Multilayer nanodrug delivery system with spatiotemporal drug release improves tumor microenvironment for synergistic anticancer therapy.

The inflammatory response is one of the general symptoms that accompany tumorigenesis, the pro-inflammatory factors cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandin-2 (PGE-2) in the inflammatory environment surrounding tumors possess promoting tumor development, metastasis and angiogenesis effects. In addition, the hypoxic environment of tumors severely limits the effectiveness of photodynamic therapy (PDT). In this study, a universal extracellular-intracellular 'on-demand' release nanomedicine DOX@PDA-ICG@MnO2@GN-CEL was developed for the combined fight against malignant tumors using a spatiotemporal controlled gelatin coated polydopamine (PDA@GN) as the carrier and loaded with the chemotherapeutic drug doxorubicin (DOX), the photosensitizer indocyanine green (ICG), the PDT enhancer MnO2and the anti-inflammatory drug celecoxib (CEL) individually. Our results showed that DOX@PDA-ICG@MnO2@GN-CEL could release CEL extracellularly by matrix metalloproteinase-2 response and inhibit the COX-2/PGE-2 pathway, reduce chemotherapy resistance and attenuate the concurrent inflammation. After entering the tumor cells, the remaining DOX@PDA-ICG@MnO2released DOX, ICG and MnO2intracellularly through PDA acid response. MnO2promoted the degradation of endogenous H2O2to generate oxygen under acidic conditions to alleviate the tumor hypoxic environment, enhance PDT triggered by ICG. PDA and ICG exhibited photothermal therapy synergistically, and DOX exerted chemotherapy with reduced chemotherapy resistance. The dual responsive drug release switch enabled the chemotherapeutic, photothermal, photodynamic and anti-inflammatory drugs precisely acted on different sites of tumor tissues and realized a promising multimodal combination therapy.

Long-Term Organic Fertilization Strengthens the Soil Phosphorus Cycle and Phosphorus Availability by Regulating the pqqC- and phoD-Harboring Bacterial Communities.

The pqqC and phoD genes encode pyrroloquinoline quinone synthase and alkaline phosphomonoesterase (ALP), respectively. These genes play a crucial role in regulating the solubilization of inorganic phosphorus (Pi) and the mineralization of organic phosphorus (Po), making them valuable markers for P-mobilizing bacterial. However, there is limited understanding of how the interplay between soil P-mobilizing bacterial communities and abiotic factors influences P transformation and availability in the context of long-term fertilization scenarios. We used real-time polymerase chain reaction and high-throughput sequencing to explore the characteristics of soil P-mobilizing bacterial communities and their relationships with key physicochemical properties and P fractions under long-term fertilization scenarios. In a 38-year fertilization experiment, six fertilization treatments were selected. These treatments were sorted into three groups: the non-P-amended group, including no fertilization and mineral NK fertilizer; the sole mineral-P-amended group, including mineral NP and NPK fertilizer; and the organically amended group, including sole organic fertilizer and organic fertilizer plus mineral NPK fertilizer. The organically amended group significantly increased soil labile P (Ca2-P and enzyme-P) and Olsen-P content and proportion but decreased non-labile P (Ca10-P) proportion compared with the sole mineral-P-amended group, indicating enhanced P availability in the soil. Meanwhile, the organically amended group significantly increased soil ALP activity and pqqC and phoD gene abundances, indicating that organic fertilization promotes the activity and abundance of microorganisms involved in P mobilization processes. Interestingly, the organically amended group dramatically reshaped the community structure of P-mobilizing bacteria and increased the relative abundance of Acidiphilium, Panacagrimonas, Hansschlegelia, and Beijerinckia. These changes had a greater positive impact on ALP activity, labile P, and Olsen-P content compared to the abundance of P-mobilizing genes alone, indicating their importance in driving P mobilization processes. Structural equation modeling indicated that soil organic carbon and Po modulated the relationship between P-mobilizing bacterial communities and labile P and Olsen-P, highlighting the influence of SOC and Po on the functioning of P-mobilizing bacteria and their impact on P availability. Overall, our study demonstrates that organic fertilization has the potential to reshape the structure of P-mobilizing bacterial communities, leading to increased P mobilization and availability in the soil. These findings contribute to our understanding of the mechanisms underlying P cycling in agricultural systems and provide valuable insights for enhancing microbial P mobilization through organic fertilization.

Long-term nitrogen fertilization and sweetpotato cultivation in the wheat-sweetpotato rotation system decrease alkaline phosphomonoesterase activity by regulating soil phoD-harboring bacteria communities.

The alkaline phosphomonoesterase (ALP)-harboring community (phoD-harboring community) plays a crucial role in the conversion of organic phosphorus (P) into available P (AP). However, the response mechanisms of phoD-harboring communities to fertilization strategies, crop types, and their interactions within the wheat-sweetpotato rotation are poorly understood. A nine-year field experiment of different fertilization strategies was established under the wheat-sweetpotato rotation. After harvesting the crop, we collected soil samples without fertilization (CK), inorganic NK fertilization (NK), inorganic NPK fertilization (NPK), and a combined application of inorganic NPK and organic fertilizer (NPKM). We employed high-throughput sequencing and enzymology techniques to analyze the composition and functional activity of phoD-harboring bacterial communities as well as their correlation with soil physicochemical properties. The results showed that long-term nitrogen (N) fertilization, especially inorganic N, significantly reduced soil pH and ALP activity while increasing AP compared with CK. The AP content in sweetpotato season was significantly higher than that in wheat season. Inorganic N fertilization dramatically reshaped the communities of phoD-harboring bacteria and decreased diversity. The phoD-harboring bacterial communities in sweetpotato season were significantly different from those in wheat season. The N fertilization significantly reduced the relative abundance of Acuticoccus, Methylibium, Rhizobacter, and Roseivivax, which was positively correlated with ALP activity. These groups in sweetpotato season decreased significantly compared with wheat season. A structural equation model indicates that pH and AP play a significant role in regulating the phoD-harboring bacteria communities, ALP activity, and their interactions. We demonstrate that fertilization strategies and crop types have a substantial impact on the phoD-harboring bacteria communities and functions, which are closely linked to soil pH and AP levels. Our study highlights the detrimental effects of soil acidification resulting from inorganic N fertilization on P-cycling bacterial communities and functions. However, the combination of inorganic and organic fertilizer can mitigate these adverse effects.

Aptamer-functionalized quercetin thermosensitive liposomes for targeting drug delivery and antitumor therapy.

Chemo-thermotherapy, as a promising cancer combination therapy strategy, has attracted widespread attention. In this study, a novel aptamer functionalized thermosensitive liposome encapsulating hydrophobic drug quercetin was fabricated as an efficient drug delivery system. This aptamer-functionalized quercetin thermosensitive liposomes (AQTSL) combined the merits of high-loading yield, sustained drug release, long-term circulation in the body of PEGylated liposomes, passive targeting provided by 100-200 nm nanoparticles, active targeting and improved internalization effects offered by AS1411 aptamer, and temperature-responsive of quercetin release. In addition, AQTSL tail vein injection combined with 42 °C water bath heating on tumor site (AQTSL + 42 °C)treatment inhibited the tumor growth significantly compared with the normal saline administration (p< 0.01), and the inhibition rate reached 75%. Furthermore, AQTSL + 42 °C treatment also slowed down the tumor growth significantly compared with QTSL combined with 42 °C administration (p< 0.05), confirming that AS1411 decoration on QTSL increased the active targeting and internalization effects of the drug delivery system, and AS1411 aptamer itself might also contribute to the tumor inhibition. These data indicate that AQTSL is a potential carrier candidate for different hydrophobic drugs and tumor targeting delivery, and this kind of targeted drug delivery system combined with temperature responsive drug release mode is expected to achieve an ideal tumor therapy effect.

Hydroxy-selenomethionine supplementation promotes the in vitro rumen fermentation of dairy cows by altering the relative abundance of rumen microorganisms.

AIMS: This study aims to investigate the effect of hydroxy-selenomethionine supplementation on the in vitro rumen fermentation characteristics and microorganisms of Holstein cows. METHODS AND RESULTS: Five fermentation substrates, including control (without selenium supplementation, CON), sodium selenite supplementation (0.3 mg kg-1 DM, SS03), and hydroxy-selenomethionine supplementation (0.3, 0.6 and 0.9 mg kg-1 DM, SM03, SM06 and SM09, respectively) were incubated with rumen fluid in vitro. The results showed that in vitro dry matter disappearance and gas production at 48 h was significantly higher in SM06 than SM03, SS03 and CON; propionate and total volatile fatty acid (VFA) production was higher in SM06 than CON. Moreover, higher species richness of rumen fluid was found in SM06 than others. Higher relative abundance of Prevotella and Prevotellaceae-UCG-003 and lower relative abundance of Ruminococcus-1 were detected in SM06 than CON. Besides, higher relative abundance of Ruminococcaceae_UCG-005 was found in CON than other treatments. CONCLUSIONS: It is observed that 0.6 mg kg-1 DM hydroxy-selenomethionine supplementation could increase cumulative gas production, propionate, and total VFAs production by altering the relative abundance of Prevotella, Prevotellaceae-UCG-003, Ruminococcaceae_UCG-005 and Ruminococcus-1, so that it can be used as a rumen fermentation regulator in Holstein cows. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides an optimal addition ratio of hydroxy-selenomethionine on rumen fermentation and bacterial composition via an in vitro test.

[Systematic review of Kudiezi injection drug safety].

To systematically evaluate the safety of Kudiezi injection. Databases such as Cochrane library, Medline, EMbase, Web of Science, Clinical Trials, CBM, CNKI, VIP, Wanfang and Chinese Clinical Trial Register were searched to collect the literature on all the study types of Kudiezi injection. Two researchers screened literature, assessed quality and extracted data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria; Meta-analysis of adverse drug reaction/adverse events (ADR/AE) of Kudiezi injection was performed by using Stata 12.0 software. There were 411 clinical studies included, out of which 315 studies were analyzed finally. 18 072 patients in total used kudiezi injection, and there were 330 cases with ADRs and 13 cases with AEs. The most common ADR related system was the central and peripheral nervous system, with a weighted incidence of 2.9% [95%CI(0.022, 0.036)]. From the current evidence, the overall safety of Kudiezi injection was acceptable. Although data could be collected from all kinds of published reports, there are lack of mechanism experiments or observational studies with large samples of Kudiezi injection. Therefore, it is necessary to carry out further research on the safety of Kudiezi injection. Meanwhile, off label use of Kudiezi injection is common, so it is urgent for relevant governmental departments to formulate drug use specifications and provide better guidance for clinical drug use.

New Eudesmane Sesquiterpenoids from Salvia plebeia R. Br.

Three new sesquiterpenoids, salplebeones A - C (1 - 3), were isolated from the ethanol-soluble extract of the aerial part of Salvia plebeia R. Br. Their structures were established by detailed analysis of NMR and MS spectra. Salplebeone A was an eudesmane lactone, while salplebeones B and C were rare eudesmane sesquiterpenoids, containing 12,8-lactam groups. Antiproliferative activities of salplebeones A - C to myeloid leukemia cell lines were evaluated.

New milbemycin metabolites from the genetically engineered strain Streptomyces bingchenggensis BCJ60.

Two new milbemycin derivatives, 27-methoxylmilbemycin α31 (1) and 27-oxomilbemycin α31 (2), were isolated from the genetically engineered strain Streptomyces bingchenggensis BCJ60. Their structures were determined by 1D NMR, 2D NMR and HR-ESI-MS spectral analysis, and comparison with previous reports. The acaricidal and nematocidal capacities of compounds 1 and 2 were evaluated against Tetranychus cinnabarinus and Bursaphelenchus xylophilus, respectively. The results showed that the two new macrocyclic lactones 1 and 2 possessed potent acaricidal and nematocidal activities.

[Systematic review on safety of Xinyuan capsules].

To systematically review the adverse drug reactions/adverse events(ADRs/AEs) of Xinyuan capsules in clinical application. A systematic literature search was performed in the databases of the Cochrane Library, Medline, EMBASE, the Web of Science, Clinical trials, CNKI, VIP, WanFang Data and CBM. The literature was screened and data was extracted according to the inclusion and exclusion criteria. Because of the substantial heterogeneity among different studies, we assessed them only with descriptive analysis by study type, disease diagnosis, and ADRs/AEs conditions. All included studies were assessed by using the internationally recognized report quality evaluation standard or methodological quality assessment tools. A total of 42 studies involving 3 671 patients were included finally. Two thouand four hundred and thirty-mine patients of them took Xinyuan capsules, and 1 242 patients did not take Xinyuan capsules. No serious ADRs occurred in all patients. One patient died as AE during the research. Sixteen patients of the 2 439 patients taking Xinyuan capsules (alone or in combination) had ADRs, including 7 patients with polytherapy of Xinyuan capsules and 9 patients with monotherapy. The most common ADRs were in gastrointestinal tract, mainly including thirst, nausea, vomiting and abdominal pain, etc. The ADRs included 10 gastrointestinal tract ADRs, 3 renal ADRs and 1 ADR respective in skin system, respiratory system and cardiovascular system. Xinyuan capsules was generally safe in clinical application. The reports on the study of Xinyuan capsules were dispersed in various clinical studies, the study on drug safety still should be strengthened in the future. Further mechanism studies or clinical observation studies of the drug safety shall be conducted to better guide clinical application in the future.

[Shenshuaining capsules as adjuvant treatment for chronic renal failure： systematic review and Meta-analysis of randomized controlled trials].

Chronic renal failure(CRF) is one of the common diseases. Shenshuaining capsule (SSN) can be used to treat patients with CRF, and many randomized control trials(RCTs) have been conducted to investigate its efficacy. The current review aims to systematically evaluate the efficacy and safety of SSN as an adjuvant treatment for patients with CRF. Eleven English and Chinese electronic databases (up to October 2015), were searched to identify RCTs on SSN for CRF. Two reviewers independently extracted the data and assessed the quality of included studies by using Cochrane Handbook 5.1.Meta-analysis was carried out by using Revman 5.3 software. If the Meta-analysis was not suitable for some outcomes, only descriptive analysis would be conducted.429 related articles were identified and finally a total of 25 RCTs (1 937 patients including 1 059 patients of treatment group and 878 patients of control group) were included. The SSN treatment group was more effective than the control group in terms of clinical efficiency, blood urea nitrogen(BUN), serum creatinine(Scr) and creatinine clearance(Ccr). However, the efficacy of SSN on increasing hemoglobin (Hb) could not be determined. No serious adverse drug events or reactions were reported. SSN capsules have certain efficacy and safety in the adjuvant treatment for chronic renal failure. However, due to the generally low methodological quality of the included studies, this review can not provide high-quality evidence to prove the clinical efficacy of this drug. More well-designed and large-scale multi-center randomized controlled trials should be conducted in the future for verification.

Preparation of a novel rape pollen shell microencapsulation and its use for protein adsorption and pH-controlled release.

This study aims to synthesize hollow microspheres (HMS) from rape pollen via H3PO4 hydrothermal carbonization. The rape pollen hollow shell was used as the carrier and bovine serum albumin as a model protein. The properties of HMS were characterized by scanning electron microscope (SEM), solid-state nuclear magnetic resonance and elemental analysis. The SEM images clearly showed that the HMS had perfect spherical morphology and porous hollow surface. In the separated filtrate, a large number of sucroses were detected by high-performance liquid chromatography, suggesting that the hydrolysis of starch molecules occurred during the hydrothermal process. The formation of HMS was that the rape pollen inclusion was removed from rape pollen shell to preserve integral HMS by H3PO4 hydrothermal. The HMS possessed amphiphilic surfaces, which was suitable for protein adsorpion and pH-controlled release application.

[Study on efficacy of liujunzi decoction combined with zuojin pills in treating acute radioactive duodenitis and their mechanism].

OBJECTIVE: To evaluate the therapeutic effect of Liujunzi decoction combined with Zuojin pills in treating the radioactive duodenitis and their mechanism, and compare with clinical routine acid suppressants combined with mucous membrane protective preparations to study the mechanism of their efficacy. METHOD: According to the study of Williams J P and characteristics of duodenitis, and by reference to the radiation enteritis modeling standard, we took the lead in establishing the mouse radioactive duodenal injury model. The model mice were randomly divided into the control group (n = 26), traditional Chinese medicine (TCM) group (n = 16) and the western medicine (oral administration with famotidine 0.5 mL + almagate suspension 0.3 mL per mouse, once a day) group (n = 16). After the standard administrating, such objective indexes as general condition, weight, changes in health score, pathology and expression of inflammatory factors were observed to evaluate the efficacy. RESULT: The radioactive duodenitis model of mice was successfully established with 12 Gy. Mice in the control group suffered from weight loss, anorexia, low fluid intake, loose stools, and occasionally mucous bloody stool, poor spirit, dim fur, lack of exercise and arch back. Mice in drug intervention groups were generally better than those in the pure irradiation group. The IL-6, IL-1beta, TNF-alpha mRNA expressions in spleen and mesenteric lymph node tissues in TCM and western medicine groups showed a declining trend compared with the control group. Their concentrations in peripheral blood serum also slightly changed. The TCM group revealed notable advantage in reducing inflammatory factors. The microscopic observation showed that a better mucosa repair in intervention groups than the pure irradiation group. The improved Chiu's scoring method showed a statistical significance in the difference between TCM and western medicine groups (P < 0.05). CONCLUSION: Liujunzi decoction combined with Zuojin pills could treat acute radiation enteritis, regulate organic immunity, and inhibit acute injury, promote local tissue repair, with the potential to resist such adverse effects as radiation intestinal fibrosis. The regulation of inflammatory factor release is one of efficacy generation mechanisms.

A novel macrocyclic lactone with insecticidal bioactivity from Streptomyces microflavus neau3.

A novel macrocyclic lactone (1) was isolated from the fermentation broth of Streptomycesmicroflavus neau3, and the structure was elucidated by extensive spectroscopic analysis. Compound 1 showed high acaricidal activity against adult mites (IC(50)=11.1 µg mL(-1)), and nematocidal activity against Caenorhabditis elegans (IC(50)=17.4 µg mL(-1)), especially the acaricidal activity against mite eggs with an IC(50) of 37.1 µg mL(-1), which was relative higher than that of the commercial acaricide and nematocide milbemycins A(3)/A(4).

Relative biological effectiveness and cell-killing efficacy of continuous low-dose-rate 125I seeds on prostate carcinoma cells in vitro.

The aim of this study was to determine the effects of (125)I seeds on prostate carcinoma (PC3) cells. The relative biological effectiveness of (125)I seeds on PC3 cells with respect to (60)Co gamma rays was 1.4. Both 4 Gy of (60)Co gamma ray and (125)I seed irradiation increased the percentage of cells in G(2) phase, but there was no significant difference between these 2 types of radiation. Significantly, (125)I seeds induced higher apoptotic rates of PC3 cells compared with (60)Co gamma ray irradiation. Furthermore, Bcl-2 expression, but not caspase-3 activity, in PC3 cells was downregulated after irradiation with (125)I seed or (60)Co gamma rays.

The direct biologic effects of radioactive 125I seeds on pancreatic cancer cells PANC-1, at continuous low-dose rates.

The relative biologic effectiveness of model 6711 125I seeds (Ningbo Junan Pharmaceutical Technology Company,Ningbo, China) and their effects on growth, cell cycle, and apoptosis in human pancreatic cancer cell line PANC-1 were examined in the present study. PANC-1 cells were exposed to the absorbed doses of 1, 2, 4, 6, 8, and 10 Gyeither with 125I seeds (initial dose rate, 2.59 cGy=h) or with 60Co g-ray irradiation (dose rate, 221 cGy=min),respectively. Significantly greater numbers of apoptotic PANC-1 cells were detected following the continuouslow-dose-rate (CLDR) irradiation of 125I seeds, compared with cells irradiated with identical doses of 60Co g-ray. The D(0) for 60Co g-ray and 125I seed irradiation were 2.30 and 1.66, respectively. The survival fraction after 125Iseed irradiation was significantly lower than that of 60Co g-ray, with a relative biologic effectiveness of 1.39.PANC-1 cells were dose dependently arrested in the S-phase by 60Co g-rays and in the G2=M phase by 125I seeds,24 hour after irradiation. CLDR irradiation by 125I seeds was more effective in inducing cell apoptosis in PANC-1cells than acute high-dose-rate 60Co g irradiation. Interestingly, CLDR irradiation by 125I seeds can cause PANC-1cell-cycle arrest at the G2=M phase and induce apoptosis, which may be an important mechanism underlying 125Iseed-induced PANC-1 cell inhibition.

The biological effect of 125I seed continuous low dose rate irradiation in CL187 cells.

BACKGROUND: To investigate the effectiveness and mechanism of 125I seed continuous low-dose-rate irradiation on colonic cell line CL187 in vitro. METHODS: The CL187 cell line was exposed to radiation of 60Cogamma ray at high dose rate of 2 Gy/min and 125I seed at low dose rate of 2.77 cGy/h. Radiation responses to different doses and dose rates were evaluated by colony-forming assay. Under 125I seed low dose rate irradiation, a total of 12 culture dishes were randomly divided into 4 groups: Control group, and 2, 5, and 10 Gy irradiation groups. At 48 h after irradiation, apoptosis was detected by Annexin and Propidium iodide (PI) staining. Cell cycle arrests were detected by PI staining. In order to investigate the influence of low dose rate irradiation on the MAPK signal transduction, the expression changes of epidermal growth factor receptor (EGFR) and Raf under continuous low dose rate irradiation (CLDR) and/or EGFR monoclonal antibodies were determined by indirect immunofluorescence. RESULTS: The relative biological effect (RBE) for 125I seeds compared with 60Co gamma ray was 1.41. Apoptosis rates of CL187 cancer cells were 13.74% +/- 1.63%, 32.58% +/- 3.61%, and 46.27% +/- 3.82% after 2 Gy, 5 Gy, and 10 Gy irradiation, respectively; however, the control group apoptosis rate was 1.67% +/- 0.19%. G2/M cell cycle arrests of CL187 cancer cells were 42.59% +/- 3.21%, 59.84% +/- 4.96%, and 34.61% +/- 2.79% after 2 Gy, 5 Gy, and 10 Gy irradiation, respectively; however, the control group apoptosis rate was 26.44% +/- 2.53%. P < 0.05 vs. control groups by Student's t-test were found in every treated group both in apoptosis and in G2/M cell cycle arrest. After low dose rate irradiation, EGFR and Raf expression increased, but when EGFR was blocked by a monoclonal antibody, EGFR and Raf expression did not change. CONCLUSION: 125I seeds resulted in more effective inhibition than 60Co gamma ray high dose rate irradiation in CL187 cells. Apoptosis following G2/M cell cycle arrest was the main mechanism of cell-killing effects under low dose rate irradiation. CLDR could influence the proliferation of cells via MAPK signal transduction.