Spatial Distribution and Risk Assessment of Antibiotics in 15 Pharmaceutical Plants in the Pearl River Delta.

Pharmaceutical plants are an essential source of antibiotics emitted into the aqueous environment. The monitoring of target antibiotics in pharmaceutical plants through various regions is vital to optimize contaminant release. The occurrence, distribution, removal, and ecological risk of 30 kinds of selected antibiotics in 15 pharmaceutical plants in the Pearl River Delta (PRD) were investigated in this study. Lincomycin (LIN) showed the highest concentration (up to 56,258.3 ng/L) in the pharmaceutical plant influents from Zhongshan city. Norfloxacin (NFX) showed a higher detection frequency than other antibiotics. In addition, the spatial distribution of antibiotics in pharmaceutical plants showed significant differences, with higher concentrations of total antibiotics found in pharmaceutical plant influents in Shenzhen City than those of different regions in PRD. The treatment processes adopted by pharmaceutical plants were commonly ineffective in removing antibiotics, with only 26.7% of antibiotics being effectively removed (average removal greater than 70%), while 55.6% of antibiotics had removal rates of below 60%. The anaerobic/anoxic/oxic (AAO)-membrane bioreactor (MBR) combined process exhibited better treatment performance than the single treatment process. Sulfamethoxazole (SMX), ofloxacin (OFL), erythromycin-H2O (ETM-H2O), sulfadiazine (SDZ), sulfamethazine (SMZ), norfloxacin (NFX), and ciprofloxacin (CIP) in pharmaceutical plant effluents posed high or moderate ecological risk and deserve particular attention.

A phase 2 study of sorafenib combined with conventional therapies in refractory central nervous system leukemia.

BACKGROUND: Patients with refractory central nervous system leukemia (CNSL) have a dismal prognosis and lack effective therapy. Case reports have shown that sorafenib is effective against brain metastases, including leukemia. METHODS: To explore the efficacy of sorafenib combined with conventional therapies for refractory CNSL, a phase 2 study was conducted. The primary end point was the complete remission rate (CRR) within 8 weeks of treatment. Secondary end points included the overall response rate (ORR), event-free survival (EFS), overall survival (OS), and adverse events (AEs). RESULTS: Twenty-six patients with refractory CNSL were enrolled; they included 17 with isolated CNSL, 7 with hematological relapse, and 2 with another extramedullary relapse. After 8 weeks of treatment, 21 patients achieved complete remission, 2 achieved partial remission, and 3 achieved no remission for a CRR of 80.8% (95% CI, 62.1%-91.5%) and an ORR of 88.5% (95% CI, 71.0%-96.0%). Twenty patients survived, and 6 died. The 2-year EFS and OS rates were 75.0% (95% CI, 54.5%-88.3%) and 76.9% (95% CI, 54.2%-90.4%), respectively. Six patients experienced grade 3 or 4 treatment-related AEs, including moderate chronic graft-vs-host disease (n = 3), grade 3 or 4 acute graft-vs-host disease (n = 2), and grade 3 skin rash (n = 1). No treatment-related deaths occurred during the therapy of refractory CNSL. CONCLUSIONS: Sorafenib combined with conventional therapies is effective and safe for refractory CNSL. LAY SUMMARY: Sorafenib combined with conventional therapies is effective and safe for refractory central nervous system leukemia.

The antiinflammatory effects of Xuefu Zhuyu decoction on C3H/HeJ mice with alopecia areata.

BACKGROUND: As a traditional and typical prescription of prominently activating blood circulation to remove blood stasis, Xuefu Zhuyu decoction (XZD) consists of 15 kinds of herbal medicine. Clinical investigations have showed that XZD could significantly promote the new hair generation of alopecia areata (AA) patients characterized by Qi stagnation and blood stasis. PURPOSE: The purpose of this study was executed to determine whether the mechanisms by which XZD stimulated newborn hair were related to its anti-inflammatory effects. METHODS: Clinical AA individuals were recruited to confirm the efficies of XZD. High performance liquid chromatography (HPLC) analysis was performed to qualitatively and quantitatively determine the contents of 15 compounds in XZD. Schrodinger molecular docking and in vivo surface plasmon resonance (SPR) techniques were used to evaluate the potential binding properties of compounds to target proteins. C3H/HeJ mice were randomly assigned to groups control, AA, and the XZD administration (6.5, 13.0 and 26.0 g/kg/d). Except for mice in control group, all the mice in the other groups were treated with a 21-day chronic unpredictable mild stress (CUMS) induced AA. Hematoxylin-eosin (H&E) staining was performed to determine the degree of pathological damage to the skin. Enzyme-linked immunosorbent assay (ELISA) was performed to detect levels of interleukin-6 (IL-6), interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) and in serum and skin tissues. Western blot, immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were used to examine the expression levels of IL-6, IL-1ß, TNF-α and osteopontin proteins and genes in skin tissues. RESULTS: XZD could visibly promote hair regeneration of AA patients. The potential active ingredients in XZD prescription included at least amygdalin, hydroxysafflor yellow A, kaempferide, ferulic acid, catalpol, verbascoside, ß-ecdysone, platycodin D, paeoniflorin, naringin, neohesperidin, liquiritin, glycyrrhizic acid, saikosaponin A and saikosaponin D. The results of molecular docking and SPR analysis showed that verbascoside, liquiritin, kaempferide and amygdalin showed the best potential binding properties with IL-6, IL-1ß, TNF-α and osteopontin, respectively. Pathological evaluation showed that compared with the CUMS group, the administration of XZD significantly promoted hair regeneration, evidenced by increased number of skin hair follicles in C3H/HeJ AA mice. Compared with control group, ELISA data showed that the levels of IL-6, IL-1ß and TNF-α in serum and skin tissues of CUMS induced AA mice were significantly increased, while XZD administration dramatically restrained the contents of the three pro-inflammatory factors. Western blot, immunohistochemistry, and qRT-PCR results further demonstrated that XZD administration notably down-regulated the protein and gene expression levels of osteopontin, IL-6, IL-1ß and TNF-α in comparation with CUMS group. CONCLUSION: XZD could dramatically ameliorate CUMS-induced AA damage in the skin of C3H/HeJ mice, possibly by suppressing the levels of IL-6, IL-1ß, TNF-α and osteopontin.

Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway.

Endocytosis is an essential component of cell motility, which facilitates the malignant behavior of cancer. Sorting nexin (SNX) family members are associated with tumor progression. However, the role and mechanism of SNX5 in hepatocellular carcinoma (HCC) progression remain largely unknown. In this study, we investigated the clinical significance and possible involvement of SNX5 in the progression of HCC. Here, we showed that SNX5 was upregulated in tumors compared with adjacent nontumorous tissues in HCC patients. The upregulation of SNX5 in HCC was associated with vascular invasion, intrahepatic metastasis, and poor prognosis. The overexpression of SNX5 promoted HCC cell proliferation, migration, invasion, and metastasis, whereas silencing SNX5 expression resulted in decreased cell proliferation, migration, and invasion. Knockdown of SNX5 significantly inhibited HCC cell proliferation by inducing G1/S transition arrest. Mechanistically, we demonstrated that SNX5 promoted cell proliferation, migration, and invasion via the activation of the EGFR-ERK1/2 pathway by blocking EGF-mediated EGFR internalization. We found that SNX5 interacted with EGFR in HCC cells. Moreover, SNX5-induced cell proliferation, migration, and invasion were partially reversed by the knockdown of EGFR or by ERK1/2 inhibitors. In addition, we demonstrated that SNX5 knockdown sensitized HCC cells to tyrosine kinase inhibitors, including erlotinib and sorafenib. Taken together, our results indicate that SNX5 promotes HCC cell proliferation and metastasis via inhibiting the endocytosis and degradation of EGFR, thereby activating the ERK1/2 signaling pathway. Our work also suggests that SNX5 is a potential therapeutic target for HCC.

Structural characterization and osteogenic bioactivities of a novel Humulus lupulus polysaccharide.

Humulus lupulus is a perennial climbing plant of the subfamily Cannabioideae native to the Northern Hemisphere. The primary use of H. lupulus is in the brewing industry, where it is an essential ingredient for imparting a unique flavor (bitterness and aroma) to beer. The female flowers of H. lupulus are also used in traditional Chinese medicine, but the biologically active ingredients underlying its benefits remain unclear. China is the largest producer and consumer of H. lupulus in Asia. Using the waste from the beer-brewing process of H. lupulus as raw materials, the biologically active polysaccharides can be screened. This is useful for the full utilization of H. lupulus, potentially leading to disease prevention and treatment. In this study, we isolated a homogeneous polysaccharide (HLP50-1) with a molecular weight of 49.13 kDa from female flowers of H. lupulus via a DEAE-Cellulose 52 anion exchange column and a Sephadex G-75 gel filtration column. Methylation, GC-MS, and NMR analyses revealed that the HLP50-1 comprised →4)-α-d-Glcp-(1→, →6)-α-d-Manp-(1→, →3)-α-l-Rhap-(1→, ß-d-Glcp-(1→, α-l-Araf-(1→, →4,6)-2-OAc-ß-d-Galp-(1→, ß-d-Galp-(1→, →3,6)-ß-d-Glcp-(1→, →2,3,4)-α-d-Xylp-(1→, →6)-α-d-Glcp-(1→, →3)-α-d-Galp-(1→, →4)-α-d-Galp-(1→. Advanced structural analysis showed that the HLP50-1 contained irregular fragments of different sizes and shapes with a smooth surface. The aggregates appeared be composed of accumulated crystals. Furthermore, the osteogenic activities of the HLP50-1 were evaluated via MC3T3-E1 cells in vitro. The results showed that 0.13 µM HLP50-1 led to outstanding proliferation, differentiation, and mineralization of the MC3T3-E1 cells. Therefore, HLP50-1 has osteogenic effects, and it may be a candidate for the treatment of osteoporosis. It has broad application prospects in functional foods, health-care products, and pharmaceuticals.

Screening Five Qi-Tonifying Herbs on M2 Phenotype Macrophages.

Tumor-associated macrophages (TAMs) with M2 phenotype play an essential role in tumor microenvironment (TME) during the progression and development of numerous cancers and associated with poor prognosis. Thus, regulation of TAMs polarization emerged as a new strategy for tumor immune therapy. According to Traditional Chinese Medicine (TCM) theory, herbs with Qi-tonifying character are involved in improving the defense capacity of immune system. In this study, we screened extracts and ingredients from five Qi-tonifying herbs exhibiting an inhibitory effect on M2 polarization of murine macrophages RAW264.7 induced by IL-4 and IL-13. Among these candidates, total flavonoids from Glycyrrhiza Radix et Rhizoma (TFRG) and ethanol extract of Ginseng Radix et Rhizoma significantly inhibited the expression of Arginase-1 (Arg-1) (above 90% at 100µg/mL), one of the phenotype markers of M2 macrophages. The inhibition of total saponins of Ginseng Radix et Rhizoma, ethanol extract of Cordyceps, ethanol extract of Acanthopanacis senticosi Radix et Rhizoma Seu caulis, and ethanol extract of Astragali Radix reached above 50% at 100µg/mL. The inhibition of ingredients including glabridin, isoliquiritin apioside, lysionotin, cordycepin, astragaloside IV, and calycosin reached above 50% at 50µM. Then, we investigated the molecular mechanisms of TFRG. TFRG abolished the migration of murine breast cancer 4T1 stimulated by the conditioned medium from M2 macrophages (M2-CM). In addition to Arg-1, TFRG also antagonized the IL-4/13-mediated mRNA upregulation of the M2 markers including found in inflammatory zone 1 (FIZZ1), chitinase-3-like protein 3 (YM1), and mannose receptor (CD206) and upregulated the expression of inducible nitric oxide synthase (iNOS), one of the M1 markers. The further exploration showed that TFRG decreased the phosphorylation of STAT6 and increased the expression of miR-155. Our study provides a series of potential immune regulating natural products from five Qi-tonifying herbs on M2 phenotype. For instance, TFRG suppressed M2 polarization of macrophages partly by inactivating STAT6 pathway and enhanced the level of miR-155 to regulate the expressions of M1 and M2 markers.

Structural identification and osteogenic activity of a novel heteropolysaccharide obtained from female flowers of Humulus lupulus.

Humulus lupulus is distributed mainly in Asia, Europe, and North America, and the flowers and infructescences are used worldwide in beer brewing as an essential flavoring ingredient. In China, the main producing areas are the Xinjiang Uygur Autonomous Region and Gansu provinces. The annual production of H. lupulus in China accounts for about 13% of worldwide production, ranking third after the United States and Germany. The female flower of H. lupulus also is used in traditional Chinese medicine, but the bioactive components responsible for its benefits remain unclear. In this study, we isolated a homogeneous polysaccharide (HLP50-2) from female flowers of H. lupulus via DEAE-52 cellulose and Sephadex G-75 gel filtration chromatography. The molecular weight was 73.25 kDa. Chemical methods, gas chromatography-mass spectrometry, and nuclear magnetic resonance analyses showed that HLP50-2 consisted of →4)-ß-d-GlcAp-(1→, →4)-α-l-Rhap-(1→, →5)-α-l-Araf-(1→, α-l-Araf-(1→, →3,6)-ß-d-Galp-(1→, α-d-Galp-(1→, →3,4,6)-ß-d-Galp-(1→, ß-d-Xylp-(1→, →6)-α-d-Galp-(1→, and →4)-ß-d-Galp-(1→. Advanced structural analysis indicated that HLP50-2 has a sheet-like structure with uneven distribution and the surface was smooth. In addition, we used MC3T3-E1 cells to evaluate the osteogenic activity of HLP50-2. The results show that HLP50-2 significantly promoted the proliferation, differentiation, and mineralization of MC3T3-E1 cells at concentrations of 12.5 µg mL-1 and 25 µg mL-1. In particular, at 25 µg mL-1, the promoting mineralization effect of HLP50-2 was better than that of the positive control, 17ß-estradiol, and the alkaline phosphatase activity after 10 d of treatment was comparable to that of the positive control. The extraction, isolation, purification, structural identification, and osteogenic activity of H. lupulus polysaccharides suggest that homogeneous polysaccharide HLP50-2 has pronounced anti-osteoporosis activity. Therefore, it has broad application prospects in pharmaceutical industries and health-care products.

Ethyl Acetate Fraction from Hedyotis diffusa plus Scutellaria barbata Exerts Anti-Inflammatory Effects by Regulating miR-155 Expression and JNK Signaling Pathway.

Hedyotis diffusa Willd and Scutellaria barbata D. Don (HDSB) were the core couplet in medicines that were commonly used for the purpose of anti-inflammation and anticancer treatments in China. However, biological properties of this couplet have not been fully elucidated. In this study, we screened fractions of HDSB for their anti-inflammatory activities and explored pertinent molecular mechanisms on murine macrophage RAW264.7 cell model. Ethyl acetate fraction from the aqueous extract of the couplet at equal weight ratio (EA11) showed the strongest inhibition of the nitrite accumulation in supernatant of RAW264.7 cells stimulated with lipopolysaccharide (LPS)/interferon-γ (IFN-γ). In addition, EA11 inhibited iNOS and IL-1ß expression in a concentration-dependent manner while promoting the expression of HO-1 and PPAR-γ. Anti-inflammatory capability is most likely facilitated by its inhibitory effect on JNK signaling pathway and miR-155 expression. This study suggests that EA11 may be represented as a potential anti-inflammatory therapeutic candidate.

A case report of chemo-sensitive intimal pulmonary artery sarcoma.

The incidence rate of pulmonary artery sarcoma is very low, but its prognosis is extremely poor. In this case report, after various initial diagnoses at the early stage, pulmonary artery sarcoma was confirmed by surgery. 1 year later, the tumor recurred. After chemotherapy, the patient showed improvement of the subjective complaint of tightness in the chest, and radiological lesion decreased in size. The survival time was extended by 2.5 years. This is the first case report of pulmonary artery sarcoma with such chemo-sensitivity.

Analysis of bilirubin UDP-glucuronosyltransferase gene mutations in an unusual Crigler-Najjar syndrome patient.

Crigler-Najjar (CN) syndrome is a rare autosomal recessive inherited disorder characterized by non-hemolytic, unconjugated hyperbilirubinemia. The levels of serum bilirubin and the response to phenobarbital treatment have been used to classify CN syndrome into two types: CN I and II. Mutations of the UGT1A1 gene have been found to be responsible for cases of CN syndrome. In the present study, the clinical features of a boy with an unusual type of CN syndrome were analysed. A DNA sample was obtained from the patient, and the promoter region, the exons and flanking intronic sequences of the UGT1A1 gene were analysed using the polymerase chain reaction and sequencing. The case was similar to CN type I in clinical features, but the therapeutic efficacy in the patient was superior to that typically observed in CN type II disease. Sequencing revealed compound heterozygous mutations, c.211G>A (p.G71R), c.1470C>T (p.D490D) and a normal homozygous A[TA]6TAA. No similar case has been reported worldwide and, considering the specific clinical features and therapeutic efficacy, a distinct type of CN was suspected. The phenotype of this unusual CN syndrome patient may be associated with the specific genotype.

Acupuncture versus metoclopramide in treatment of postoperative gastroparesis syndrome in abdominal surgical patients: a randomized controlled trial.

BACKGROUND: Postoperative gastroparesis syndrome (PGS) is a common complication after abdominal surgery in patients with primary liver cancer. However, surgeons usually do not have effective treatment for them. OBJECTIVE: To explore the effects of acupuncture applied to Zusanli and other acupoints on PGS in patients after abdominal surgery. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Sixty-three PGS patients of abdominal surgery, from Eastern Hepatobiliary Surgical Hospital, were randomized into acupuncture group (32 cases) and metoclopramide group (31 cases). The patients in acupuncture group were treated with acupuncture applied to Zusanli and other acupoints once a day, while the patients in metoclopramide group were intramuscularly injected 20 mg metoclopramide three times a day. MAIN OUTCOME MEASURES: Volume of gastric drainage, number of treatment and cure rate in the two groups were measured and evaluated. RESULTS: Acupuncture and metoclopramide could significantly reduce gastric drainage volume. In acupuncture group, the cure rate was 90.6% and the number of treatment was 6.58+/-4.26, while in metoclopramide group, the cure rate and the number of treatment were 32.3% and 10.13+/-3.60 respectively. There were significant differences in gastric drainage volume, cure rate and number of treatment between the two groups (P<0.05, P<0.01). CONCLUSION: Acupuncture is a good treatment for PGS, with fewer treatments, high cure rate and rapid effect.

Watershed land use controls on chemical inputs to lake ontario embayments.

There is considerable interest in understanding the role of land use in controlling surface water quality. This study was conducted to assess the role of land cover in regulating temporal and spatial patterns in nutrients and major solutes in rivers that drain into Lake Ontario. Water samples were collected monthly from 22 river sites in subwatersheds of eight embayments along the New York coast of Lake Ontario over the period 2001-2003. Samples were analyzed for nutrients and major solutes. The land cover of the subwatersheds was varied, but largely a mixture of forest and agricultural lands. Rivers draining largely agricultural lands exhibited distinct seasonal patterns, particularly for nutrients. Nitrate and total nitrogen (TN) concentrations were generally low during the summer growing season, increased markedly during fall and decreased during winter and spring. Total phosphorus (TP), dissolved organic carbon (DOC), and most ion (Na(+), K(+), Ca(2+), Mg(2+), Cl(-), SO(4)(2-)) concentrations varied with seasonal discharge patterns. Distinct spatial patterns were observed in river solute concentrations that closely corresponded with land use. Solute concentrations increased markedly with increases in the percentage of the watershed occurring as agricultural lands. Such a pattern has been commonly observed for nutrients (e.g., TP, TN, NO(3)(-)), but this relationship was also evident for most non-nutrient solutes (e.g., DOC, Ca(2+), F(-), SO(4)(2-)), a pattern which has not previously been reported. These observations suggest that agricultural activities mobilize most major elements, enhancing transport across the temperate landscape and impacting downstream water resources, including embayments and the Lake Ontario ecosystem.

[The effect of sorphoridine on neuron ultrastructure in CA3 of hippocampus in rats].

OBJECTIVE: To observe the effect of sorphoridine (SR) on electroencephalograph (EEG) and ethological changes as well as neurons ultrastructure alterations in CA3 of hippocampus in rats. METHODS: Tiny electrodes were embedded into hippocampus of male SD rats. The EEG and behavior changes were observed simultaneously and ultrastructure of morphological deformation of neurons in CA3 of hippocampus were observed with electron microscope at 0.5, 1.5, 8 hours after SR were injected intraperitoneally on freely moving rats. RESULTS: There were no epileptiform discharges and seizure activities observed in control group. There was no abnormality seen on neuron in hippocampus of CA3 in control group. While there were epileptiform discharges and convulsions observed simultaneously when SR were administrated at the dose of 55 mg/kg intraperitoneally. 0.5, 1.5, 8 hours after SR, mitochondrion showed swelling cristae and ruptured membrane. Organelle burst and degeneration of synapses were seen with electromicroscope in CA3 of hippocampus ,especially at 1.5 hours after SR administration. CONCLUSION: Sophoridine can induce acute seizure activity on rats and cause mitochondrion ultrastructural damage. The ultrastructural damage of mitochondrion occurs in the early period after SR administration. It indicates that the injury of mitochondria could be critical in neuron damage caused by sorphoridine.

[Relationship between female ages and the theory of five tones correlated with five zang viscera in Huangdi Neijing].

OBJECTIVE: To find out some evidence that may indicate the theory of voice pitch of the five tones being correlated with the five zang viscera in Huangdi Neijing, which was lost 2 000 years. METHODS: Eight-four healthy females were divided into younger group (<34 years old) and older group (> or =34 years old) according to their ages. The pronunciations of these females were examined by sono-frequency analysis facility. RESULTS: The frequency of Jiao tone was much higher than those of the other tones in both groups (P<0.01) and the frequency of Jiao tone increased as aging. The frequency of Zhi tone in the younger group was higher than that in the older group (P<0.05). CONCLUSION: The results of higher frequency of Jiao tone in females is in accordance with the theory put forward by Ye Gui (a famous doctor in Qing Dynasty of China) that the liver is the congenital base of female life. In traditional Chinese medicine, Jiao tone is correlated with the liver, and Zhi tone is correlated with the heart. The high frequency of Zhi tone in younger females implies that regulating the Small Intestine Meridian of Hand-Taiyang and Heart Meridian of Hand-Shaoyin may be beneficial to the health maintenance of younger female.