Catalytic Glycosylation for Minimally Protected Donors and Acceptors.

Oligosaccharides have myriad functions throughout biology.1,2 To investigate these functions requires multi-step chemical synthesis of these structurally complex molecules. With a dense concentration of stereocentres and hydroxyl groups, oligosaccharide assembly through O-glycosylation requires simultaneous control of site-, stereo-, and chemoselectivities3,4. Chemists have traditionally relied on protecting group manipulations for this purpose,5-8 adding a lot of synthetic work. Here, we report a glycosylation platform that enables selective coupling between unprotected or minimally protected donor and acceptor sugars, producing 1,2-cis-O-glycosides in a catalyst-controlled, site-selective manner. Radical-based activation9 of allyl glycosyl sulfones forms glycosyl bromides. A designed aminoboronic acid catalysts bring this reactive intermediate close to an acceptor through a network of noncovalent hydrogen bonding and reversible covalent B-O bonding interactions, allowing precise glycosyl transfer. The site of glycosylation can be switched with different aminoboronic acid catalysts by affecting their interaction modes with substrates. The method accommodates a wide range of sugar types, amenable to preparing naturally occurring sugar chains and pentasaccharides containing 11 free hydroxyls. Experimental and computational studies provide insights into the origin of selectivity outcomes.

[Effect of Xuming Decoction in Records of Proved Prescriptions, Ancient a nd Modern on cerebral ischemic injury and angiogenesis in rat model of acute cerebral infarction].

This paper aims to explore the effect of Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern on cerebral ischemic injury and angiogenesis in the rat model of acute cerebral infarction. SD rats were randomized into 6 groups: sham group, model group, low-, medium-, and high-dose(5.13, 10.26, and 20.52 g·kg~(-1), respectively) Xuming Decoction groups, and butylphthalide(0.06 g·kg~(-1)) group. After the successful establishment of the rat model by middle cerebral artery occlusion(MCAO), rats in the sham and model groups were administrated with distilled water and those in other groups with corresponding drugs for 7 consecutive days. After the neurological function was scored, all the rats were sacrificed, and the brain tissue samples were collected. The degree of cerebral ischemic injury was assessed by the neurological deficit score and staining with 2,3,5-triphenyltetrazolium chloride. Hematoxylin-eosin staining was performed to observe the pathological changes in the brain. Transmission electron microscopy was employed to observe the ultrastructures of neurons and microvascular endothelial cells(ECs) on the ischemic side of the brain tissue. Immunofluorescence assay was employed to detect the expression of von Willebrand factor(vWF) and hematopoietic progenitor cell antigen CD34(CD34) in the ischemic brain tissue. Real-time PCR and Western blot were employed to determine the mRNA and protein levels, respectively, of Runt-related transcription factor 1(RUNX1), vascular endothelial growth factor(VEGF), angiopoietin-1(Ang-1), angiopoietin-2(Ang-2), and VEGF receptor 2(VEGFR2) in the ischemic brain tissue. The results showed that compared with the sham group, the model group showed increased neurological deficit score and cerebral infarction area(P<0.01), pathological changes, and damaged ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Furthermore, the modeling up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.05 or P<0.01). Compared with the model group, high-dose Xuming Decoction and butylphthalide decreased the neurological deficit score and cerebral infarction area(P<0.01) and alleviated the pathological changes and damage of the ultrastructure of neurons and microvascular ECs in the ischemic brain tissue. Moreover, they up-regulated the mRNA levels of RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01) and the protein levels of vWF, CD34, RUNX1, VEGF, Ang-1, Ang-2, and VEGFR2(P<0.01). The results suggest that Xuming Decoction in the Records of Proved Prescriptions, Ancient and Modern can promote the angiogenesis and collateral circulation establishment to alleviate neurological dysfunction of the ischemic brain tissue in MCAO rats by regulating the RUNX1/VEGF pathway.

Photoinduced Site-Selective Aryl C-H Borylation with Electron-Donor-Acceptor Complex Derived from B2Pin2 and Isoquinoline.

Due to boron's metalloid properties, aromatic boron reagents are prevalent synthetic intermediates. The direct borylation of aryl C-H bonds for producing aromatic boron compounds offers an appealing, one-step solution. Despite significant advances in this field, achieving regioselective aryl C-H bond borylation using simple and readily available starting materials still remains a challenge. In this work, we attempted to enhance the reactivity of the electron-donor-acceptor (EDA) complex by selecting different bases to replace the organic base (NEt3) used in our previous research. To our delight, when using NH4HCO3 as the base, we have achieved a mild visible-light-mediated aromatic C-H bond borylation reaction with exceptional regioselectivity (rr > 40:1 to single isomers). Compared with our previous borylation methodologies, this protocol provides a more efficient and broader scope for aryl C-H bond borylation through the use of N-Bromosuccinimide. The protocol's good functional-group tolerance and excellent regioselectivity enable the functionalization of a variety of biologically relevant compounds and novel cascade transformations. Mechanistic experiments and theoretical calculations conducted in this study have indicated that, for certain arenes, the aryl C-H bond borylation might proceed through a new reaction mechanism, which involves the formation of a novel transient EDA complex.

Phenotypic characterisation of regulatory T cells in patients with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a common complication that occurs during pregnancy. Emerging evidence suggests that immune abnormalities play a pivotal role in the development of GDM. Specifically, regulatory T cells (Tregs) are considered a critical factor in controlling maternal-fetal immune tolerance. However, the specific characteristics and alterations of Tregs during the pathogenesis of GDM remain poorly elucidated. Therefore, this study aimed to investigate the changes in Tregs among pregnant women diagnosed with GDM compared to healthy pregnant women. A prospective study was conducted, enrolling 23 healthy pregnant women in the third trimester and 21 third-trimester women diagnosed with GDM. Participants were followed up until the postpartum period. The proportions of various Treg, including Tregs, mTregs, and nTregs, were detected in the peripheral blood of pregnant women from both groups. Additionally, the expression levels of PD-1, HLA-G, and HLA-DR on these Tregs were examined. The results revealed no significant differences in the proportions of Tregs, mTregs, and nTregs between the two groups during the third trimester and postpartum period. However, GDM patients exhibited significantly reduced levels of PD-1+ Tregs (P < 0.01) and HLA-G+ Tregs (P < 0.05) in the third trimester compared to healthy pregnant women in the third trimester. Furthermore, GDM patients demonstrated significantly lower levels of PD-1+ mTregs (P < 0.01) and HLA-G+ (P < 0.05) mTregs compared to healthy pregnant women in the third trimester. Overall, the proportion of Tregs did not exhibit significant changes during the third trimester in GDM patients compared to healthy pregnant women. Nevertheless, the observed dysregulation of immune regulation function in Tregs and mTregs may be associated with the development of GDM in pregnant women.

Rational design of super reductive EDA photocatalyst for challenging reactions: a theoretical and experimental study.

We reported a novel electron-donor-acceptor (EDA) photocatalyst formed in situ from isoquinoline, a diboron reagent, and a weak base. To further optimize the efficiency of this photocatalyst, Density Functional Theory (DFT) calculations were conducted to investigate the substituent effects on the properties of vertical excitation energy and redox potential. Subsequently, we experimentally validated these effects using a broader range of substituents and varying substitution positions. Notably, the 4-NH2 EDA complex derived from 4-NH2-isoquinoline exhibits the highest photocatalytic efficiency, enabling feasible metal free borylation of aromatic C-H bond and detosylaion of Ts-anilines under green and super mild conditions. These experimental results demonstrate the effectiveness of our strategy for photocatalyst optimization.

[CiteSpace knowledge map of gut microbiota research involving traditional Chinese medicine in recent twenty years].

We employed bibliometrics to comprehensively study the hotspots and frontiers of gut microbiota research involving traditional Chinese medicine(TCM), aiming to provide new ideas for the subsequent research in this field. The studies of gut microbiota with TCM published from January 1, 2002 to December 31, 2021 were retrieved from CNKI, Wanfang, VIP and Web of Science(WoS). After data screening and cleaning, CiteSpace 5.8.R3 was used to visualize and analyze the authors, journals, and keywords. A total of 1 119 Chinese articles and 815 English articles were included in the study. The period of 2019-2021 witnessed the surge in the number of articles published in this field, being the peak research period. TAN Zhou-jin and DUAN Jin-ao were the authors publishing the most articles in Chinese and English, respectively. The two authors ranked top in both Chinese and English articles, playing a central role in this research field. The top five Chinese and English journals in this field had a large influence in the international research field. High-frequency keywords and keyword clustering showed that the research hotspots in this field were concentrated in four areas: trial and clinical research on the regulation of gut microbiota in disease treatment by TCM, metabolic transformation of Chinese medicines by gut microbiota, and the effect of TCM added to feed on the gut microbiota and growth performance of animals. The study of gut microbiota structure in patients with different TCM syndromes, as well as that of TCM combined with probiotics/flora transplantation in the treatment of diseases, can provide new ideas for clinical diagnosis and traditional drug treatment of diseases and has great research space and research value in the future.

Systematic evaluation and re-evaluation of buyang huanwu decoction in treating ischemic stroke.

BACKGROUND: The Buyang Huanwu Decoction (BYHWD) originated from Wang Qingren's "Yi Lin Gai Cuo". It has the effect of tonifying qi and activating blood circulation and dredging collaterals which is recommended for the treatment of Ischemic stroke in China. In recent years, there have been many systematic reviews of Ischemic stroke treated by BYHWD assessing the efficacy of BYHWD in the treatment of Ischemic stroke in the acute, convalescent and sequelae stages. Because of the different methods of analysis, the quality and quality of the evidence obtained in these systematic reviews is different, so a systematic re-evaluation was needed to comprehensively evaluate the strength of these studies. METHODS: Systematic reviews and meta-analyses of Ischemic stroke treated by BYHWD were identified through the Web of Science, PubMed, CNKI, Weipu, and Wanfang databases. The included studies were selected for literature screening, methodological quality evaluation, and evidence level evaluation by two investigators. The methodological quality was evaluated by the 2020 PRISMA guidelines, Assessing the Methodological Quality of Systematic Reviews (AMSTAR) scale, and the evidence quality was evaluated by the GRADE criteria. RESULTS: Overall, 12 studies involving 28,594 patients between 2006-2021 were included in this analysis. The methodological quality evaluation based on 2020 PRISMA guidelines results showed that there were many weaknesses in registration and protocol, support, competing interests, competing interests and availability of data, code and other materials. The AMSTAR scale evaluation results showed that the 12 studies were very low quality. The results of the GRADE criteria evaluation showed that the quality of the evidence was scattered, with mainly low-quality evidence. CONCLUSION: The methodological quality of systematic reviews and meta-analyses of BYHWD in treating Ischemic stroke was generally poor, and the quality of evidence was generally low.

[Visual analysis on regulation of necroptosis with Chinese medicine based on VOSviewer and CiteSpace knowledge graphs].

The study was conducted by searching the literature related to the regulation of necroptosis with Chinese medicine from January 1, 2005 to December 31, 2021 in CNKI, VIP, Wanfang, Web of Science(WoS), and PubMed. The obtained literature were imported into NoteExpress for eliminating duplicates and screening, and the final included articles were imported into Excel to plot the publication trend. The core authors were identified according to Price's law, and VOSviewer 1.6.17 was used to draw a collaborative view of the core authors and sort the high-frequency keywords. Then CiteSpace 5.8.R3 was employed to analyze keywords clustering, burst, and timeline view. Finally, 98 Chinese articles and 72 English articles were included in the study. The number of publications on the regulation of necroptosis with Chinese medicine has been increasing year by year. China ranked among the top in the world in terms of the number of publications, and Chinese authors played a central role in this field. Specifically, LIU Hua published the most Chinese literature while CHEN X P had the most English publications. The collaborative view of the core authors showed more intra-team cooperation and less inter-team cooperation. The Chinese and English keywords formed ten clusters separately, indicating that the research hotspots of regulation of necroptosis with Chinese medicine mainly focused on disease, prescription, related factors, and mecha-nism. Further, the analysis of Chinese and English keywords revealed that regarding disease treatment, tumor, ischemia-reperfusion injury, neurodegenerative diseases, and inflammatory diseases were studied most. The Chinese medicines that received much attention in this field were curcumin, shikonin and tanshinone. The main protein factors involved were Ripk1, Ripk3, Mlkl, and TNF-α, and Ripk1/Ripk3/Mlkl and p53 signaling pathways were predominant. Moreover, single herbs and herbal monomers were the hotspots of the included articles. In the future, scholars need to expand the study of classical Chinese herbal compounds and explore their mechanism of action in the occurrence and development of various diseases, to provide new ideas and experimental basis for the treatment of clinical diseases with Chinese medicine.

Photoinduced metal-free borylation of aryl halides catalysed by an in situ formed donor-acceptor complex.

Organoboron compounds are very important building blocks which can be applied in medicinal, biological and industrial fields. However, direct borylation in a metal free manner has been very rarely reported. Herein, we described the successful direct borylation of haloarenes under mild, operationally simple, catalyst-free conditions, promoted by irradiation with visible light. Mechanistic experiments and computational investigations indicate the formation of an excited donor-acceptor complex with a -3.12 V reduction potential, which is a highly active reductant and can facilitate single-electron-transfer (SET) with aryl halides to produce aryl radical intermediates. A two-step one-pot method was developed for site selective aromatic C-H bond borylation. The protocol's good functional group tolerance enables the functionalization of a variety of biologically relevant compounds, representing a new application of aryl radicals merged with photochemistry.

Merging Hydrogen Atom Transfer and Halogen Atom Transfer for Iodide-Catalyzed Radical Reductive Cyclization of 1,6-Enynes.

Described herein is the development of a metal-free iodide-catalyzed radical reductive cyclization of 1,6-enynes. A strategy involving in situ iodination/radical cyclization/silyl radical-mediated halogen atom transfer/hydrogen atom transfer for the synthesis of functionalized pyrrolidines has been proposed. Using this halogen-atom abstraction protocol, 1,6-enynes with various vinyl halides including inert fluorides, chlorides, and reactive bromides could be transformed into substituted pyrroles via a multistep radical isomerization process.

The Effect of Probiotics in Stroke Treatment.

OBJECTIVE: We conducted a systematic review and meta-analysis to evaluate the curative effect of probiotics combined with enteral nutrition (EN) in patients with stroke. METHODS: We retrieved randomized controlled trials and case-controlled trials on the use of probiotics for stroke treatment from PubMed, Web of Science, CNKI, Wanfang, and Weipu databases. Retrieval times were from the databases' inception to November 6, 2020. Two researchers conducted a strict evaluation of the literature quality and extracted the data, which were then entered into RevMan 5.3 for meta-analysis. RESULTS: Twenty-three articles were included, including 1,816 patients. The meta-analysis revealed that probiotics combined with EN did not reduce NIHSS scores of patients with stroke (P > 0.05). However, it did shorten hospital stays and bedrest periods (P < 0.05). Probiotics combined with EN also improved patients' nutritional status and increased hemoglobin, albumin, serum total protein, and physical and chemical properties of prealbumin (P < 0.05). In terms of relieving inflammation, we found that probiotics combined with EN reduced neither high-sensitivity C-reactive protein nor procalcitonin (P > 0.05). However, it did cause a significant reduction in TNF-α, IL-6, and IL-10. Probiotics combined with EN significantly reduced esophageal reflux, bloating, constipation, diarrhea, gastric retention, and gastrointestinal bleeding. It relieved intestinal stress and reduced the occurrence of adverse reactions such as esophageal reflux, bloating, constipation, diarrhea, gastric retention, and gastrointestinal bleeding (P < 0.05). In terms of reducing stroke complications, probiotics combined with EN reduced the incidence of lung, gastrointestinal, and urinary tract infections (P < 0.05). It also reduced fatality rates and intestinal flora imbalance rates (P < 0.05). CONCLUSION: The probiotics combined with EN group's therapeutic effects were superior to those of the EN alone. Thus, probiotics combined with EN is worthy of both clinical application and promotion in stroke treatment.

Zhuifeng Tougu capsules improve rheumatoid arthritis symptoms in rats by regulating the toll-like receptor 2/4-nuclear factor kappa-B signaling pathway.

OBJECTIVE: To investigate the efficacy of Zhuifeng tougu capsules (, ZFTG) in the treatment of rheumatoid arthritis (RA) in rats and study its mechanism, focusing on the toll-like receptor 2/4-nuclear factor kappa-B (TLR2/4-NF-κB) signaling pathway. METHODS: Type Ⅱ collagen and an artificial climate box were used to construct the rat model of collagen-induced arthritis with wind-cold-dampness arthralgia syndrome. The rats were divided randomly into a control group, wind-cold-dampness syndrome model group, and high-, medium-, and low-dose ZFTG groups. The methotrexate (MTX) control group was treated with the corresponding drug intervention for 28 d. The joint temperature, pain threshold, joint swelling degree, and arthritis index (AI) score were measured. The production of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and rheumatoid factors (RFs) in the blood was detected by enzyme-linked immunosorbent assay. The protein expression of TLR2, TLR4, and NF-κB in synovial tissues was detected by Western blotting, and the mRNA expression of TLR2, TLR4, and NF-κB was detected by real-time polymerase chain reaction. RESULTS: Compared with the model group, the joint temperature in each treatment group, the MTX control group, and MTX group recovered, the degree of foot swelling, pain threshold, AI score decreased, serum CRP, ESR, RF level and the levels of TLR2, TLR4, and NF-κB in synovial tissue were decreased (P < 0.05). Among them, the curative effect in the medium-dose and MTX groups was more evident (P < 0.01). CONCLUSION: ZFTG has a significant effect on RA in rats, and its mechanism may involve regulating CRP levels, the ESR, and RFs via the TLR2/4-NF-κB signaling pathway.

Effect of Tongqiao Huoxue Decoction Combined with Western Medicine on Ischemic Stroke: A Systematic Review.

OBJECTIVE: We conducted a systematic review and meta-analysis to systematically evaluate the curative effect of Tongqiao Huoxue Decoction (TQHXD) combined with Western medicine treatment (WMT) on Ischemic Stroke (IS). METHODS: Randomized controlled trials (RCTs) of TQHXD in the treatment of IS by computer retrieval of PubMed, Embase, Web of Science, Chinese Biomedical Literature Service System, CNKI, Wanfang Database, and Weipu Database. The retrieval time was taken from the establishment of the database to July 30, 2020. Two researchers, respectively, conducted a strict evaluation of the quality of the literature and extracted the data which were then entered in the RevMan5.3 software for meta-analysis. RESULTS: 40 articles were listed, which involved 3260 patients. Meta-analysis results show that TQHXD combined with WMT can significantly reduce patients' NIHSS score, serum hypersensitivity C-reactive protein (hs-CRP), plasma viscosity, serum fibrinogen, serum total cholesterol, and serum triglycerides and improve patients' ADL-Barthel scoring and treatment efficiency. However, there is no evidence that TQHXD combined with the WMT group can significantly decrease the incidence of adverse events. CONCLUSION: The therapeutic effect of TQHXD combined with the WMT group was significantly better than that of the WMT alone group. For the treatment of patients with IS, TQHXD combined with WMT is worthy of application and promotion.

Electroacupuncture ameliorates cerebral ischemia/reperfusion injury by suppressing autophagy via the SIRT1-FOXO1 signaling pathway.

Cerebral ischemia/reperfusion (CIR) injury occurs when blood flow is restored in the brain, causing secondary damage to the ischemic tissues. Previous studies have shown that electroacupuncture (EA) treatment contributes to brain protection against CIR injury through modulating autophagy. Studies indicated that SIRT1-FOXO1 plays a crucial role in regulating autophagy. Here we investigated the mechanisms underlying the neuroprotective effect of EA and its role in modulating autophagy via the SIRT1-FOXO1 signaling pathway in rats with CIR injury. EA pretreatment at "Baihui", "Quchi" and "Zusanli" acupoints (2/15Hz, 1mA, 30 min/day) was performed for 5 days before the rats were subjected to middle cerebral artery occlusion, and the results indicated that EA pretreatment substantially reduced the Longa score and infarct volume, increased the dendritic spine density and lessened autophagosomes in the peri-ischemic cortex of rats. Additionally, EA pretreatment also reduced the ratio of LC3-II/LC3-I, the levels of Ac-FOXO1 and Atg7, and the interaction of Ac-FOXO1 and Atg7, but increased the levels of p62, SIRT1, and FOXO1. The above effects were abrogated by the SIRT1 inhibitor EX527. Thus, we presume that EA pretreatment elicits a neuroprotective effect against CIR injury, potentially by suppressing autophagy via activating the SIRT1-FOXO1 signaling pathway.

Modulators of microglia activation and polarization in ischemic stroke (Review).

Ischemic stroke is one of the leading causes of mortality and disability worldwide. However, there is a current lack of effective therapies available. As the resident macrophages of the brain, microglia can monitor the microenvironment and initiate immune responses. In response to various brain injuries, such as ischemic stroke, microglia are activated and polarized into the proinflammatory M1 phenotype or the anti­inflammatory M2 phenotype. The immunomodulatory molecules, such as cytokines and chemokines, generated by these microglia are closely associated with secondary brain damage or repair, respectively, following ischemic stroke. It has been shown that M1 microglia promote secondary brain damage, whilst M2 microglia facilitate recovery following stroke. In addition, autophagy is also reportedly involved in the pathology of ischemic stroke through regulating the activation and function of microglia. Therefore, this review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke. The effects of autophagy on microglia polarization in ischemic stroke were also reviewed. Finally, future research areas of ischemic stroke and the implications of the current knowledge for the development of novel therapeutics for ischemic stroke were identified.

MicroRNA-23a promotes colorectal cancer cell survival by targeting PDK4.

MicroRNA (miR) is important regulators of gene expression, and aberrant miR expression has been linked to oncogenesis; however, little is understood about their contribution to colorectal cancer (CRC). Here, we determined that miR-23a is overexpressed in human colorectal cancer cell lines and tissues compared with that of normal cells. The stable over-expression of miR-23a in CRC cells was sufficient to promote cell proliferation in vitro and in vivo. Further studies showed that miR-23a can directly bind to the 3'untranslated region (3'UTR) of PDK4 mRNA and subsequently repress both the mRNA and protein expressions of PDK4. PDK4 negatively regulate CRC proliferation via suppressing PDH activity. Ectopic expression of PDK4 by transiently transfected with PDK4 vector encoding the entire coding sequence could reverse the effects of miR-23a on CRC proliferation. By this way, miR-23a promotes PDH activation and oxidative phosphorylation to generate sufficient ATP for cell proliferation. Our results illustrated that the up-regulation of miR-23a played an important role in CRC cell proliferation through direct repressing PDK4, suggesting a potential application of miR-23a in prognosis prediction and therapeutic application in CRC.

Novel, nano-sized, liposome-encapsulated polyamidoamine dendrimer derivatives facilitate tumour targeting by overcoming the polyethylene glycol dilemma and integrin saturation obstacle.

Drug delivery systems (DDSs) commonly employ arginine-glycine-aspartic acid (RGD) peptides with polyethylene glycol (PEG)-dependent enhanced permeability and retention (EPR) effect to optimise tumour-targeting. However, the PEG dilemma and integrin saturation obstacle are major challenges. To address these issues, we constructed a novel, nano-sized DDS by encapsulating doxorubicin (DOX)-loaded folic acid derivatives of polyamidoamine dendrimer (PAMAM G5.0) in cyclic RGD-tyrosine-lysine pentapeptide (c[RGDyK])-modified liposomes (RGD-SL[FND/DOX]), prepared using thin-film hydration, film-dispersion and hydration-sonication. The liposomes were PEGylated, sterically stabilised and pH-sensitive. In vitro, RGD-SL[FND/DOX] showed pH-sensitive holistic FND/DOX release, and pH-dependent uptake and cytotoxicity in human cancer KB cells. At pH 7.4, RGD-SL[FND/DOX] demonstrated greater cellular uptake and cytotoxicity than relevant control formulations (except FND/DOX) did, although this advantage disappeared at pH 6.5. In vivo, RGD-SL[FND/DOX] inhibited S180 sarcoma xenografted tumour growth in Kunming mice more effectively than FND/DOX did. These findings demonstrate the feasibility of constructing double-stage tumour-targeting nano-sized DDSs such as RGD-SL[FND/DOX]. c[RGDyK] and the EPR effect, facilitated by the particle size (about 110 nm) and PEGylation, helped to target the DDS to the tumour tissue, while the subsequent pH-dependent release of FND/DOX and folic acid-mediated endocytosis specifically targeted the tumour cells, thereby overcoming the PEG dilemma and integrin saturation obstacle.

[Pharmacodynamics of liposomes modified with different chain length of sialic acid derivatives].

A large number of experimental and clinical data indicates that tumor-associated macrophages(TAMs) were involved in the whole process of tumor growth, invasion and metastasis. Like macrophages in other tissues, TAMs originate from blood monocytes, which are recruited to the tumor tissues by cytokines and then differentiated into TAMs. It is interesting that the monocytes overexpress siglec receptor in their surface, which has a high binding specificity to sialic acid(SA). From this point of view, we hypothesize that if SA was used as a ligand in the surfaces of drug delivery systems, SA would enhance the targeting efficiency to monocytes, and thus to achieve a higher specificity to TAMs. In our previous study, an SA derivative of SA-octadecylamine(SA-18) was synthesized and was found to enhance cytotoxicity on TAMs in vitro. The chain length is a critical factor for SA efficiency in liposomes and it has a significant influence on the TAM targeting effects of the carriers. So in this study, four kinds of different chain length of SA fatty amine derivatives were synthesized, including SA-18, SA-hexadecylamine(SA-16), SA-tetradecylamine(SA-14) and SA-dodecylamine(SA-12), and were modified on the surfaces of blank liposomes(BLK-Sn L, n = 18, 16, 14, 12) and pixantrone maleate-loaded liposomes(Pix-Sn L, n = 18, 16, 14, 12). TAM targeting effects of these SA derivatives were evaluated by acute toxicity and antitumor efficacy in vivo. The results of acute toxicity experiments showed that the toxicities of the SA derivatives deceased gradually with the reduction in the length of lipophilic chain. The in vivo antitumor efficacies of SA-modified blank liposomes showed that these blank formulations had no effect on the tumor inhibition except BLK-S14L(61.4% ± 18.8%), and BLK-S16 L even promoted the tumor growth(-31.7% ± 13.1%, the 18 th day). The in vivo antitumor efficacies of SA-modified Pix liposomes showed that the tumor inhibition effects were Pix-S18L(97.4% ± 2.1%) > Pix-S14L(73.1% ±21.1%) > Pix-S12L(53.9% ± 17.8%) > Pix-S16L(32.9%). Because of the relatively strong binding ability of SA-18, it was hard to fall off from the liposomes in the transport process, leading to a good TAM targeting ability and less toxicity to the normal tissues. Meanwhile, 50% of the mice in Pix-S18 L group showed "tumor shedding" and "wound healing" phenomena without recurrence in two months following the treatment. Therefore, SA-18 is the most potential TAM targeting material among these SA fatty amine derivatives.

["PEG dilemma" for liposomes and its solving approaches].

Polyethylene glycol (PEG) is extensively used to increasing the in vivo and in vitro stability of liposomes. However, PEGylated liposomes also produce some negative effects with further research, such as low cellular uptake, poor "endosomal escape" of pH sensitive liposome (PSL) and accelerated blood clearance (ABC) phenomenon, and this situation is referred as the "PEG dilemma". "PEG dilemma" posed severe challenges for the targeted delivery of PEGylated liposomes-loaded anticancer drugs, effective intracellular release of PEGylated PSL-encapsulated gene and protein drugs, and repeated administration of PEGylated liposomes. Therefore, it is urgent to solve the "PEG dilemma". This review focused on the definition, classification of "PEG dilemma", and discussed several possible approaches to overcome "PEG dilemma".

Lignans from the bark of Zanthoxylum simulans.

Investigation on the EtOAc extract of the bark of Zanthoxylum simulans led to the isolation of four new lignans including zanthoxylumin A (1), zanthoxylumin B (2), ( - )-magnolin (3), and ( - )-pinoresinol-di-3,3-dimethylallyl ether (4). Their structures were established by comprehensive analysis of the spectral data, especially 1D and 2D NMR spectra.