The efficacy and adverse events of arsenic trioxide for the patients with myelodysplastic syndrome: a systematic review and component network meta-analysis.

BACKGROUND: Arsenic trioxide (ATO) might be effective for myelodysplastic syndrome (MDS) by apoptosis induction and demethylation. But ATO has not been widely recommended for small sample and conflicting conclusion of existing trials. This review aimed to systematically evaluate the efficacy of regimens containing ATO for the MDS and explore optimal combination. METHOD: Randomized clinical trials (RCTs) about ATO regimens were retrieved from China National Knowledge Infrastructure, Embase and PubMed. With odds ratio (OR) as the effect size, network meta-analysis (NMA) and component network meta-analysis (CNMA) were conducted by R and 'netmeta' package, after study selection, quality assessment and data extraction. RESULT: Thirty-night RCTs were included with a total of 2125 patients, including 1235 treated by ATO containing regimen. With support therapy alone as reference, no inconsistency and heterogeneity were observed. Although NMA did not demonstrate better efficacy of ATO alone, the result of CNMA indicated that ATO was effective in the improvement of overall remission (ORR) [OR = 2.09(1.61, 2.71)] and complete remission (CR) [OR = 1.66(1.25, 2.21)]. Five ATO-containing regimens reported could effectively improve ORR, some of them benefit in CR or hematological improvement (HI) as well. ATO + Traditional Chinese Medicine (TCM), ATO + Thalidomide (T)+TCM, ATO + Chemotherapy (Chem)+T + TCM were regarded as the optimal combination, which improved both ORR, CR and HI in theory. ATO did not increase the risk of common adverse events compared to supportive therapy [(OR = 0.90(0.67, 1.21)]. CONCLUSION: ATO may be an effective and well-tolerant option for patients with myelodysplastic syndrome.

Chromosome-Level Genome Assembly and Multi-Omics Dataset Provide Insights into Isoflavone and Puerarin Biosynthesis in Pueraria lobata (Wild.) Ohwi.

Pueraria lobata (wild.) Ohwi is a leguminous plant and one of the traditional Chinese herbal medicines. Its puerarin extract is widely used in the pharmaceutical industry. This study reported a chromosome-level genome assembly for P. lobata and its characteristics. The genome size was ~939.2 Mb, with a contig N50 of 29.51 Mbp. Approximately 97.82% of the assembled sequences were represented by 11 pseudochromosomes. We identified that the repetitive sequences accounted for 63.50% of the P. lobata genome. A total of 33,171 coding genes were predicted, of which 97.34% could predict the function. Compared with other species, P. lobata had 757 species-specific gene families, including 1874 genes. The genome evolution analysis revealed that P. lobata was most closely related to Glycine max and underwent two whole-genome duplication (WGD) events. One was in a gamma event shared by the core dicotyledons at around 65 million years ago, and another was in the common ancestor shared by legume species at around 25 million years ago. The collinearity analysis showed that 61.45% of the genes (54,579 gene pairs) in G. max and P. lobata had collinearity. In this study, six unique PlUGT43 homologous genes were retrieved from the genome of P. lobata, and no 2-hydroxyisoflavanone 8-C-glucoside was found in the metabolites. This also revealed that the puerarin synthesis was mainly from the glycation of daidzein. The combined transcriptome and metabolome analysis suggested that two bHLHs, six MYBs and four WRKYs were involved in the expression regulation of puerarin synthesis structural genes. The genetic information obtained in this study provided novel insights into the biological evolution of P. lobata and leguminous species, and it laid the foundation for further exploring the regulatory mechanism of puerarin synthesis.

A NIR-II light-modulated injectable self-healing hydrogel for synergistic photothermal/chemodynamic/chemo-therapy of melanoma and wound healing promotion.

The development of an injectable multifunctional hydrogel with tumor therapy, antibacterial treatment and wound healing properties is essential for simultaneously eradicating melanoma and promoting wound healing of tumor-initiated skin defects. Herein, iron ion-doped polyaniline (PANI(Fe)) tethered with guar gum (GG) chains is employed for the first time as a building unit for constructing a superior hydrogel (GG@PANI(Fe)-borax) crosslinked by borate/didiol bonds. Due to the dynamic and reversible properties of boronate ester bonds, the GG@PANI(Fe)-borax hydrogels had convenient injectability, rapid self-healing ability, and reversible gel-sol transformations under thermal- or pH-stimuli. More importantly, they took advantage of the second near-infrared (NIR-II) responsive photothermal conversion capability, accompanied by the photothermal-enhanced high cytotoxic ˙OH generation in the H2O2-enriched tumor microenvironment induced by iron-doped PANI. The as-prepared hydrogels exhibited excellent photothermal effects and controllable NIR-triggered drug release, leading to distinctly synergistic photothermal/chemodynamic/chemo-therapy effects of melanoma both in vitro (98.2%) and in vivo (98.8%). In addition, the obtained hydrogels also exhibited good anti-bacterial activity (>97.1%) against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria because they were based on PANI(Fe) and borax, which exhibit antibacterial activity. Furthermore, these GG@PANI(Fe)-incorporated scaffolds could improve fibroblast cell proliferation and angiogenesis for accelerating wound repair in tumor-bearing and infected wound mice. Taken together, GG@PANI(Fe)-borax hydrogels may be used simultaneously for eradication of skin-tumor cells, inhibiting infection and accelerating wound healing. This work offers an effective and facile strategy to fabricate an "all-in-one" multifunctional hydrogel platform for synergetic multimodal integrated therapy of tumors.

Genome-scale transcriptomic insights into the gene co-expression network of seed abortion in triploid Siraitia grosvenorii.

BACKGROUND: Siraitia grosvenorii (Swingle) C. Jeffrey, also known as Luohanguo or monk fruit, is a famous traditional Chinese medicine ingredient with important medicinal value and broad development prospects. Diploid S. grosvenorii has too many seeds, which will increase the utilization cost of active ingredients. Thus, studying the molecular mechanism of seed abortion in triploid S. grosvenorii, identifying the abortion-related genes, and regulating their expression will be a new direction to obtain seedless S. grosvenorii. Herein, we examined the submicroscopic structure of triploid S. grosvenorii seeds during abortion. RESULTS: Upon measuring the endogenous hormone content, we found that abscisic acid (ABA) and trans-zeatin (ZR) levels were significantly downregulated after days 15 and 20 of flowering. RNA sequencing of triploid seeds at different developmental stages was performed to identify key genes regulating abortion in triploid S. grosvenorii seeds. Multiple genes with differential expression between adjacent stages were identified; seven genes were differentially expressed across all stages. Weight gene co-expression network analysis revealed that the enhancement of monoterpene and terpene metabolic processes might lead to seed abortion by reducing the substrate flow to ABA and ZR. CONCLUSIONS: These findings provide insights into the gene-regulatory network of seed abortion in triploid S. grosvenorii from different perspectives, thereby facilitating the innovation of the breeding technology of S. grosvenorii.

Genes Induced by Panax Notoginseng in a Rodent Model of Ischemia-Reperfusion Injury.

Stroke is a cerebrovascular disease that results in decreased blood flow. Although Panax notoginseng (PN), a Chinese herbal medicine, has been proven to promote stroke recovery, its molecular mechanism remains unclear. In this study, middle cerebral artery occlusion (MCAO) was induced in rats with thrombi generated by thread and subsequently treated with PN. After that, staining with 2,3,5-triphenyltetrazolium chloride was employed to evaluate the infarcted area, and electron microscopy was used to assess ultrastructural changes of the neurovascular unit. RNA-Seq was performed to determine the differential expressed genes (DEGs) which were then verified by qPCR. In total, 817 DEGs were identified to be related to the therapeutic effect of PN on stroke recovery. Further analysis by Gene Oncology analysis and Kyoto Encyclopedia of Genes and Genomes revealed that most of these genes were involved in the biological function of nerves and blood vessels through the regulation of neuroactive live receptor interactions of PI3K-Akt, Rap1, cAMP, and cGMP-PKG signaling, which included in the 18 pathways identified in our research, of which, 9 were reported firstly that related to PN's neuroprotective effect. This research sheds light on the potential molecular mechanisms underlying the effects of PN on stroke recovery.

Using mRNA deep sequencing to analyze differentially expressed genes during Panax notoginseng saponin treatment of ischemic stroke.

Treatment with Panax notoginseng saponin (PNS) can prevent neurological damage in middle cerebral artery occlusion model rats to promote recovery after a stroke. However, the exact molecular mechanisms are unknown and require further study. In the present study, mRNA sequencing was employed to investigate differential gene expression between model and sham groups, and between model and PNS­treated groups. Enrichment of gene data was performed using Gene Ontology analysis and the Kyoto Encyclopedia of Genes and Genomes database. Hub genes were identified and networks were constructed using Cytoscape that were further verified by reverse transcription­quantitative PCR. A total of 1,104 genes of interest were found, which included 690 upregulated and 414 downregulated genes that were identified when the model was compared with the sham group. Additionally, 817 genes of interest, which included 390 upregulated and 427 downregulated genes, were identified when the PNS­treated group was compared with the model group. There were 303 overlapping genes of interest between the analysis of model to sham groups, and the analysis of model to PNS­treated groups. The top 10 genes from the 303 aberrantly expressed genes of interest included ubiquitin conjugating enzyme E2 variant 2, small ubiquitin­related modifier 1, small RNA binding exonuclease protection factor La, Finkel­Biskis­Reilly murine sarcoma virus (FBR­MuSV) ubiquitously expressed, centrosomal protein 290 kDa, DNA­directed RNA polymerase II subunit K, cullin­4B, matrin­3 and vascular endothelial growth factor receptor 2. In conclusion, these genes may be important in the underlying mechanism of PNS treatment in ischemic stroke. Additionally, the present data provided novel insight into the pathogenesis of ischemic stroke.

Effects of the Chinese herb formula Yufeining on stable chronic obstructive pulmonary disease: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: A Chinese herb formula Yufeining (YFN) has showed promise in the treatment of stable chronic obstructive pulmonary disease (COPD), less is known that the impact of YFN in combination with standard Western treatments on lung inflammation. This study evaluated the safety and efficacy of YFN as a treatment for stable COPD and as an anti-inflammatory agent. METHODS: Sixty patients with stable COPD were randomly assigned to two treatment groups (YFN treatment, N = 30; placebo treatment, N = 30). Both groups received inhaled steroids and bronchodilators during an 8-week intervention, and patient status was assessed at 8 weeks later and 4 months after treatment. The primary outcome included clinical efficacy. The secondary outcomes involved CAT score, mMRC grade, six-minute walking distance (6MWD). IL-8, TNF-α, IL-17A, LTB4, TGF-ß1 and CRP were also detection in peripheral serum, as well as adverse reaction conditions. RESULTS: The YFN group demonstrated a significant improvement in clinical efficacy (compare 89.3% to 63.3% in the placebo group; P < 0.05). CAT scores and mMRC grades significantly decreased (P < 0.05, P < 0.01), and 6MWD significantly increased (P<0.05), after YFN treatment. The levels of IL-8, TNF-α, LTB4 and CRP decreased significantly after 8 weeks of treatment compared to baseline levels in both groups. Only in the YFN treatment group, the levels of IL-17A decreased significantly after treatment compared to baseline levels (P < 0.05). No changes were observed inTGF-ß1 from pre-to post-treatment in either group (P > 0.05). Serum levels of IL-8, TNF-α, IL-17A, LTB4 and CRP decreased significantly after YFN treatment compared to the placebo group (P < 0.05). CONCLUSION: A combinatorial treatment approach with YFN, inhaled steroids and bronchodilators produced a clinically effective treatment for stable COPD, leading to a significant decrease in circulating inflammatory mediators. The study appeared YFN was safety. CLINICAL TRIAL REGISTRATION NUMBER: No. ChiCTR-IOR-17013577.

Diagnostic value of fractional exhaled nitric oxide for asthma-chronic obstructive pulmonary disease overlap syndrome.

To examine the difference in the fractional exhaled nitric oxide (FeNO) between chronic obstructive pulmonary disease (COPD) patients with asthma-COPD overlap syndrome (ACOS) and patients with Non-ACOS COPD (Non-ACOS) and to investigate the correlation between FeNO levels and the differential cell counts of eosinophils in induced sputum, in order to explore the diagnostic value of FeNO in ACOS.A prospective, case-control study was performed on 53 cases of ACOS group and 53 cases of Non-ACOS group in the Respiratory Medicine Outpatient of Zhangzhou Municipal TCM Hospital, Affiliated to Fujian University of Traditional Chinese Medicine. The FeNO levels and induced sputum cell counts were determined and the correlation between FeNO levels and eosinophile percentage was analyzed by Pearson linear correlation analysis.The FeNO levels in patients with ACOS (37[24.5-53.0]) ppb were significantly higher than those of patients with Non-ACOS (20 [15.5-24.5] ppb) (P < .01). Also, the percentage of eosinophils in induced sputum in the ACOS group (5.70 [1.50-17.62]%) were significantly higher than those of the Non-ACOS group (0.50 [0.00-1.00]%) (P < .01). FeNO in both groups correlated positively with the percentage of eosinophils in induced sputum (P < .01), with a correlation coefficient r of 0.521. The area under the receiver operating curve of FeNO for the diagnosis of ACOS phenotype was 0.815 (P < .01), the sensitivity and specificity reach highest when the cut off value was 25.50 ppb.The FeNO in patients from the ACOS group were significantly higher than those in Non-ACOS group and were moderately correlated with the percentage of eosinophils in induced sputum. The results indicated that FeNO may be used as a diagnostic index for ACOS, in addition to the induced sputum.

Effects of lanthanum on Microcystis aeruginosa: Attention to the changes in composition and content of cellular microcystins.

Algal blooms threaten human health and aquatic ecosystem through the production of microcystins (MCs) by toxic strains. The accumulation of rare earth elements (REEs) in water affects the growth and physiological activities of algae. However, whether or how REEs affect cellular microcystins (MCs) is largely unknown. In this study, the effects of lanthanum ion [La(III)], a type of REE, on the MCs in Microcystis aeruginosa were investigated, and the mechanism of the effect was analyzed using ecological stoichiometry. The different concentrations of La(III) were selected to correlate environmental pollution status. Low-dose La(III) (0.2, 2.0, and 4.0 µM) exposure increased the total content of MCs and the percentage contents of microcystin-YR (MC-YR) and microcystin-LW (MC-LW) and decreased the percentage content of microcystin-LR (MC-LR). High-dose La(III) (8.0, 20, 40, and 60 µM) exposure decreased the total content of the MCs, increased the percentage content of MC-LR, and decreased the percentage contents of MC-YR and MC-LW. The changes in the total MCs content were positively associated with the ratios of C:P and N:P in algal cells. The composition of MCs was dependent on the ratio of C:N in algal cells; for example, the percentage content of MC-LR decreased and the percentage content of MC-YR and MC-LW increased as the ratio of C:N in algal cells increased. In conclusion, La(III) could affect the content and composition of MCs via changes in the growth and chlorophyll-a content of Microcystis aeruginosa, and these effects depended on the ratios of C:P, N:P, and C:N in Microcystis aeruginosa. Such changes may influence the toxicity of Microcystis blooms. The results provides a new insight into the mechanism of REEs effects on algal toxins and provide references for evaluating environmental risks of REEs pollution in aquatic ecosystems.

Chronic High Dose Zinc Supplementation Induces Visceral Adipose Tissue Hypertrophy without Altering Body Weight in Mice.

The trace element zinc plays an important role in human life. Zinc deficiency impairs growth, reproduction, metabolism and immunity in both human and animals. Thus, zinc supplementation is recommended in daily life. However, the effect of long-term chronic zinc supplementation on adipose homeostasis has not been well elucidated. In the current study, mice were supplemented with zinc sulfate in the drinking water for 20 weeks. The results suggested that chronic zinc supplementation impaired systemic glucose clearance after exogenous insulin or glucose challenges, as compared to the control mice. Further study revealed that chronic zinc supplementation made no difference to body weight, but increased visceral adipose tissue weight and adipocyte size. In addition, gene expression of leptin and IL6 in the visceral adipose tissue of zinc-supplemented mice were higher than those of control mice. Moreover, serum level of leptin of the zinc-supplemented mice was twice as high as that of the control mice. Besides, phosphorylation level of AKT T308 was attenuated in the perirenal adipose tissue of zinc-supplemented mice. In comparison, the expression of macrophage marker genes and lipogenic genes were not affected by chronic zinc supplementation, but the protein levels of FAS and SCD1 decreased or tended to decrease in the perirenal adipose tissue of zinc-supplemented mice, as compared to the control mice. Our findings suggest that chronic high dose zinc supplementation induces visceral adipose tissue hypertrophy and impairs AKT signaling in perirenal adipose tissue.

Bisphenol A effects on the chlorophyll contents in soybean at different growth stages.

Bisphenol A (BPA), a suspected endocrine disruptor, can modify normal plant growth and development. Photosynthesis provides material and energy for the growth and development of plants, in which chlorophyll (Chl) plays a significant role. Many studies have shown that the growth and metabolism of plants vary at different growth stages. Thus the sensitivity of plant's responses to environmental pollution is correspondingly different. We studied the effects of BPA on the Chl contents of soybean (Glycine Max L.) at different growth stages (seedling, flowering and podding, seed-filling and maturation) by measuring the contents of essential intermediates (5-aminolevulinic acid, porphobilinogen, protoporphyrin IX, magnesium protoporphyrin and protochlorophyll) and the activities of key enzymes (5-aminolaevulinic acid dehydratase, porphobilinogen deaminase, uroporphyrinogen III synthase, magnesium chelatase) in chlorophyll synthesis. Low-dose (1.5 mg/L) BPA exposure increased the activities of key enzymes in addition to the contents of intermediates in Chl synthesis at different growth stages, resulting in increases in Chl contents and net photosynthetic rate. In contrast, medium and high-dose (17.2, 50.0 mg/L) BPA exposure produced inhibitory effects on the indices. Following the withdrawal of BPA exposure, the indices recovered to a degree that was related to the plant growth stage. The effect level (high to low) of BPA on these indices at different growth stages was: seedling stage > maturation stage > flowering and podding stage > seed-filling stage. The reverse effect was observed following the withdrawal of BPA exposure. The responses of key enzymes in plant Chl synthesis to BPA illustrate how BPA affects Chl contents. The effects of BPA show clear differences at different plant growth stages.

A pathway of bisphenol A affecting mineral element contents in plant roots at different growth stages.

Bisphenol A (BPA), an environmental endocrine disruptor, is an important industrial raw material. The wide use of BPA has increased the risk of BPA release into the environment, and it has become a new environmental pollutant. In this work, the ecological deleterious effects of this new pollutant on soybean roots at different growth stages were investigated by determining the contents of mineral elements (P, K, Ca, and Mg) and analyzing root activity and the activities of critical respiratory enzymes (hexokinase, phosphofructokinase, pyruvate kinase, and isocitrate dehydrogenase). Our results revealed that low dose (1.5mg/L) of BPA increased the levels of P, K, Mg, and Ca in soybean roots at different growth stages. Whereas, high doses (6.0 and 12.0mg/L) of BPA decreased the levels of P, K, and Mg contents in a dose-dependent manner. BPA had a promotive effect on the content of Ca in soybean roots. Synchronous observation showed that the aforementioned dual response to BPA were also observed in the root activity and respiratory enzyme activities. The effects of BPA on the mineral element contents, root activity and respiratory enzyme activities in soybean roots at different growth stages followed the order: flowering and podding stage>seed-filling stage>seedling stage (mineral element contents); seedling stage>flowering and podding stage>seed-filling stage (root activity and respiratory enzyme activities). In a word, the response of plant root activity and respiratory enzyme activities to BPA pollution is a pathway of BPA affecting mineral element contents in plant roots.

Ball mill assisted rapid mechanochemical extraction method for natural products from plants.

A ball mill assisted mechanochemical extraction method was developed to extract compounds of natural product (NP) from plant using ionic liquid (IL). A small volume ball mill, also known as PastPrep(®) Homogenizer, which is often used for high-speed lysis of biological samples and for other applications, was used to dramatically increase the speed, completeness and reproducibility of the extraction process at room temperature to preserve the chemical integrity of the extracted compounds. In this study, tanshinones were selected as target compounds to evaluate the performance of this extraction method. Factors affecting the extraction efficiency, such as the duration, IL concentration and solid/liquid ratio were systematically optimized using the response surface methodology. Under the optimized conditions, the described method was more efficient and much faster than the conventional extraction methods such as methanol based ultrasound assisted extraction (UAE) and heat reflux extraction (HRE) that consumes a lot more organic solvent. In addition, the natural products of interest were enriched by anion metathesis of ionic liquids, combining extraction and preconcentration in the same process. The extractant was analyzed by HPLC and LC-MS. The reproducibility (RSD, n=5), correlation coefficient (r(2)) of the calibration curve, and the limit of detection, were determined to be in the range of 4.7-5.2%, 0.9992-0.9995, and 20-51ng/mL, respectively.

Analysis of effects of a new environmental pollutant, bisphenol A, on antioxidant systems in soybean roots at different growth stages.

Bisphenol A (BPA) is an important industrial raw material. Because of its widespread use and increasing release into environment, BPA has become a new environmental pollutant. Previous studies about BPA's effects in plants focus on a certain growth stage. However, the plant's response to pollutants varies at different growth stages. Therefore, in this work, BPA's effects in soybean roots at different growth stages were investigated by determining the reactive oxygen species levels, membrane lipid fatty acid composition, membrane lipid peroxidation, and antioxidant systems. The results showed that low-dose BPA exposure slightly caused membrane lipid peroxidation but didn't activate antioxidant systems at the seedling stage, and this exposure did not affect above process at other growth stages; high-dose BPA increased reactive oxygen species levels and then caused membrane lipid peroxidation at all growth stages although it activated antioxidant systems, and these effects were weaker with prolonging the growth stages. The recovery degree after withdrawal of BPA exposure was negatively related to BPA dose, but was positively related to growth stage. Taken together, the effects of BPA on antioxidant systems in soybean roots were associated with BPA exposure dose and soybean growth stage.

Phosphocholine conjugation: an unexpected in vivo conjugation pathway associated with hepatitis c ns5b inhibitors featuring a bicyclo[1.1.1]pentane.

During a medicinal chemistry campaign to identify inhibitors of the hepatitis C virus nonstructural protein 5B (RNA-dependent RNA polymerase), a bicyclo[1.1.1]pentane was introduced into the chemical scaffold to improve metabolic stability. The inhibitors bearing this feature, 5-(3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)-4-fluorophenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (1) and 5-(3-(bicyclo[1.1.1]pentan-1-ylcarbamoyl)phenyl)-2-(4-fluorophenyl)-N-methyl-6-(3,3,3-trifluoropropyl)furo[2,3-b]pyridine-3-carboxamide (2), exhibited low turnover in incubations with liver S9 or hepatocytes (rat, human), with hydroxylation of the bicyclic moiety being the only metabolic pathway observed. In subsequent disposition studies using bile-duct-cannulated rats, the metabolite profiles of bile samples revealed, in addition to multiple products of bicyclopentane-oxidation, unexpected metabolites characterized by molecular masses that were 181 Da greater than those of 1 or 2. Further LC/MSn and NMR analysis of the isolated metabolite of 1 demonstrated the presence of a phosphocholine (POPC) moiety bound to the methine carbon of the bicyclic moiety through an ester bond. The POPC conjugate of the NS5B inhibitors was assumed to result from two sequential reactions: hydroxylation of the bicyclic methine to a tertiary alcohol and addition of POPC by CDP-choline: 1,2-diacylglycerol cholinephosphotransferase, an enzyme responsible for the final step in the biosynthesis of phosphatidylcholine. However, this pathway could not be recapitulated using CDP-choline-supplemented liver S9 or hepatocytes due to inadequate formation of the hydroxylation product in vitro. The observation of this unexpected pathway prompted concerns about the possibility that 1 and 2 might interfere with routine phospholipid synthesis. These results demonstrate the participation in xenobiotic metabolism of a process whose function is ordinarily limited to the synthesis of endogenous compounds.

Photosensitizer-loaded gold nanorods for near infrared photodynamic and photothermal cancer therapy.

Despite the advancement of photodynamic therapy and photothermal therapy, the ability to form compact nanocomplex for combined photodynamic and photothermal cancer therapy under a single near infrared irradiation remains limited. In this work, we prepared an integrated sub-100 nm nanosystem for simultaneous near infrared photodynamic and photothermal cancer therapy. The nanosystem was formed by adsorption of silicon 2,3-naphthalocyanine dihydroxide onto gold nanorod followed by covalent stabilization with alkylthiol linked polyethylene glycol. The effects of alkylthiol chain length on drug loading, release and cell killing efficacy were examined using 6-mercaptohexanoic acid, 11-mercaptoundecanoic acid and 16-mercaptohexadecanoic acid. We found that the loading efficiency of silicon 2,3-naphthalocyanine dihydroxide increased and the release rate decreased with the increase of the alkylthiol chain length. We demonstrated that the combined near infrared photodynamic and photothermal therapy using the silicon 2,3-naphthalocyanine dihydroxide-loaded gold nanorods exhibit superior efficacy in cancer cell destruction as compared to photodynamic therapy and photothermal therapy alone. The nanocomplex stabilized with 16-mercaptohexadecanoic acid linked polyethylene glycol provided highest cell killing efficiency as compared to those stabilized with the other two stabilizers under low drug dose. This new nanosystem has potential to completely eradicate tumors via noninvasive phototherapy, preventing tumor reoccurrence and metastasis.

Near-infrared-absorbing gold nanopopcorns with iron oxide cluster core for magnetically amplified photothermal and photodynamic cancer therapy.

We present the synthesis and application of a new type of dual magnetic and plasmonic nanostructures for magnetic-field-guided drug delivery and combined photothermal and photodynamic cancer therapy. Near-infrared-absorbing gold nanopopcorns containing a self-assembled iron oxide cluster core were prepared via a seed-mediated growth method. The hybrid nanostructures are superparamagnetic and show great photothermal conversion efficiency (η=61%) under near-infrared irradiation. Compact and stable nanocomplexes for photothermal-photodynamic therapy were formed by coating the nanoparticles with near-infrared-absorbing photosensitizer silicon 2,3-naphthalocyannie dihydroxide and stabilization with poly(ethylene glycol) linked with 11-mercaptoundecanoic acid. The nanocomplex showed enhanced release and cellular uptake of the photosensitizer with the use of a gradient magnetic field. In vitro studies using two different cell lines showed that the dual mode photothermal and photodynamic therapy with the assistance of magnetic-field-guided drug delivery dramatically improved the therapeutic efficacy of cancer cells as compared to the combination treatment without using a magnetic field and the two treatments alone. The "three-in-one" nanocomplex has the potential to carry therapeutic agents deep into a tumor through magnetic manipulation and to completely eradicate tumors by subsequent photothermal and photodynamic therapies without systemic toxicity.

Can hyperthermic intraperitoneal chemotherapy efficiency be improved by blocking the DNA repair factor COP9 signalosome?

PURPOSE: A frequently used chemotherapeutic agent in hyperthermic intraperitoneal chemotherapy (HIPEC) is mitomycin C (MMC) which induces DNA damage and apoptosis in tumor cells. In addition, MMC activates DNA damage response (DDR) leading to repair mechanisms counteracting the effect of chemotherapy. COP9 signalosome (CSN) positively influences the DDR pathway by its intrinsic deneddylating and associated kinase activities. In an in vitro HIPEC model, we studied the impact of curcumin, an inhibitor of CSN-associated kinases, and of the microRNA (miRNA) let-7a-1, an inhibitor of CSN subunit expression, on the MMC-induced apoptosis in human HT29 colon cancer cells. METHODS: Cells were incubated at 37 °C and indicated concentrations of MMC in a medium preheated to 42 °C as under HIPEC conditions for 1 or 4 h. HT29 cells were cotreated with 50 µM curcumin or transfected with let-7a-1 miRNA mimic. After incubation, cells were analyzed by Western blotting, densitometry, and caspase-3 ELISA. RESULTS: An increase of CSN subunits in response to MMC treatment was detected. Apoptosis was only measured after 4 h with 50 µM MMC. MMC-induced apoptosis was elevated by cotreatment with curcumin. Transfection of HT29 cells with let-7a-1 reduced the expression of tested CSN subunits associated with the accumulation of the pro-apoptotic factors p27 and p53. CONCLUSIONS: In response to MMC treatment, the CSN is elevated as a regulator of DDR retarding apoptosis in tumor cells. The therapeutic effect of HIPEC can be increased by inhibiting CSN-associated kinases via curcumin or by blocking CSN expression with let-7a-1 miRNA.

Gold nanorods carrying paclitaxel for photothermal-chemotherapy of cancer.

Nanotechnology-based photothermal therapy has emerged as a promising treatment for cancer during the past decade. However, heterogeneous laser heating and limited light penetration can lead to incomplete tumor cell eradication. Here, we developed a method to overcome these limitations by combining chemotherapy with photothermal therapy using paclitaxel-loaded gold nanorods. Paclitaxel was loaded to gold nanorods with high density (2.0 × 10(4) paclitaxel per gold nanorod) via nonspecific adsorption, followed by stabilization with poly(ethylene glycol) linked with 11-mercaptoundecanoic acid. Paclitaxel was entrapped in the hydrophobic pocket of the polymeric monolayer on the surface of gold nanorods, which allows direct cellular delivery of the hydrophobic drugs via the lipophilic plasma membrane. Highly efficient drug release was demonstrated in a cell membrane mimicking two-phase solution. Combined photothermal therapy and chemotherapy with the paclitaxel-loaded gold nanorods was shown to be highly effective in killing head and neck cancer cells and lung cancer cells, superior to photothermal therapy or chemotherapy alone due to a synergistic effect. The paclitaxel-gold nanorod enabled photothermal chemotherapy has the potential of preventing tumor reoccurrence and metastasis and may have an important impact on the treatment of head and neck cancer and other malignancies in the clinic.

Comparative study of photothermolysis of cancer cells with nuclear-targeted or cytoplasm-targeted gold nanospheres: continuous wave or pulsed lasers.

We conduct a comparative study on the efficiency and cell death pathways of continuous wave (cw) and nanosecond pulsed laser photothermal cancer therapy using gold nanospheres delivered to either the cytoplasm or nucleus of cancer cells. Cytoplasm localization is achieved using arginine-glycine-aspartate peptide modified gold nanospheres, which target integrin receptors on the cell surface and are subsequently internalized by the cells. Nuclear delivery is achieved by conjugating the gold nanospheres with nuclear localization sequence peptides originating from the simian virus. Photothermal experiments show that cell death can be induced with a single pulse of a nanosecond laser more efficiently than with a cw laser. When the cw laser is applied, gold nanospheres localized in the cytoplasm are more effective in inducing cell destruction than gold nanospheres localized at the nucleus. The opposite effect is observed when the nanosecond pulsed laser is used, suggesting that plasmonic field enhancement of the nonlinear absorption processes occurs at high localization of gold nanospheres at the nucleus. Cell death pathways are further investigated via a standard apoptosis kit to show that the cell death mechanisms depend on the type of laser used. While the cw laser induces cell death via apoptosis, the nanosecond pulsed laser leads to cell necrosis. These studies add mechanistic insight to gold nanoparticle-based photothermal therapy of cancer.