro. Antibody array and western blot were performed to analyze the signal pathway of involvement by CHBP in the IR model and renal tubular epithelial cells. In this study, thioether-cyclized peptide was significantly stable in vivo and in vitro. One dose of 8nmol/kg CHBP administered intraperitoneally at the onset of reperfusion improved renal protection compared with three doses of 8nmol/kg linear HBSP in a 48h murine IR model. In a one-week model, the one dose CHBP-treated group exhibited remarkably improved renal function over the IR group, and attenuated kidney injury, including reduced inflammation and apoptosis. Interestingly, we found that the phosphorylation of autophagy protein mTORC1 was dramatically reduced upon CHBP treatment. We also demonstrated that CHBP induced autophagy via inhibition of mTORC1 and activation of mTORC2, leading to renoprotective effects on IR. Our results indicate that the novel metabolically stable CHBP is a promising therapeutic medicine for kidney IR injury treatment.

[Responses of winter wheat tillers at different positions to low temperature stress at stem elongation stage and their freezing resistance evaluation].

Taking two winter wheat cultivars Ji' nan 17 and Shannong 8355 as test materials, this paper measured the superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activities and the malondialdehyde (MDA) and soluble protein contents in the functional leaves and sheaths of the tillers at different positions at stem elongation stage under low temperature stress, and then, the freezing resistance of the tillers was comprehensively evaluated by the methods of principal component analysis and cluster analysis. The results showed that under low temperature stress, the SOD, POD, and CAT activities in the functional leaves and sheaths of each tiller at stem elongation stage increased, but the MDA and soluble protein contents increased or decreased to some extent. By using principal component analysis and cluster analysis, the tillers of each cultivar were grouped into three kinds of freezing resistance type. For Ji' nan 17, the main stem, tiller I, and tiller II belonged to high freezing resistance type, the tiller III, tiller IV, and tiller I p belonged to medium freezing resistance type, and the tiller II p belonged to low freezing resistance type. For Shannong 8355, the main stem, tiller I, tiller II, and tiller III belonged to high freezing resistance type, the tiller IV and tiller I p belonged to medium freezing resistance type, and the tiller II p belonged to low freezing resistance type. It was concluded that the freezing resistance of the winter wheat tillers at different positions at stem elongation stage differed, with the lower position tillers being more resistant than the higher position tillers.

Study strategies for acupuncture treatment of chronic nonbacterial prostatitis.

By retrospectively reviewing the current status of traditional Chinese medicine (TCM) and Western medicine treatments of chronic nonbacterial prostatitis (CNP), the TCM understanding of its etiologies and pathogenesis, the therapeutic principles and the mechanisms of acupuncture treatment of CNP, the clinical study strategies of acupuncture treatment for CNP were further proposed, which could provide more scientific basis and support for the definite longer-term therapeutic efficacy of acupuncture treatment of CNP. Breakthrough in the treatment of CNP will be achieved with the application of acupuncture therapy both in clinical practice and experimental research.

Research advances in treatment of cerebral ischemic injury by acupuncture of conception and governor vessels to promote nerve regeneration.

Cerebral ischemia is one of the most common diseases treated by acupuncture therapeutics. Recent studies indicated that acupuncture treatment by needling the conception and governor vessels had positive effects in promoting neural regeneration in patients after cerebral ischemia injury. Acupuncture intervention could continuously promote the proliferation and differentiation of the neural stem cells in the brain, obviously up-regulate expression of growth factors, accelerate angiogenesis and inhibit apoptosis. Hence, it is necessary to present an exhaustive review on the mechanisms. The present review gives a detailed description of pathological changes of cerebral ischemia and acupuncture intervention applied to the conception and governor vessels, and proposes research prospects in the future.

[Effects of planting density and spraying PP333 on winter wheat lodging-resistance and grain yield].

Taking two winter wheat varieties Gaocheng 8901 and Yannong 21 with different end-use qualities as test objects, a field experiment was conducted in the experimental farm of Shandong Agricultural University from 2008 to 2010, aimed to study the effects of different planting density and spraying PP333 on the basal stem morphological characteristics, snapping-resistance, lodging-resistant index, and grain yield. Gaocheng 8901 had higher lodging-resistance but lower grain yield than Yannong 21. Comparing with low planting density (180 x 10(4) basic seedlings per hm2), high planting density (240 x 10(4) basic seedlings per hm2) decreased the culm snapping-resistance and lodging-resistant index of the two varieties, especially Yannong 21. Spraying PP333 decreased the plant height and the basal internodes length, increased the snapping-resistance and lodging-resistant index, strengthened the lodging-resistance, and improved the spike number and grain yield. Correlation analysis showed that the second internode length, percentage of basal internodes (1 + 2) length to total internode length, and apparent lodging ratio were significantly negatively correlated with culm lodging resistant index. Therefore, to adopt an appropriate planting density combined with spraying PP333 could improve the lodging-resistance of winter wheat and its grain yield, being an important high-yielding cultivation technique for wheat production in sub-humid zone.

Study strategies for bloodletting therapy in treatment of acute soft tissue injuries.

Bloodletting therapy is one of the typical treatment modes of traditional Chinese medicine, and acute soft tissue injury (ASTI) is one of the most common indications for acupuncture therapeutics. In this paper, the current situation of treatments and pathological mechanisms of ASTIs, the existing problems of bloodletting therapy in the treatment of ASTIs and the study strategies are systematically analyzed, indicating that bloodletting therapy is significantly effective in the treatment of ASTIs. Breakthroughs in the treatment of ASTIs will be achieved with the application of bloodletting therapy both in clinical practice and experimental research.