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Ning Pang, Ji Li, Aning Sun, Zhenzhen Yang, Shixuan Cheng, Xian-Rong Qi Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China Background: Abnormal expression of stromal cells and extracellular matrix in tumor stroma creates a tight barrier, leading to insufficient extravasation and penetration of therapeutic agents. Cancer-associated fibroblasts (CAFs) take on pivotal roles encouraging tumor progression.Method: To surmount the refractoriness of stroma, we constructed a multi-targeting combined scenario of anti-CAFs agent tranilast and antitumor agent docetaxel micelles (DTX-Ms). Tranilast cut down crosstalk between tumor cells and stromal cells, ameliorated the tumor microenvironment, and enhanced the antiproliferation efficacy of DTX-Ms on cancer cells.Results: Diverse experiments demonstrated that tranilast enhanced DTX-Ms’ antitumor effect in a two-stage pattern by CAFs ablation, tumor cell migration blocking, and metastasis inhibition. Along with activated CAFs decreasing in vivo, the two-stage therapy succeeded in reducing interstitial fluid pressure, normalizing microvessels, improving micelles penetration and retention, and inhibiting tumor growth and metastasis. Interestingly, tranilast alone failed to inhibit tumor growth in vivo, and it could only be used as an adjuvant medicine together with an antitumor agent.Conclusion: Our proposed two-stage therapy offers a promising strategy to enhance antitumor effects by breaking down CAFs barrier and increasing micellar delivery efficiency. Keywords: two-stage therapy, tumor microenvironment normalization, cancer-associated fibroblasts, tranilast, stromal ablation

Nian-Qiu Shi,1 Yan Li,2 Yong Zhang,3 Zheng-Qiang Li,4 Xian-Rong Qi5 1School of Pharmacy, Jilin Medical University, Jilin, Jilin, 132013, China; 2Immunology Department, Laboratory Medical College, Jilin Medical University, Jilin, Jilin, 132013, China; 3College of Life Science, Jilin University, Changchun, Jilin, 130012, China; 4Key Laboratory for Molecular Enzymology and Engineering, Ministry of Education, College of Life Science, Jilin University, Changchun, Jilin, 130012, China; 5Department of Pharmaceutics, School of Pharmaceutical Science, Peking University, Beijing, 100191, China Introduction: Acceleration and improvement of penetration across cell-membrane interfaces of active targeted nanotherapeutics into tumor cells would improve tumor-therapy efficacy by overcoming the issue of poor drug penetration. Cell-penetrating peptides, especially synthetic polyarginine, have shown promise in facilitating cargo delivery. However, it is unknown whether polyarginine can work to overcome the membrane interface in an inserted pattern for cyclic peptide ligand-mediated active targeting drug delivery. Here, we conducted a study to test the hypothesis that tandem-insert nona-arginine (tiR9) can act as an accelerating component for intracellular internalization, enhance cellular penetration, and promote antitumor efficacy of active targeted cyclic asparagine–glycine–arginine (cNGR)-decorated nanoliposomes. Methods: Polyarginine was coupled with the polyethylene glycol (PEG) chain and the cNGR moiety, yielding a cNGR–tiR9–PEG2,000–distearoylphosphatidylethanolamine conjugate. Results: The accelerating active targeted liposome (Lip) nanocarrier (cNGR-tiR9-Lip–doxorubicin [Dox]) constructed in this study held suitable physiochemical features, such as appropriate particle size of ~150 nm and sustained-release profiles. Subsequently, tiR9 was shown to enhance cellular drug delivery of Dox-loaded active targeted systems (cNGR-Lip-Dox) significantly. Layer-by-layer confocal microscopy indicated that the tandem-insert polyarginine accelerated active targeted system entry into deeper intracellular regions based on observations at marginal and center locations. tiR9 enhanced the penetration depth of cNGR-Lip–coumarin 6 through subcellular membrane barriers and caused its specific accumulation in mitochondria, endoplasmic reticulum, and Golgi apparatus. It was also obvious that cNGR-tiR9-Lip-Dox induced enhanced apoptosis and activated caspase 3/7. Moreover, compared with cNGR-Lip-Dox, cNGR-tiR9-Lip-Dox induced a significantly higher antiproliferative effect and markedly suppressed tumor growth in HT1080-bearing nude mice. Conclusion: This active tumor-targeting nanocarrier incorporating a tandem-insert polyarginine (tiR9) as an accelerating motif shows promise as an effective drug-delivery system to accelerate translocation of drugs across tumor-cell/subcellular membrane barriers to achieve improved specific tumor therapy. Keywords: accelerating active targeting nanotherapeutics, tandem-insert nona-arginine, tiR9, cyclic asparagine–glycine–arginine, cNGR, penetration and tumor therapy, multifunctional nanomedicines

Bai Xiang,1,* Xue-Li Jia,1,* Jin-Long Qi,2 Li-Ping Yang,1 Wei-Hong Sun,1 Xiao Yan,1 Shao-Kun Yang,1 De-Ying Cao,1 Qing Du,1 Xian-Rong Qi3 1Department of Pharmaceutics, School of Pharmaceutical Sciences, 2Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei, 3School of Pharmaceutical Sciences, Peking University, Beijing, China *These authors contributed equally to this work Abstract: As a potent therapeutic agent, small interfering RNA (siRNA) has been exploited to silence critical genes involved in tumor initiation and progression. However, development of a desirable delivery system is required to overcome the unfavorable properties of siRNA such as its high degradability, molecular size, and negative charge to help increase its accumulation in tumor tissues and promote efficient cellular uptake and endosomal/lysosomal escape of the nucleic acids. In this study, we developed a new activatable cell-penetrating peptide (ACPP) that is responsive to an acidic tumor microenvironment, which was then used to modify the surfaces of siRNA-loaded liposomes. The ACPP is composed of a cell-penetrating peptide (CPP), an acid-labile linker (hydrazone), and a polyanionic domain, including glutamic acid and histidine. In the systemic circulation (pH 7.4), the surface polycationic moieties of the CPP (polyarginine) are “shielded” by the intramolecular electrostatic interaction of the inhibitory domain. When exposed to a lower pH, a common property of solid tumors, the ACPP undergoes acid-catalyzed breakage at the hydrazone site, and the consequent protonation of histidine residues promotes detachment of the inhibitory peptide. Subsequently, the unshielded CPP would facilitate the cellular membrane penetration and efficient endosomal/lysosomal evasion of liposomal siRNA. A series of investigations demonstrated that once exposed to an acidic pH, the ACPP-modified liposomes showed elevated cellular uptake, downregulated expression of polo-like kinase 1, and augmented cell apoptosis. In addition, favorable siRNA avoidance of the endosome/lysosome was observed in both MCF-7 and A549 cells, followed by effective cytoplasmic release. In view of its acid sensitivity and therapeutic potency, this newly developed pH-responsive and ACPP-mediated liposome system represents a potential platform for siRNA-based cancer treatment. Keywords: siRNA, ACPP, hydrazone, liposome, endosomal/lysosomal escape

The first measurement of (Formula presented) and an upper limit for (Formula presented) are determined from 22.3 (Formula presented) of (Formula presented) annihilation data at a c.m. energy of 4.03 GeV. The data were recorded by the Beijing Spectrometer (BES) at BEPC. A recoil charge method is applied to charm threshold data to determine the charge of the D meson in the recoil from (Formula presented) reconstructed (Formula presented) (Formula presented) mesons. The branching fractions (Formula presented) and (Formula presented) are determined from 10 events with a reconstructed D and a recoiling (Formula presented) In addition, a 90% C.L. upper limit of (Formula presented) is determined from a search for semileptonic decays of the (Formula presented) © 2000 The American Physical Society.

Using a sample of 3.8 M (Formula presented) events accumulated with the BES detector, the process (Formula presented) is studied. The angular distributions are compared with the general decay amplitude analysis of Cahn. We find that the dipion system requires some D wave amplitude, as well as S wave. On the other hand, the (Formula presented) relative angular momentum is consistent with being pure S wave. The decay distributions have been fit to heavy quarkonium models, including the Novikov-Shifman model. This model, which is written in terms of the parameter (Formula presented) predicts that D wave pions should be present. We determine (Formula presented) based on the joint (Formula presented) distribution. The fraction of D wave amplitude as a function of (Formula presented) is found to decrease with increasing (Formula presented) in agreement with the model. We have also fit the Mannel-Yan model, which is another model that allows D wave pions. © 2000 The American Physical Society.

The cross section for charmed meson production at √s=4.03 and 4.14 GeV has been measured with the Beijing Spectrometer. The measurement was made using 22.3 pb-1 of e+e- data collected at 4.03 GeV and 1.5 pb-1 of e+e- data collected at 4.14 GeV. Inclusive observed cross sections for the production of charged and neutral D mesons and momentum spectra are presented. Observed cross sections were radiatively corrected to obtain tree level cross sections. Measurements of the total hadronic cross section are obtained from the charmed meson cross section and an extrapolation of results from below the charm threshold. ©2000 The American Physical Society.

Using a sample of 3.8 M (Formula presented) events accumulated with the BES detector, the process (Formula presented) is studied. The angular distributions are compared with the general decay amplitude analysis of Cahn. We find that the dipion system requires some D wave amplitude, as well as S wave. On the other hand, the (Formula presented) relative angular momentum is consistent with being pure S wave. The decay distributions have been fit to heavy quarkonium models, including the Novikov-Shifman model. This model, which is written in terms of the parameter (Formula presented) predicts that D wave pions should be present. We determine (Formula presented) based on the joint (Formula presented) distribution. The fraction of D wave amplitude as a function of (Formula presented) is found to decrease with increasing (Formula presented) in agreement with the model. We have also fit the Mannel-Yan model, which is another model that allows D wave pions. © 2000 The American Physical Society.

The first measurement of (Formula presented) and an upper limit for (Formula presented) are determined from 22.3 (Formula presented) of (Formula presented) annihilation data at a c.m. energy of 4.03 GeV. The data were recorded by the Beijing Spectrometer (BES) at BEPC. A recoil charge method is applied to charm threshold data to determine the charge of the D meson in the recoil from (Formula presented) reconstructed (Formula presented) (Formula presented) mesons. The branching fractions (Formula presented) and (Formula presented) are determined from 10 events with a reconstructed D and a recoiling (Formula presented) In addition, a 90% C.L. upper limit of (Formula presented) is determined from a search for semileptonic decays of the (Formula presented) © 2000 The American Physical Society.

Hadronic decays of the P-wave spin-triplet charmonium states (Formula presented) are studied using a sample of (Formula presented) decays collected by the BES detector operating at the BEPC storage ring. Branching fractions for the decays (Formula presented) (Formula presented) (Formula presented) (Formula presented) (Formula presented) and (Formula presented) are measured for the first time, and those for (Formula presented) (Formula presented) (Formula presented) and (Formula presented) are measured with improved precision. In addition, we determine the masses of the (Formula presented) and (Formula presented) to be (Formula presented) and (Formula presented) © 1999 The American Physical Society.

A sample of 3.79 × 106ψ(2S) events is used to study the decays of charmonium to axial-vector plus pseudoscalar mesons. The branching fraction for the decay ψ(2S) → b±1(1235)π∓ agrees with expectations based on scaling the corresponding J/ψ branching fraction. Flavor-SU(3)-violating K1(1270)- K1(1400) asymmetries with opposite character for ψ(2S) and J/ψ decays are observed. This contrasting behavior cannot be accommodated by adjustments of the singlet-triplet mixing angle. © 1999 The American Physical Society.

Hadronic decays of the P-wave spin-triplet charmonium states (Formula presented) are studied using a sample of (Formula presented) decays collected by the BES detector operating at the BEPC storage ring. Branching fractions for the decays (Formula presented) (Formula presented) (Formula presented) (Formula presented) (Formula presented) and (Formula presented) are measured for the first time, and those for (Formula presented) (Formula presented) (Formula presented) and (Formula presented) are measured with improved precision. In addition, we determine the masses of the (Formula presented) and (Formula presented) to be (Formula presented) and (Formula presented) © 1999 The American Physical Society.

The decays of the ψ(2S) into vector plus tensor meson final states have been studied for the first time using the BES detector. We determine upper limits on branching fractions for ψ(2S) decays into ωf2, ρa2, K*0K*02 + c.c., and φf'2(1525) that are, in each case, significantly smaller than the corresponding branching fractions for the J/ψ meson, scaled according to the expectations of perturbative QCD. © 1998 The American Physical Society.

The processes ψ(2S) → I π+ π−, γK+ K−, and γpp¯ have been studied using a sample of 3.79 × 106 ψ(2S) decays. We determine the total width of the χc0 to be γtotχc0 = 14.3 ± 2.0 ± 3.0 MeV. We present the first measurement of the branching fraction B(χc0 → pp¯) = (15.9 ± 4.3 ± 5.3) × 10−5, where the first error is statistical and the second one is systematic. Branching fractions of χc0, 2 → π+ π− and K+ K− are also reported. © 1998 American Physical Society.

A search is performed for the production of the (Formula presented) in (Formula presented) annihilation at a center-of-mass energy of 4.03 GeV using the BES detector operated at the Beijing Electron Positron Collider (BEPC). The kinematic features of the reconstructed (Formula presented) signal are consistent with its being produced only in association with an energetic photon resulting from initial state radiation (ISR). Limits are placed on (Formula presented) production from the decay of unknown charmonia or metastable hybrids that might be produced in (Formula presented) annihilations at 4.03 GeV. Under the assumption that the observed cross section for (Formula presented) production is due entirely to ISR, the partial width (Formula presented) of the (Formula presented) is measured to be (Formula presented). © 1998 The American Physical Society.

A search is performed for the production of the (Formula presented) in (Formula presented) annihilation at a center-of-mass energy of 4.03 GeV using the BES detector operated at the Beijing Electron Positron Collider (BEPC). The kinematic features of the reconstructed (Formula presented) signal are consistent with its being produced only in association with an energetic photon resulting from initial state radiation (ISR). Limits are placed on (Formula presented) production from the decay of unknown charmonia or metastable hybrids that might be produced in (Formula presented) annihilations at 4.03 GeV. Under the assumption that the observed cross section for (Formula presented) production is due entirely to ISR, the partial width (Formula presented) of the (Formula presented) is measured to be (Formula presented). © 1998 The American Physical Society.

Nian-Qiu Shi, Wei Gao, Bai Xiang, Xian-Rong QiDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of ChinaAbstract: The use of activable cell-penetrating peptides (ACPPs) as molecular imaging probes is a promising new approach for the visualization of enzymes. The cell-penetrating function of a polycationic cell-penetrating peptide (CPP) is efficiently blocked by intramolecular electrostatic interactions with a polyanionic peptide. Proteolysis of a proteinase-sensitive substrate present between the CPP and polyanionic peptide affords dissociation of both domains and enables the activated CPP to enter cells. This ACPP strategy could also be used to modify antitumor agents for tumor-targeting therapy. Here, we aimed to develop a conjugate of ACPP with antitumor drug doxorubicin (DOX) sensitive to matrix metalloproteinase-2 and -9 (MMP-2/9) for tumor-targeting therapy purposes. The ACPP-DOX conjugate was successfully synthesized. Enzymatic cleavage of ACPP-DOX conjugate by matrix metalloproteinase (MMP)-2/9 indicated that the activation of ACPP-DOX occurred in an enzyme concentration–dependent manner. Flow cytometry and laser confocal microscope studies revealed that the cellular uptake of ACPP-DOX was enhanced after enzymatic-triggered activation and was higher in HT-1080 cells (overexpressed MMPs) than in MCF-7 cells (under-expressed MMPs). The antiproliferative assay showed that ACPP had little toxicity and that ACPP-DOX effectively inhibited HT-1080 cell proliferation. These experiments revealed that the ACPP-DOX conjugate could be triggered by MMP-2/9, which enabled the activated CPP-DOX to enter cells. ACPP-DOX conjugate may be a potential prodrug delivery system used to carry antitumor drugs for MMP-related tumor therapy.Keywords: activable cell-penetrating peptide, matrix metalloproteinase, proteinase-sensitive substrate, cellular uptake, antiproliferative, enzymatic cleavage, tumor extracellular environment

Wei Zhao, Song Zhuang, Xian-Rong QiDepartment of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of ChinaAbstract: Neutral liposomes (NLP) exhibit preferential localization in solid tumors based on the enhanced permeation and retention (EPR) effect. Cationic liposomes (CLP) have a propensity for localizing in newly formed tumor vessels and they have a potentially enhanced antitumor effect. However, an increased amount of cationic lipids in liposomes also induces aggregation through electrostatic interactions between the liposomes and the anionic species in the circulation, which results in a reduced EPR effect. Consequently, it is important to investigate the characteristics of liposomes with different surface potentials in vitro to achieve an optimal intratumoral distribution and antitumor effect in vivo. In this study, the authors evaluated the characteristics of doxorubicin (DOX)-loaded NLPs, CLPs, polyethylene glycol (PEG)-modified NLPs (NLP-PEG), and PEGylated CLPs (CLP-PEG) (ie, encapsulation efficacy, zeta potential, size, membrane fluidity, aggregation in serum, and uptake of liposomes into rat aortic endothelial cells (RAECs)) to further understand their influences on the pharmacokinetics, biodistribution, and antitumor therapy in vivo. The results showed that increased amounts of cationic lipids resulted in severe liposome aggregation in the presence of serum, yet it did not alter the membrane fluidity to a large extent. The uptake of liposomes into RAECs, visualized by confocal fluorescence microscopy, confirmed the rapid uptake of CLP by the endothelial cells compared with NLP. However, the pharmacokinetics, biodistribution and anticancer efficacies of these liposomes in vivo revealed that the CLP with highly positive surface potentials exhibited reduced circulation times and poor distribution in tumors. The NLP-PEG exhibited the highest anticancer efficacy; CLP-PEG, the second highest; and CLP with the most positive surface potential, the lowest. These phenomena were mostly due to the rapid aggregation in serum and subsequent accumulation in the lungs upon the intravenous injection of the CLP. Caution should be exercised when chemotherapeutic drugs are loaded into CLP for tumor therapy.Keywords: cationic liposomes, PEGylation, electrostatic interaction, aggregation, anticancer efficacy, biodistribution

Zong-Xia Lu1, Li-Ting Liu1,2, Xian-Rong Qi11Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China; 2Department of Pharmacy, School and Hospital of Stomatology, Peking University, Beijing, People's Republic of ChinaBackground: Small interfering RNA (siRNA) can silence target genes in the cytoplasm and be a major tool in gene therapy. Vascular endothelial growth factor (VEGF), a potent regulator of angiogenesis, is overexpressed in most tumors and is closely associated with tumor growth and metastasis. It has been shown that inhibition of VEGF expression by siRNA is an effective and useful method for antiangiogenic tumor therapy.Methods: In the present study, we synthesized a targeted delivery system of PEI-PEG-APRPG incorporating angiogenic vessel-homing Ala-Pro-Arg-Pro-Gly (APRPG) peptide into cationic polyethylenimine (PEI) via a hydrophilic poly(ethylene glycol) (PEG) spacer.Results: PEI-PEG-APRPG effectively condensed siRNA into 20–50 nm nanoparticles with a positive surface charge using a suitable N/P ratio. The siRNA/PEI-PEG-APRPG complex effectively enhanced the stability of siRNA in RNase A, and improved the proliferation-inhibiting ability and transfection efficiency of siRNA in vitro and tumor accumulation in vivo. In addition, the siRNA/PEI-PEG-APRPG complex exhibited high efficiency as antitumor therapy with regard to tumor growth, microvessel density, and VEGF protein and mRNA levels.Conclusion: These findings suggest that PEI-PEG-APRPG effectively delivers siRNA to tumors overexpressing VEGF and thereby inhibits tumor growth.Keywords: PEI-PEG-APRPG, VEGF siRNA, gene delivery, tumor-targeted, antiangiogenic therapy

This study aims to reveal the effects of the herb pair Astragali Radix-Salviae Miltiorrhizae Radix et Rhizoma(AR-SMRR) on phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/Akt/mTOR) pathway and autophagy in the lung tissue of the rat model of acute lung injury(ALI). Fifty adult male SD rats were randomized into sham, model, autophagy inhibition(intraperitoneal injection of chloroquine at 10 mg·kg~(-1)), autophagy induction(intraperitoneal injection of rapamycin at 15 mg·kg~(-1)), and AR-SMRR(5 g·kg~(-1), gavage) groups. The rats in the sham group received intratracheal instillation of normal saline, and those in other groups received intratracheal instillation of lipopolysaccharide(LPS, 5 mg·kg~(-1)) for the modeling of ALI. Seven days before the operation, the rats in the sham and model groups were administrated with normal saline, and those in other groups with corresponding drugs. Specimens were collected 24 h after modeling. The pathological changes of the lung tissue were observed under a light microscope. The lung wet/dry weight ratio and the lactate dehydrogenase(LDH) activity and total protein concentration in the bronchoalveolar lavage fluid(BALF) were measured. Western blot was employed to measure the protein levels of microtubule-associated protein 1-light chain 3(LC3), beclin-1, p62, PI3K, Akt, and mTOR. Compared with the sham group, the model group showed increased histopathological score of the lung tissue, lung wet/dry weight ratio, and LDH activity and protein concentration in BALF. Autophagy inhibition further increased these indicators compared with the model group, while autophagy induction and AR-SMRR lowered the levels. In addition, AR-SMRR up-regulated the protein levels of LC3-Ⅱ and beclin-1, down-regulated the expression of p62, and inhibited the expression of p-PI3K, p-Akt, and p-mTOR in the lung tissue of ALI rats. The findings suggest that AR-SMRR can alleviate the lung injury and edema in the rat model of ALI induced by LPS by enhancing autophagy via down-regulating PI3K/Akt/mTOR signaling pathway.

Objective: The efficacy of medications for Parkinson's disease (PD) tend to decline over time, which has a serious impact on patients' health and quality of life. To some extent, traditional Chinese medicine (TCM) can resolve the distressing problem of ineffective dopaminergic medication in PD patients. The purpose of this study was to investigate the attitude, acceptance, and independent predictors of TCM in PD patients admitted to the outpatient department of a tertiary hospital., Methods: A cross-sectional study of PD patients was conducted in the outpatient department of a large tertiary hospital in Beijing from March 2022 to June 2023. A self-report questionnaire was developed to investigate PD patients' attitudes and acceptance of TCM based on the questionnaire. Multivariate logistic regression analyses were also performed to further clarify the independent predictors influencing patients' adoption of TCM therapy., Results: A total of 397 patients completed the questionnaire, of which 78.09% were willing to be treated with TCM and 21.91% indicated that they were not willing to use TCM. Multifactorial logistic regression analysis showed that several parameters were correlated with a patient's willingness to include TCM in their therapeutic regime. These included education level of a bachelor's degree (odds ratio [OR) = 8.554; 95% confidence interval [CI]: 4.112-17.794; P < 0.001, vs junior high school education), living in an urban setting (OR = 8.022; 95% CI: 4.577-14.060; P < 0.001, vs rural), having other underlying diseases (OR = 5.126; 95% CI: 3.078-8.537; P < 0.001, vs none), having previously used TCM (OR = 3.083; 95% CI: 1.852-5.134; P < 0.001, vs not used), believing that TCM therapy is safe (OR = 3.530; 95% CI: 1.446-8.616; P = 0.006, vs not thought), believing that TCM therapy is effective (OR = 3.859; 95% CI: 1.482-10.047; P = 0.006, vs not understood), and being willing to discuss ongoing TCM therapy with an attending physician (OR = 62.468; 95% CI: 30.350-128.574; P < 0.001, vs not informed)., Conclusion: This study initially investigated the acceptance, attitude, and independent predictors of TCM use among PD patients. To expand the prevalence of TCM use among patients with PD, we recommend to broadening the public outreach for TCM via contemporary means of Internet and broadcast communication, enhancing access to TCM services in rural communities, and strengthening the communication between doctors and patients. Please cite this article as: Wang P, Hong J, Tang ZQ, Gong BZ, Qi XR, Jiang H, Pan B, Chen Q. The acceptance of traditional Chinese medicine among patients with Parkinson's disease: A hospital survey. J Integr Med. 2024; 22(2): 180-187., (Copyright © 2024 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

An abnormal glutamate signaling pathway has been proposed in the mechanisms of autism spectrum disorder (ASD). However, less is known about the involvement of alterations of glutaminase 1 (GLS1) in the pathophysiology of ASD. We show that the transcript level of GLS1 is significantly decreased in the postmortem frontal cortex and peripheral blood of ASD subjects. Mice lacking Gls1 in CamKIIα-positive neurons display a series of ASD-like behaviors, synaptic excitatory and inhibitory (E/I) imbalance, higher spine density, and glutamate receptor expression in the prefrontal cortex, as well as a compromised expression pattern of genes involved in synapse pruning and less engulfed synaptic puncta in microglia. A low dose of lipopolysaccharide treatment restores microglial synapse pruning, corrects synaptic neurotransmission, and rescues behavioral deficits in these mice. In summary, these findings provide mechanistic insights into Gls1 loss in ASD symptoms and identify Gls1 as a target for the treatment of ASD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Circulatory and respiratory depression are common  problems that occur in propofol alone sedation during gastroscopy. As a widely used analgesic adjuvant, intravenous lidocaine can reduce the consumption of propofol during Endoscopic retrograde cholangiopancreatography (ERCP) or colonoscopy. However, it is still unknown the median effective dose (ED 50 ) of propofol when combined with lidocaine intravenously. This study aimed to compare the ED 50 of propofol with or without intravenous lidocaine for inserting gastrointestinal endoscope successfully., Methods: Fifty nine patients undergoing gastroscopy or gastrointestinal (GI) endoscopy were randomly divided into control group (Group C, normal saline + propofol) or lidocaine group (Group L, lidocaine + propofol). Patients were initially injected a bolus of 1.5 mg/kg lidocaine in Group L, whereas equivalent volume of 0.9% saline in Group C. Anaesthesia was then induced with a single bolus of propofol in all subjects. The induction dose of propofol was determined by the modified Dixon's up-and-down method, and the initial dose was 1.5 mg/kg in both groups. The primary outcome was the ED 50 of propofol induction dose with or without intravenous lidocaine. The secondary outcomes were the induction time, the first propofol bolus time (FPBT: from MOAA/S score ≤ 1 to first rescue bolus propofol), and adverse events (AEs: hypoxemia, bradycardia, hypotension, and body movements)., Results: Totally, 59 patients were enrolled and completed this study. The ED 50 of propofol combined with lidocaine was 1.68 ± 0.11 mg/kg, significantly reduced compared with the normal saline group, 1.88 ± 0.13 mg/kg (P = 0.002). There was no statistical difference in induction time (P = 0.115) and the FPBT (P = 0.655) between the two groups. There was no significantly difference about the AEs between the two groups., Conclusion: The ED 50 of propofol combined with intravenous lidocaine for successful endoscope insertion in adult patients, was 1.68 ± 0.11 mg/kg significantly reduced compared with the control group., Trial Registration: Chinese Clinical Trial Registry, No: ChiCTR2200059450. Registered on 29 April 2022. Prospective registration. http://www.chictr.org.cn ., (© 2022. The Author(s).)

Background: Oxygen-desaturation episodes, blood pressure drops, and involuntary body movement are common problems that occur in propofol-based sedation in the procedure of painless gastrointestinal (GI) endoscopy. As a widely used analgesic adjuvant, intravenous lidocaine can reduce the consumption of propofol during ERCP or colonoscopy. However, it is still unknown how lidocaine affects the incidence of oxygen-desaturation episodes and cardiovascular events, and involuntary movement during painless GI endoscopy. Therefore, we aimed to assess the effectiveness and safety of intravenous lidocaine in propofol-based sedation for GI endoscopy., Methods: We will conduct a single-center, prospective, randomized, double-blind, saline-controlled trial. A total number of 300 patients undergoing painless GI procedures will be enrolled and randomly divided into the lidocaine group (Group L) and the control group (Group C). After midazolam and sufentanil intravenous injection, a bolus of 1.5 mg/kg lidocaine was immediately injected and followed by a continuous infusion of 4 mg/kg/h in the lidocaine group, whereas the same volumes of saline solution in the control group. Then, propofol was titrated to produce unconsciousness during the procedure. The primary outcome will be the incidence of oxygen-desaturation episodes. Secondary outcomes will be the incidence of involuntary body movement, discomfort symptoms, propofol consumption, endoscopist, and patient satisfaction., Discussion: Propofol-based deep sedation without intubation is widely used in painless GI endoscopy. However, adverse events such as hypoxemia often occur clinically. We expect to assess the effect of lidocaine on reducing the incidence of oxygen-desaturation episodes, cardiovascular events, and involuntary body movement. We believe that the results of this trial will provide an effective and safe method for painless GI endoscopy., Trial Registration: Chinese Clinical Trial Registry ChiCTR2100053818. Registered on 30 November 2021., (© 2022. The Author(s).)

Background: Deep learning (DL) could predict isocitrate dehydrogenase (IDH) mutation status from MRIs. Yet, previous work focused on CNNs with refined tumor segmentation. To bridge the gap, this study aimed to evaluate the feasibility of developing a Transformer-based network to predict the IDH mutation status free of refined tumor segmentation. Methods: A total of 493 glioma patients were recruited from two independent institutions for model development (TCIA; N = 259) and external test (AHXZ; N = 234). IDH mutation status was predicted directly from T2 images with a Swin Transformer and conventional ResNet. Furthermore, to investigate the necessity of refined tumor segmentation, seven strategies for the model input image were explored: (i) whole tumor slice; (ii-iii) tumor mask and/or not edema; (iv-vii) tumor bounding box of 0.8, 1.0, 1.2, 1.5 times. Performance comparison was made among the networks of different architectures along with different image input strategies, using area under the curve (AUC) and accuracy (ACC). Finally, to further boost the performance, a hybrid model was built by incorporating the images with clinical features. Results: With the seven proposed input strategies, seven Swin Transformer models and seven ResNet models were built, respectively. Based on the seven Swin Transformer models, an averaged AUC of 0.965 (internal test) and 0.842 (external test) were achieved, outperforming 0.922 and 0.805 resulting from the seven ResNet models, respectively. When a bounding box of 1.0 times was used, Swin Transformer (AUC = 0.868, ACC = 80.7%), achieved the best results against the one that used tumor segmentation (Tumor + Edema, AUC = 0.862, ACC = 78.5%). The hybrid model that integrated age and location features into images yielded improved performance (AUC = 0.878, Accuracy = 82.0%) over the model that used images only. Conclusions: Swin Transformer outperforms the CNN-based ResNet in IDH prediction. Using bounding box input images benefits the DL networks in IDH prediction and makes the IDH prediction free of refined glioma segmentation feasible.

To address which mitochondria-related nuclear differentially expressed genes (DEGs) and related pathways are altered during human oocyte maturation, single-cell analysis was performed in three oocyte states: in vivo matured (M-IVO), in vitro matured (M-IVT), and failed to mature in vitro (IM-IVT). There were 691 DEGs and 16 mitochondria-related DEGs in the comparison of M-IVT vs. IM-IVT oocytes, and 2281 DEGs and 160 mitochondria-related DEGs in the comparison of M-IVT vs. M-IVO oocytes, respectively. The GO and KEGG analyses showed that most of them were involved in pathways such as oxidative phosphorylation, pyruvate metabolism, peroxisome, and amino acid metabolism, i.e., valine, leucine, isoleucine, glycine, serine, and threonine metabolism or degradation. During the progress of oocyte maturation, the metabolic pathway, which derives the main source of ATP, shifted from glucose metabolism to pyruvate and fatty acid oxidation in order to maintain a low level of damaging reactive oxygen species (ROS) production. Although the immature oocytes could be cultured to a mature stage by an in vitro technique (IVM), there were still some differences in mitochondria-related regulations, which showed that the mitochondria were regulated by nuclear genes to compensate for their developmental needs. Meanwhile, the results indicated that the current IVM culture medium should be optimized to compensate for the special need for further development according to this disclosure, as it was a latent strategy to improve the effectiveness of the IVM procedure.

Glutaminase 1 (GLS1) has recently been reported to be expressed in microglia and plays a crucial role in neuroinflamation. Significantly increased level of GLS1 mRNA expression together with neuroinflammation pathway were observed in postmortem prefrontal cortex from depressed patients. To find out the function of microglial GLS1 in depression and neuroinflammation, we generated transgenic mice (GLS1 cKO), postnatally losing GLS1 in microglia, to detect changes in the lipopolysaccharide (LPS)-induced depression model. LPS-induced anxiety/depression-like behavior was attenuated in GLS1 cKO mice, paralleled by a significant reduction in pro-inflammatory cytokines and an abnormal microglia morphological phenotype in the prefrontal cortex. Reduced neuroinflammation by GLS1 deficient microglia was a result of less reactive astrocytes, as GLS1 deficiency enhanced miR-666-3p and miR-7115-3p levels in extracellular vesicles released from microglia, thus suppressing astrocyte activation via inhibiting Serpina3n expression. Together, our data reveal a novel mechanism of GLS1 in neuroinflammation and targeting GLS1 in microglia may be a novel strategy to alleviate neuroinflammation-related depression and other disease., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: We aimed to assess the association between gut bacterial biomarkers during early pregnancy and subsequent risk of gestational diabetes mellitus (GDM) in Chinese pregnant women., Methods: Within the Tongji-Shuangliu Birth Cohort study, we conducted a nested case-control study among 201 incident GDM cases and 201 matched controls. Fecal samples were collected during early pregnancy (at 6-15 weeks), and GDM was diagnosed at 24 to 28 weeks of pregnancy. Community DNA isolated from fecal samples and V3-V4 region of 16S rRNA gene amplicon libraries were sequenced., Results: In GDM cases versus controls, Rothia, Actinomyces, Bifidobacterium, Adlercreutzia, and Coriobacteriaceae and Lachnospiraceae spp. were significantly reduced, while Enterobacteriaceae, Ruminococcaceae spp., and Veillonellaceae were overrepresented. In addition, the abundance of Staphylococcus relative to Clostridium, Roseburia, and Coriobacteriaceae as reference microorganisms were positively correlated with fasting blood glucose, 1-hour and 2-hour postprandial glucose levels. Adding microbial taxa to the base GDM prediction model with conventional risk factors increased the C-statistic significantly (P < 0.001) from 0.69 to 0.75., Conclusions: Gut microbiota during early pregnancy was associated with subsequent risk of GDM. Several beneficial and commensal gut microorganisms showed inverse relations with incident GDM, while opportunistic pathogenic members were related to higher risk of incident GDM and positively correlated with glucose levels on OGTT., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Amorphous solid dispersions (ASD) are one of most commonly used supersaturating drug delivery systems (SDDS) to formulate insoluble active pharmaceutical ingredients. However, the development of polymer-guided stabilization of ASD systems faces many obstacles. To overcome these shortcomings, co-amorphous supersaturable formulations have emerged as an alternative formulation strategy for poorly soluble compounds. Noteworthily, current researches around co-amorphous system (CAS) are mostly focused on preparation and characterization of these systems, but more detailed investigations of their supersaturation ("spring-parachute" process), stability, in vivo bioavailability and molecular mechanisms are inadequate and need to be clarified. In present study, we chose pharmacological relevant BCS II drugs to fabricate and characterize "felodipine-indomethacin" CAS. To enrich the current inadequate but key knowledge on CAS studies, we carried out following highlighted investigations including dissolution/solubility, semi-continuous "spring-parachute" process, long-term stability profile of amorphous state, in vivo bioavailability and underlying molecular mechanisms (molecular interaction, molecular miscibility and crystallization inhibition). Generally, the research provides some key information in the field of current "drug-drug" CAS supersaturable formulations., (Copyright © 2021. Published by Elsevier B.V.)

Our continuing search for marine bioactive secondary metabolites led to the screening of crude extracts of sea cucumbers by the model of Pyricularia oryzae. A new sulfated triterpene glycoside, coloquadranoside A (1), together with four known triterpene glycosides, philinopside A, B, E and pentactaside B (2-5) were isolated from the sea cucumber Colochirus quadrangularis, and their structures were elucidated using extensive spectroscope analysis (ESI-MS, 1D and 2D NMR) and chemical methods. Coloquadranoside A possesses a 16-acetyloxy group in the holostane-type triterpene aglycone with a 7(8)-double bond, a double bond (25,26) at its side chain, and two β-d-xylose in the carbohydrate chain. Coloquadranoside A exhibits in vitro some antifungus, considerable cytotoxicity (IC 50 of 0.46-2.03 μM) against eight human tumor cell lines, in vivo antitumor, and immunomodulatory activity., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Growing evidence indicates that microglia activation and a neuroinflammatory trigger contribute to dopaminergic cell loss in Parkinson's disease (PD). Furthermore, increased density of histaminergic fibers and enhanced histamine levels have been observed in the substantia nigra of PD-postmortem brains. Histamine-induced microglial activation is mediated by the histamine-4 receptor (H 4 R). In the current study, gene set enrichment and pathway analyses of a PD basal ganglia RNA-sequencing dataset revealed that upregulation of H 4 R was in the top functional category for PD treatment targets. Interestingly, the H 4 R antagonist JNJ7777120 normalized the number of nigrostriatal dopaminergic fibers and striatal dopamine levels in a rotenone-induced PD rat model. These improvements were accompanied by a reduction of α-synuclein-positive inclusions in the striatum. In addition, intracerebroventricular infusion of JNJ7777120 alleviated the morphological changes in Iba-1-positive microglia and resulted in a lower tumor necrosis factor-α release from this brain region, as well as in ameliorated apomorphine-induced rotation behaviour. Finally, JNJ7777120 also restored basal ganglia function by decreasing the levels of γ-aminobutyric acid (GABA) and the 5-hydroxyindoleactic acid to serotonin (5-HIAA/5-HT) concentration ratios in the striatum of the PD model. Our results highlight H 4 R inhibition in microglia as a promising and specific therapeutic target to reduce or prevent neuroinflammation, and as such the development of PD pathology., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Early-life stress (ELS) leads to stress-related psychopathology in adulthood. Although dysfunction of corticotropin-releasing hormone (CRH) signaling in the bed nucleus of the stria terminalis (BNST) mediates chronic stress-induced maladaptive affective behaviors that are historically associated with mood disorders such as anxiety and depression, it remains unknown whether ELS affects CRH function in the adult BNST. Here we applied a well-established ELS paradigm (24 h maternal separation (MS) at postnatal day 3) and assessed the effects on CRH signaling and electrophysiology in the oval nucleus of BNST (ovBNST) of adult male mouse offspring. ELS increased maladaptive affective behaviors, and amplified mEPSCs and decreased M-currents (a voltage-gated K + current critical for stabilizing membrane potential) in ovBNST CRH neurons, suggesting enhanced cellular excitability. Furthermore, ELS increased the numbers of CRH + and PACAP + (the pituitary adenylate cyclase-activating polypeptide, an upstream CRH regulator) cells and decreased STEP + (striatal-enriched protein tyrosine phosphatase, a CRH inhibitor) cells in BNST. Interestingly, ELS also increased BNST brain-derived neurotrophic factor (BDNF) expression, indicating enhanced neuronal plasticity. These electrophysiological and behavioral effects of ELS were reversed by chronic application of the CRHR1-selective antagonist R121919 into ovBNST, but not when BDNF was co-administered. In addition, the neurophysiological effects of BDNF on M-currents and mEPSCs in BNST CRH neurons mimic effects and were abolished by PKC antagonism. Together, our findings indicate that ELS results in a long-lasting activation of CRH signaling in the mouse ovBNST. These data highlight a regulatory role of CRHR1 in the BNST and for BDNF signaling in mediating ELS-induced long-term behavioral changes.

This study aimed to explore the link between block copolymers' interfacial properties and nanoscale carrier formation and found out the influence of length ratio on these characters to optimize drug delivery system. A library of diblock copolymers of PEG-PCL and triblock copolymers with additional PEI (PEG-PCL-PEI) were synthesized. Subsequently, a systematic isothermal investigation was performed to explore molecular arrangements of copolymers at air/water interface. Then, structural properties and drug encapsulation in self-assembly were investigated with DLS, SLS and TEM. We found the additional hydrogen bond in the PEG-PCL-PEI contributes to film stability upon the hydrophobic interaction compared with PEG-PCL. PEG-PCL-PEI assemble into smaller micelle-like (such as PEG-PCL4006-PEI) or particle-like structure (such as PEG-PCL8636-PEI) determined by their hydrophilic and hydrophobic block ratio. The distinct structural architectures of copolymer are consistent between interface and self-assembly. Despite the disparity of constituent ratio, we discovered the arrangement of both chains guarantees balanced hydrophilic-hydrophobic ratio in self-assembly to form stable construction. Meanwhile, the structural differences were found to have significant influence on model drugs incorporation including docetaxel and siRNA. Taken together, these findings indicate the correlation between molecular arrangement and self-assembly and inspire us to tune block compositions to achieve desired nanostructure and drug loading., (© 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Gut peptide hormones are one group of secretory factors produced from gastrointestinal endocrine cells with potent functions in modulating digestive functions. In recent decades, they have been found across different brain regions, many of which are involved in autism-related social, emotional and cognitive deficits. Clinical studies have revealed possible correlation between those hormones and autism spectrum disorder pathogenesis. In animal models, gut peptide hormones modulate neurodevelopment, synaptic transmission and neural plasticity, explaining their behavioral relevance. This review article will summarize major findings from both clinical and basic research showing the role of gut peptide hormones in mediating autism-related neurological functions, and their potential implications in autism pathogenesis. The pharmaceutical value of gut hormones in alleviating autism-associated behavioral syndromes will be discussed to provide new insights for future drug development., (Copyright © 2020 Qi and Zhang.)

"Social mindfulness" refers to being thoughtful of others and considering their needs before making decisions, and can be characterized by low-cost and subtle gestures. The present study compared the behavioral and neural responses triggered by observing others' socially mindful/unmindful choices and how these responses were modulated by the social status of the agency. At the behavioral level, observing socially mindful choices made observers feel better, rate the actors as more likable, and behave more cooperatively than did observing socially unmindful choices. Analysis of event-related potentials in the brain revealed that compared with socially unmindful choices, mindful choices elicited more negative feedback-related negativity (FRN). Notably, while this effect of social mindfulness was only significant when the actor's social status was medium and high, it was undetectable when the actor's social status was low. These results demonstrate that the social mindfulness of others can be rapidly detected and processed, as reflected by FRN, even though it does not seem to receive further, more elaborate evaluation. These findings indicated that low-cost cooperative behaviors such as social mindfulness can also be detected and appreciated by our brain, which may result in better mood and more cooperative behaviors in the perceivers. Besides, the perception of social mindfulness is sensitive to important social information, such as social status., (Copyright © 2020 Lu, Huang, Liao, Guan, Qi and Cui.)

Glia alterations in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) have been postulated to play an important role in the pathophysiology of psychiatric disorders. Astroglia is the most abundant type of glial cells in the central nervous system. The expression levels of astrocyte markers (glial fibrillary acidic protein (GFAP), synemin-α, synemin-β, vimentin, nestin) in isolated gray matter from postmortem ACC and DLPFC were determined to investigate the possible involvement of astrocytes in depression. Donors were aged non-suicidal subjects with bipolar disorder (BPD) or major depressive disorder (MDD), and matched controls. GFAP mRNA levels were significantly increased in the ACC of BPD patients. However, GFAP immunohistochemistry showed that the area fraction of GFAP immunoreactive astrocytes was decreased in the ACC of BPD patients, while there were no changes in the cell density and integrated optical density (IOD), indicating that there might be a reduction of GFAP-positive astrocyte processes and remodeling of the astrocyte network in BPD. Furthermore, in controls, DLPFC GFAP mRNA levels were significantly lower with a time of death at daytime (08:01-20:00 h) compared to nighttime (20:01-08:00 h). In depression, such a diurnal pattern was not present. These findings in BPD and MDD subjects warrant further studies given the crucial roles of astrocytes in the central nervous system., (Copyright © 2019 Qi, Kamphuis and Shan.)

Objective: The current difficulties in the treatment of tumor include repeated administration and high recurrence rate after tumor resection. In order to reduce the number of doses, avoid side effects of chemotherapeutic drugs, suppress tumor growth and delay tumor recurrence after surgery, a temperature-sensitive in situ gel with paclitaxel microspheres (PTX/M gel) was prepared. PTX/M gel was administered by intratumoral injection once a month., Methods: First of all, paclitaxel microspheres (PTX/M) were prepared by emulsion solvent evaporation method. A laser particle size distribution analyzer was used to investigate the size, distribution, specific surface area of microspheres. Paclitaxel content was determined by high performance liquid chromatography (HPLC). Then encapsulation efficiency of paclitaxel was calculated and in vitro release characteristics were studied. Secondly, PTX/M gel was prepared by cold dissolution method. The phase transition temperature, elastic modulus, dissolution curve, correlation between dissolution and release were measured. Finally, U87 MG and 4T1 subcutaneous tumor models were established respectively to study the efficacy of PTX/M gel in suppressing tumor growth and delaying tumor recurrence after surgery., Results: The median diameter of the selected PTX/M was (32.24±1.09) μm, the specific surface area was (206.61±10.23) m 2 /kg, the encapsulation efficiency was 85.29%±1.34%, and the cumulative release percentage of paclitaxel from PTX/M was 33.56%±3.33% in one month. Phase transition temperature of PTX/M gel was 33 °C. The elastic modulus of PTX/M gel at 25 °C and 37 °C were 4.2×103 Pa and 18×103 Pa, respectively. The gel could stay in the body for up to 48 hours. It could be seen from the results of animal experiments that were compared with the saline group and the Taxol group, and the tumor-bearing mice of the PTX/M gel group had the slowest tumor growth (P<0.05). Similarly, in the tumor recurrence experiments, the mice of PTX/M gel group had the latest tumor recurrence after surgery., Conclusion: As a local sustained-release preparation, PTX/M gel can effectively suppress tumor growth and delay postoperative recurrence of tumors. It has potential advantages in tumor treatment.

Investigating the pathophysiological mechanisms underlying brain disorders is a priority if novel therapeutic strategies are to be developed. In vivo studies of animal models and in vitro studies of cell lines/primary cell cultures may provide useful tools to study certain aspects of brain disorders. However, discrepancies among these studies or unsuccessful translation from animal/cell studies to human/clinical studies often occur, because these models generally represent only some symptoms of a neuropsychiatric disorder rather than the complete disorder. Human brain slice cultures from postmortem tissue or resected tissue from operations have shown that, in vitro, neurons and glia can stay alive for long periods of time, while their morphological and physiological characteristics, and their ability to respond to experimental manipulations are maintained. Human brain slices can thus provide a close representation of neuronal networks in vivo, be a valuable tool for investigation of the basis of neuropsychiatric disorders, and provide a platform for the evaluation of novel pharmacological treatments of human brain diseases. A brain bank needs to provide the necessary infrastructure to bring together donors, hospitals, and researchers who want to investigate human brain slices in cultures of clinically and neuropathologically well-documented material.

Many strategies have been employed to improve oral drug delivery. One such approach involves the use of supersaturable delivery systems such as amorphous self-micellizing solid dispersions (SmSDs). SmSDs have attracted more attention recently, but little is known regarding the impact of production methods on profiles and internal mechanisms of final SmSDs in spite of its importance. In this study, amorphous SmSDs containing self-micellizing Soluplus® and BCS II drug (either indomethacin (IND) or fenofibrate (FEN)) were generated using various methods: solvent evaporation (SOL), freeze-drying (FD), microwave radiation-quench cooling (MQC), and hot melt extrusion (HME). Microscopic morphology, amorphous state, thermal behavior, dissolution/solubility, and "spring-parachute" data were used to assemble physicochemical profiles for SmSD systems prepared using each method. Analysis of intermolecular interactions, solubilization, and crystallization inhibition further uncovered internal mechanisms explaining observed physicochemical properties. Generally, SmSD/IND and SmSD/FEN systems generated using HME exhibited superior dissolution, solubility, and spring-parachute profiles. The superior advantages of HME-generated SmSD/IND systems were attributed to relatively stronger intermolecular interactions than observed in SmSD/IND systems fabricated using other methods. Moreover, self-micellizing Soluplus® carrier was able to solubilize IND or FEN and suppress drug crystallization from a supersaturated state, which seemed to be an important mechanism for the properties enhancement caused by SmSD/FEN HME . This knowledge should be useful for guiding further development of self-micellizing solid dispersions and for gaining deeper understanding of how HME technology can improve supersaturable drug delivery based on SmSDs strategy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nanomedicines are often designed to target and treat solid tumors. Unfortunately, tumor and stroma composed of dense extracellular matrix, abnormal vascular barriers, elevated interstitial fluid pressure, et al., which impede the access and accumulation of nanomedicines into tumors. Strategies to disrupt these deterministic obstacles require a unique combination of promoter drugs and cytotoxic agents to target stroma and tumor simultaneously. Here, we engineered a novel strategy by co-delivery dexamethasone (DEX) and docetaxel (DTX) in the 2-in-1 liposome, namely (DEX + DTX)-Lip, with sequential release property. We proved that the engineered liposomal therapy approach could potentially achieve two objectives in tumor drug delivery: modulate tumor stroma and promote drug penetration and accumulation in tumor. Thus more DTX tenured in intratumoral site to kill tumor cells in a strong way with minimize systemic toxicity. The sequentially released liposomes won excellent antitumor efficacy in multifarious models, including KB, multidrug resistant KBv and metastatic 4 T1 tumor models and low toxicities compared with the combination of free drugs in vivo. Moreover, they demonstrated the potential of prevention tumor cells colonization and anti-metastasis in vivo models. These findings give insights in overcoming the deterministic stroma obstacles and provide a rational strategy to increase antitumor efficacy of combination nanomedicines with practical value., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The collective impact of cellulosic polymers on the dissolution, solubility, and crystallization inhibition of amorphous active pharmaceutical ingredients (APIs) is still far from being adequately understood. The goal of this research was to explore the influence of cellulosic polymers and incubation conditions on enhancement of solubility and dissolution of amorphous felodipine, while inhibiting crystallization of the drug from a supersaturated state. Variables, including cellulosic polymer type, amount, ionic strength, and viscosity, were evaluated for effects on API dissolution/solubility and crystallization processes. Water-soluble cellulosic polymers, including HPMC E15, HPMC E5, HPMC K100-LV, L-HPC, and MC, were studied. All cellulosic polymers could extend API dissolution and solubility to various extents by delaying crystallization and prolonging supersaturation duration, with their effectiveness ranked from greatest to least as HPMC E15 > HPMC E5 > HPMC K100-LV > L-HPC > MC. Decreased polymer amount, lower ionic strength, or higher polymer viscosity tended to decrease dissolution/solubility and promote crystal growth to accelerate crystallization. HPMC E15 achieved greatest extended API dissolution and maintenance of supersaturation from a supersaturated state; this polymer thus had the greatest potential for maintaining sustainable API absorption within biologically relevant time frames.

Altered levels of steroids have been reported in the brain, cerebral spinal fluid and plasma of patients with mood disorders. Neuroimaging studies have reported both functional and structural alterations in mood disorders, for instance in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC). In order to determine whether the endogenous production of steroids is altered in the ACC and DLPFC of patients with major depressive disorder (MDD) or bipolar disorder (BPD), quantitative real-time PCR was performed to detect mRNA expression level of key enzymes in the steroid biosynthetic pathways. In MDD, a significant decrease in mRNA level of cytochrome P450 17A1 (CYP17A1, synthesizing C19 ketosteroids) in the ACC and a significant increase in mRNA levels of hydroxysteroid sulfotransferase 2A1 [SULT2A1, catalyzing the sulfate conjugation of dehydroepiandrosterone (DHEA)] were observed in the DLPFC, suggesting alterations in DHEA and its sulfate metabolite DHEAS levels. Decreased intensity and distribution of CYP17A1 immunohistochemical staining was found in the ACC of MDD patients. Interestingly, there was a significant positive correlation between the mRNA levels of CYP17A1 and tyrosine-related kinase B (TrkB) full length isoform. In a unique post-mortem human brain slice culture paradigm, BDNF mRNA expression was found to be significantly increased following incubation with DHEA. Together, these data indicate a close relationship between DHEA and BDNF-TrkB pathways in depression. Furthermore, in the DLPFC, higher mRNA levels of 11β-hydroxysteroid dehydrogenase-1 (HSD11B1, reducing cortisone to the active hormone cortisol) and steroidogenic acute regulatory protein (STAR, facilitating the shuttle of cholesterol through the intermembrane space) were found in the MDD patients and BPD patients, respectively. In conclusion, this study suggests the presence of a disturbance in the endogenous synthesis of DHEA and DHEAS in mood disorders, which has a close relationship with BDNF-TrkB signaling., (© 2017 International Society of Neuropathology.)

Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or Soluplus ® , is a relatively new copolymer and a promising carrier of amorphous solid dispersions. Knowledge on the inherent properties of Soluplus ® (e.g. cloud points, critical micelle concentrations, and viscosity) in different conditions is relatively inadequate, and the application characteristics of Soluplus ® -based solid dispersions made by microwave methods still need to be clarified. In the present investigation, the inherent properties of a Soluplus ® carrier, including cloud points, critical micelle concentrations, and viscosity, were explored in different media and in altered conditions. Ibuprofen, a BCS class II non-steroidal anti-inflammatory drug, was selected to develop Soluplus ® -based amorphous solid dispersions using the microwave-quench cooling (MQC) method. Scanning electronic microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Raman spectroscopy (RS), and Fourier transform infrared spectroscopy (FT-IR) were adopted to analyze amorphous properties and molecular interactions in ibuprofen/Soluplus ® amorphous solid dispersions generated by MQC. Dissolution, dissolution extension, phase solubility, equilibrium solubility, and supersaturated crystallization inhibiting experiments were performed to elucidate the effects of Soluplus ® on ibuprofen in solid dispersions. This research provides valuable information on the inherent properties of Soluplus ® and presents a basic understanding of Soluplus ® as a carrier of amorphous solid dispersions.

People that committed suicide were reported to have enhanced levels of gene transcripts for synaptic proteins in their prefrontal cortex (PFC). Given the close association of suicide with major depressive disorder (MDD), we here assessed whether these changes are related to suicide or rather to depression per se. We used quantitative PCR to determine mRNA levels of 32 genes encoding for proteins directly involved in glutamatergic or GABAergic synaptic transmission in postmortem samples of the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). Seventy-two brain samples from 3 groups of subjects were derived from the Stanley Medical Research Institute (SMRI): i) patients with MDD who committed suicide (MDD-S), ii) MDD patients who died of non-suicidal causes (MDD-NS) and iii) age-matched, non-psychiatric control subjects. In the ACC, a significantly enhanced expression of genes related to glutamatergic or GABAergic synaptic transmission was found only in MDD-S patients, whereas in MDD-NS patients, decreased levels for these transcripts were found. Moreover, in the DLPFC, expression of these genes was decreased in MDD-S, relative to MDD-NS patients, whereas both groups showed increased expression compared to control subjects. In conclusion, our findings indicate that MDD is associated with increases in GABA and glutamate related genes in the DLPFC (irrespective of suicide), while in the ACC, the increase in GABA and glutamate related genes may relate to suicide, rather than to MDD per se., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The CD44 protein, as a predominant receptor for hyaluronan (HA), is highly expressed on the surface of multiple tumor cells. HA, as a targeting molecule for a CD44-contained delivery system, increases intracellular drug concentration in tumor tissue. However, due to the weak binding ability of hyaluronan oligosaccharide to CD44, targeting for tumor drug delivery has been restricted. In this study, we first use a HA tetrasaccharide cluster as the target ligand to enhance the binding ability to CD44. A polyamidoamine (PAMAM) dendrimer was modified by a HA tetrasaccharide cluster as a nonviral vector for small interfering RNA (siRNA) delivery. The dendrimer/siRNA nanocomplexes increased the cellular uptake capacity of siRNA through the CD44 receptor-mediated endocytosis pathway, allowing the siRNA to successfully escape the endosome/lysosome. Compared with the control group, nanocomplexes effectively reduced the expression of GFP protein and mRNA in MDA-MB-231-GFP cells. This delivery system provides a foundation to increase the clinical applications of PAMAM nanomaterials.

Cell-penetrating peptides (CPPs), also called "Trojan-Horse" peptides, have been used for facilitating intracellular delivery of numerous diverse cargoes and even nanocarriers. However, the lack of targeting specificity ("wildness" or nonselectivity) of CPP-nanocarriers remains an intractable challenge for many in vivo applications. In this work, we used an intelligent "peptide-gathering mechanical arm" (Int PMA) to curb CPPs' wildness and enhance the selectivity of R 9 -liposome-based cargo delivery for tumor targeting. The peptide NGR, serving as a cell-targeting peptide for anchoring, and peptide PLGLAG, serving as a substrate peptide for deanchoring, were embedded in the Int PMA motif. The Int PMA construct was designed to be sensitive to tumor microenvironmental stimuli, including aminopeptidase N (CD13) and matrix metalloproteinases (MMP-2/9). Moreover, Int PMA could be specifically recognized by tumor tissues via CD13-mediated anchoring and released for cell entry by MMP-2/9-mediated deanchoring. To test the Int PMA design, a series of experiments were conducted in vitro and in vivo. Functional conjugates Int PMA-R 9 -poly(ethylene glycol) (PEG) 2000 -distearoylphosphatidyl-ethanolamine (DSPE) and R 9 -PEG 2000 -DSPE were synthesized by Michael addition reaction and were characterized by thin-layer chromatography and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. The Int PMA-R 9 -modified doxorubicin-loaded liposomes (Int PMA-R 9 -Lip-DOX) exhibited a proper particle diameter (approximately 155 nm) with in vitro sustained release characteristics. Cleavage assay showed that Int PMA-R 9 peptide molecules could be cleaved by MMP-2/9 for completion of deanchoring. Flow cytometry and confocal microscopy studies indicated that Int PMA-R 9 -Lip-DOX can respond to both endogenous and exogenous stimuli in the presence/absence of excess MMP-2/9 and MMP-2/9 inhibitor (GM6001) and effectively function under competitive receptor-binding conditions. Moreover, Int PMA-R 9 -Lip-DOX generated more significant subcellular dispersions that were especially evident within endoplasmic reticulum (ER) and Golgi apparatus. Notably, Int PMA-R 9 -Lip-DOX could induce enhanced apoptosis, during which caspase 3/7 might be activated. In addition, Int PMA-R 9 -Lip-DOX displayed enhanced in vitro and in vivo antitumor efficacy versus "wild" R 9 -Lip-DOX. On the basis of investigations at the molecular level, cellular level, and animals' level, the control of Int PMA was effective and promoted selective delivery of R 9 -liposome cargo to the target site and reduced nonspecific uptake. This Int PMA-controlled strategy based on aminopeptidase-guided anchoring and protease-triggered deanchoring effectively curbed the wildness of CPPs and bolstered their effectiveness for in vivo delivery of nanotherapeutics. The specific nanocarrier delivery system used here could be adapted using a variety of intelligent designs based on combinations of multifunctional peptides that would specifically and preferentially bind to tumors versus nontumor tissues for tumor-localized accumulation in vivo. Thus, CPPs have a strong advantage for the development of intelligent nanomedicines for targeted tumor therapy.