A gravity-driven membrane bioreactor in treating the real decentralized domestic wastewater: Flux stability and membrane fouling.

Domestic wastewater in decentralized sites is capturing increasing attention. However, conventional treatment technology is not sufficiently cost-effective. In this study, real domestic wastewater was treated directly using a gravity-driven membrane bioreactor (GDMBR) at 45 mbar without backwashing or chemical cleaning, and the effects of different membrane pore sizes (0.22 µm, 0.45 µm, and 150 kDa) on flux development and contaminants removal were examined. The results showed that the flux initially decreased and then stabilized throughout long-term filtration and that the stabilized flux level of the GDMBR equipped the membranes with the pore size of 150 kDa and 0.22 µm was higher than that of 0.45 µm membrane and was in the range of 3-4 L m-2h-1. The flux stability was related to spongelike and permeable biofilm generation on the membrane surface in the GDMBR system. The presence of aeration shear on the membrane surface would cause the slough off of biofilm from the membrane surface, especially in the scenarios of GDMBR with the membrane pore size of 150 kDa and 0.22 µm, contributing to lower accumulation of extracellular polymeric substance (EPS) and smaller biofilm thickness compared to that of 0.45 µm membrane. Furthermore, the GDMBR system achieved efficient removals of chemical oxygen demand (COD), and ammonia, with average removal efficiencies of 60-80% and 70%. The high biological activity and microbial community diversity within the biofilm would improve its biodegradation and should be responsible for the efficient removal performance of contaminants. Interestingly, the membrane effluent could effectively retain total nitrogen (TN) and total phosphorus (TP). Therefore, it's feasible to adopt the GDMBR process to treat the actual domestic wastewater in the decentralized locations, and these findings could be expected to develop some simple and environmentally friendly strategies for decentralized wastewater treatment with fewer inputs.

[Rationality evaluation of Shuanghuanglian Injection combined with Ampicillin Sodium for Injection based on sequential analysis].

The lack of rationality evaluation method for drug combination has long restricted its clinical application. In view of this, this study took Shuanghuanglian Injection as model drug and established a "physical-chemical-biological" sequential analysis method, which is expected to provide clues for improving the safety and effectiveness of clinical drug combination. With the methods of insoluble particle testing, isothermal titration calorimetry(ITC), and real time cellular analysis(RTCA), the rationality of Shuanghuanglian Injection combined with Ampicillin Sodium for Injection was assessed. The results showed that the number of insoluble particles>10 µm in the solution of the combination met the standard of Chinese Pharmacopoeia, while the number of insoluble particles>25 µm did not meet the standard. ITC detection demonstrated that the change of Gibbs free energy(ΔG) was less than 0 during the fusion process, indicating that the process was spontaneous and enthalpy-driven reaction. Therefore, the interaction between the two was mainly chemical reaction, and the internal substances may change. RTCA found that Shuanghuanglian Injection alone and Ampicillin Sodium for Injection alone basically had no inhibitory effect on the growth of HEK293 T cells, while the combination of the two suppressed the growth of HEK293 T cells, suggesting that the combination was toxic to HEK293 T cells. This study showed that Shuanghuanglian Injection and Ampicillin Sodium for Injection reacted, yielding toxicity. This suggested that the two should not be combined for application. With the "physical-chemical-biological" sequential analysis, the molecular interaction of drugs was clarified. The method can be further applied for evaluating the rationality of other Chinese and western medicine injections.

Determination of 18 Trace Elements in 10 Batches of the Tibetan Medicine Qishiwei Zhenzhu Pills by Direct Inductively Coupled Plasma-Mass Spectrometry.

Qishiwei Zhenzhu pills (QSW) was first recorded in the Tibetan medicine classic Si Bu Yi Dian and has been used to treat "Baimai" disease, stroke, paralysis, hemiplegia, cerebral hemorrhage, and other diseases till today. This prescription contains more than 70 medicines including myrobalan, pearl, agate, opal, bezoar, coral, musk, gold, silver, and a mineral mixture Zuotai. As a result, QSW contains a large amount of mercury, copper, lead, and other trace elements. The aim of this study was to determine the 18 trace elements (lithium, beryllium, scandium, vanadium, chromium, manganese, cobalt, nickel, copper, arsenic, strontium, argentum, cadmium, cesium, barium, lead, aurum, and mercury) in 10 batches of QSW produced by 5 pharmaceutical companies (Ganlu Tibetan Medicine Co., Ltd. has 6 different batches) by direct inductively coupled plasma-mass spectrometry (ICP-MS). ICP-MS is a rapid, sensitive, accurate methodology allowing the determination of 18 elements simultaneously. The results showed that each element had an excellent linear relationship in the corresponding mass concentration range. The results showed that the rank order of the elements in QSW was copper > mercury > lead from high to low, with the mass fraction higher than 6000 µg/kg; the mass fractions of argentum, arsenic, manganese, aurum, strontium, barium, chromium, and nickel were in the range of 33-1034 µg/kg; and the mass fractions of vanadium, cobalt, lithium, beryllium, cadmium, scandium, and cesium were lower than 10 µg/kg. The reproducibility from the same manufacturer (Tibet Ganlu Tibetan Medicine Co., Ltd.) was relatively high; however, the element amounts among 5 manufacturers were different, which could affect the efficacy and toxicity of QSW. All in all, ICP-MS can be used as an effective tool for the analysis of trace elements in QSW and standard quality control needs to be enforced across different manufactures.

Tibetan Medicine Qishiwei Zhenzhu Pills Can Reduce Cerebral Ischemia-Reperfusion Injury by Regulating Gut Microbiota and Inhibiting Inflammation.

Cerebral ischemia is a series of harmful reactions, such as acute necrosis of tissue, inflammation, apoptosis, autophagy, and blood-brain barrier injury, due to the insufficient blood supply to the brain. Inflammatory response and gut microbiota imbalance are important concomitant factors of cerebral ischemia and may increase the severity of cerebral ischemia through the gut-brain axis. Qishiwei Zhenzhu pills (QSW) contain more than 70 kinds of medicinal materials, which have the effects of anti-cerebral infarction, anti-convulsion, anti-dementia, and so on. It is a treasure of Tibetan medicine commonly used in the treatment of cerebral ischemia in Tibetan areas. In this study, we gave rats QSW (66.68 mg/kg) once by gavage in advance and then immediately established the rat middle cerebral artery occlusion (MCAO) model. After 24 hours of treatment, the neuroprotection, intestinal pathology, and gut microbiota were examined. The results showed that QSW could significantly reduce the neurobehavioral abnormalities and cerebral infarction rate in MCAO rats. Furthermore, qPCR, western blot, and immunohistochemistry results showed that QSW could effectively inhibit IL-6, IL-1ß, and other inflammatory factors so as to effectively reduce the inflammatory response of MCAO rats. Furthermore, QSW could improve intestinal integrity and reduce intestinal injury. 16S rRNA sequencing showed that QSW could significantly improve the gut microbiota disorder of MCAO rats. Specifically, at the phylum level, it can regulate the abundance of Firmicutes and Proteobacteria in the gut microbiota of rats with MCAO. At the genus level, it can adjust the abundance of Escherichia and Shigella. At the species level, it can adjust the abundance of Lactobacillus johnsonii and Lactobacillus reuteri. All in all, this study is the first to show that QSW can reduce the severity of cerebral ischemia-reperfusion injury by regulating gut microbiota and inhibiting the inflammatory response.

Experimental and theoretical explorations of nanocarriers' multistep delivery performance for rational design and anticancer prediction.

The poor understanding of the complex multistep process taken by nanocarriers during the delivery process limits the delivery efficiencies and further hinders the translation of these systems into medicine. Here, we describe a series of six self-assembled nanocarrier types with systematically altered physical properties including size, shape, and rigidity, as well as both in vitro and in vivo analyses of their performance in blood circulation, tumor penetration, cancer cell uptake, and anticancer efficacy. We also developed both data and simulation-based models for understanding the influence of physical properties, both individually and considered together, on each delivery step and overall delivery process. Thus, beyond finding that nanocarriers that are simultaneously endowed with tubular shape, short length, and low rigidity outperformed the other types, we now have a suit of theoretical models that can predict how nanocarrier properties will individually and collectively perform in the multistep delivery of anticancer therapies.

The Absorption, Distribution, and Excretion of 18 Elements of Tibetan Medicine Qishiwei Zhenzhu Pills in Rats with Cerebral Ischemia.

The aim of this study is to determine 18 elements in Tibetan medicine Qishiwei Zhenzhu pills (QSW) and their absorption, distribution, and excretion in rats with cerebral ischemia. Microwave digestion and inductively coupled plasma mass spectrometry (ICP-MS) were used to determine 18 elements of QSW in simulated gastrointestinal (GI) juice. Rats were given QSW (66.68 mg/kg) followed by middle cerebral artery occlusion (MCAO). Sham rats received saline and were not subjected to MCAO. ICP-MS was applied to determine the content of 18 elements in hepatic venous blood, abdominal aortic blood, brain, liver, kidney, hair, urine, and feces 24 h after MCAO. In vitro results showed that the extraction rate of Mn, Cu, Sr, Pb, Au, and Hg of QSW in gastric juice (1 h) was higher than that in water, and the contents of Cu, Au, Sr, and As were higher in intestinal juice (4 h) than in water. In vivo results showed that the contents of elements in the blood were quite low, and QSW increased Ni, Cr, Sr, Co, and V in artery blood and decreased V in venous blood. Elements in the tissues were also low, and QSW increased brain Li but decreased Cr and Cd; QSW increased kidney Ag and Cs and liver Mn but decreased liver Ni. QSW increased urinary excretion of Li, Sr, Hg, Cs, and V; QSW increased Hg content in hair but decreased Ni. Stool is the main excretion pathway of the elements in QSW, with Ba, Mn, Sr, Cd, V, Cu, Cs, Li, Pb, Ag, Hg, Cr, As, and Co the highest. In summary, this study examined the distribution of 18 elements in QSW-treated MCAO rats. The accumulation of these elements in blood and tissues was extremely low, and the majority was excreted in feces within 24 h, highlighting the importance of the gut-microbiota-brain axis in QSW-mediated brain protection.

Dual drug delivery system of photothermal-sensitive carboxymethyl chitosan nanosphere for photothermal-chemotherapy.

Aiming at high drug loading and controlled drug release in chitosan nanocarriers, this work constructed the photothermal sensitive carboxymethyl chitosan nanospheres carrier by introducing controllable heat-sensitive groups into carboxymethyl chitosan molecules. The combination therapy system based on photothermal-chemotherapy was established by virtue of the good photothermal conversion effect of ICG and the high chemotherapy efficiency of DOX. On the one hand, the carrier owned high drug loading and improved the stability of coated-drug. On the other hand, the nanospheres generated photothermal response through NIR irradiation to improve the drug release amount and to achieve the combined treatment effect of photodynamic therapy and chemotherapy. The structures of the nanospheres were fully characterized by Fourier transform infrared (FT-IR), nuclear magnetic resonance (1H NMR) and scanning electron microscope (SEM). In vitro photothermal tests proved that the nanospheres had excellent light stability and photothermal conversion performance. The cytotoxicity test results showed that the nanospheres had no obvious toxicity, but the drug-loaded nanospheres could effectively inhibit the growth of HepG-2 cells via photo-response to release DOX and ICG for achieving photothermal-chemotherapy under NIR irradiation.

The Status quo and way forwards on the development of Tibetan medicine and the pharmacological research of tibetan materia Medica.

Tibetan medicine (TM), the second largest traditional Chinese medicine system in China, boasts a long history and an integrated theoretical system. It abounds with classical medical works constituing a unique corpus of Tibetan materia medica (TMM). China has now conceived a modern education system of TM, and Tibetan medical hospitals at different levels have been set up. Many enterprises are granted the privileges to produce preparations of TM in compliance with Good Manufacturing Practices (GMP) regulations. However, there still exist unsolved issuess in TMM research as to the mechanism of action and the active constituents of TMM which are now been tackled through pharmacology and modern science and technology. Up till now, the mechanism of action and the active constituents of 141 medicines as well as 230 preparations of TM have been preliminarily revealed. This paper reviews in detail the development of TM and the status quo of TM's pharmacological research, in hope of serving a reference value for the promotion of the modernization of TM and understanding of TM among the medical scholars.

Self-assembled amphiphilic chitosan nanomicelles to enhance the solubility of quercetin for efficient delivery.

Quercetin (QCT) has important functions such as antioxidant, anti-inflammatory and anticancer. However, its applications in food and in drug are restricted owing to its poor water solubility. In this work, a novel amphiphilic wall-material chitosan was synthesized via grafting of chitosan with deoxycholic acid (DA) as hydrophobic group and modified N-acetyl-L-cysteine (NAC) as hydrophilic group. Amphiphilic chitosan was self-assembled to load QCT as nanomicelles by a low-cost and inorganic solvent procedure. Both the encapsulation efficiencies (EE) and drug-loading rates (DL) increased when increasing the grafting rate of DA. There was a bursting release of QCT for the QCT-loaded nanomicelles (CS-DA-NAC-QNMs) from 0 to 8 h, and then the release rate decreased gradually. After releasing for 72 h, the final cumulative release percentages were more than 40%. All the QCT-loaded nanomicelles samples showed good hemocompatibility, and their water solubility and biocompatibility increased evidently. What's more, they exhibited an obvious inhibition rate of A549 cells.

Nanolongan with Multiple On-Demand Conversions for Ferroptosis-Apoptosis Combined Anticancer Therapy.

As a type of programmed cell death, ferroptosis is distinct from apoptosis. The combination of the two thus provides a promising modality with which to significantly improve anticancer treatment efficacy. To fully utilize this combination, we herein designed a nanolongan delivery system, which possessed a typical structure of one core (up-conversion nanoparticles, UCNP) in one gel particle (Fe3+ cross-linked oxidized starch) with multiple on-demand conversions. The charge conversion of the nanolongan surface in a slightly acidic microenvironment enhanced circulation time for utilizing the enhanced permeability and retention effect, enabled efficient uptake by tumor cells, and induced subsequently lysosomal escape. As the core component, the UCNP with light conversion from near-infrared light to ultraviolet light circumvented the impediment of limited penetration depth and enabled the reduction of Fe3+ to Fe2+. Accordingly, gel networks of nanolongan could be deconstructed due to this valence conversion, leading to the rapid release of Fe2+ and doxorubicin (Dox). In this case, the Fenton reaction between Fe2+ and intracellular H2O2 generated potent reactive oxygen species for ferroptosis, while the co-released Dox penetrated into nucleus and induced apoptosis in a synergistic way. As a result, superior anticancer therapeutic effects were achieved with little systemic toxicity, indicating that our nanolongan could serve as a safe and high-performance platform for ferroptosis-apoptosis combined anticancer therapy.

Defoliation and gibberellin synergistically induce tree peony flowering with non-structural carbohydrates as intermedia.

Although the natural florescence of the tree peony is short, it can be lengthened by forcing culture. In this study, both defoliation or gibberellic acid (GA3) treatment individually induced tree peony (Paeonia suffruticosa 'Luo Yang Hong') flowering under forcing culture, and their combination (D + G) accelerated flowering with a GA3-overdose-like phenomenon, indicating that synergism between defoliation and GA3 treatment may occur. Both defoliation and GA3 treatment induced a GA response, including (i) increased GA3 production, (ii) increased PsCPS and PsGA3ox expression, and (iii) decreased PsGA2ox, PsGID1c, and PsGID2 expression; both treatments also positively influenced non-structural carbohydrate (NSC) accumulation. According to the expression of five PsSWEETs, PsSWEET2 and PsSWEET17 may redundantly exercise the crosstalk of defoliation and GA3 treatment by NSC distribution, whereas PsSWEET12 may act by GA modulation; no synergism resulting from the D + G treatment was detected. Tissue-specific analysis indicated that, in sepals, PsSWEET2 and PsSWET7 are both induced by defoliation and GA3 treatment, whereas PsSWEET2 expression showed synergism with the D + G treatment. In summary, defoliation and GA3 treatment synergistically induce tree peony flowering under forcing culture, and NSCs are suggested as key intermedia. Moreover, sepals may play key roles in their synergism, although more direct evidence is still needed.

Elevated expression of KLK8 predicts poor prognosis in colorectal cancer.

KLK8, also known as neuropsin, is one of fifteen members of the human kallikrein-related peptidase (KLK) gene family, which consists of enzymes with serine protease enzymatic activity. Aberrant KLK8 expression has been reported in several malignancies. However, the clinicopathological significance and prognostic value of KLK8 expression in colorectal cancer (CRC) are unknown. Therefore, analysis of public datasets, quantitative real-time PCR and western blot analysis were performed to assess KLK8 expression in CRC at both the mRNA and protein level. KLK8 expression was also assessed by immunohistochemistry in a tissue microarray containing 124 CRC specimens. We observed that KLK8 was overexpressed in CRC tissues and was significantly associated with TNM stage, vascular invasion, differentiation and AJCC stage. Univariate and multivariate Cox analyses confirmed that KLK8 is a significant independent prognostic factor for both DFS and OS. Cell function assays also indicated that KLK8 could facilitate CRC cell proliferation, migration and invasion in vitro. In conclusion, elevated KLK8 expression was correlated with the progression of CRC and is a potential independent prognostic indicator for CRC.

TEMPO-oxidized Konjac glucomannan as appliance for the preparation of hard capsules.

TEMPO-oxidized Konjac glucomannan (OKGM) was developed as new material for preparing vegetarian hard capsules. OKGM of different degrees of oxidation: DO30%, DO50%, and DO80% were prepared to select optimum DO for capsule formation. FT-IR results proved that the primary alcohol groups on KGM were oxidized into carboxyl groups. XRD analysis suggested that TEMPO-oxidation decreased the crystallinity of KGM. DO80% was considered as the optimum candidate for capsule preparation owing to its superior solubility, transparency and reduced viscosity. The hydrophilicity of OKGM films, measured by contact angle measurement, increased with increasing DO. The elongation at break and tensile strength of the OKGM films enhanced with increasing DO. In vitro drug dissolution profile of OKGM capsules showed that the shell rupture time of DO80% capsule is about 5-10 min, and 80% of the drugs were released within 30-45 min. Thus DO80% OKGM was qualified to be used for gastric soluble hard capsules.

Intestine-Specific Delivery of Hydrophobic Bioactives from Oxidized Starch Microspheres with an Enhanced Stability.

An intestine-specific delivery system for hydrophobic bioactives with improved stability was developed. It consists of oxidized potato starch polymers, where the carboxyl groups were physically cross-linked via ferric ions. The model hydrophobic ingredients (ß-carotene) were incorporated inside the starch microspheres via a double-emulsion method. Confocal laser scanning microscopy images showed that ß-carotene were distributed homogeneously in the inner oil phase of the starch microspheres. The negative value of the ζ-potential of microspheres increased with increasing pH and decreasing ionic strength. In vitro release experiments showed that the microspheres were stable at acidic stomach conditions (pH < 2), whereas at neutral intestinal conditions (pH 7.0), they rupture to release the loaded ß-carotene. The 1,1-diphenyl-2-picrylhydrazyl radical, 2,2-diphenyl-1-(2,4,6-trinitriphenyl), scavenging activity results suggested that microsphere-encapsulated ß-carotene had an improved activity after thermal treatment at 80 °C. The storage stability of encapsulated ß-carotene at room temperature was also enhanced. The starch microspheres showed potential as intestine-specific carriers with an enhanced stability.