Publications by authors named "An Liu"

380 Publications

Overexpression of LIMK1 in hippocampal excitatory neurons improves synaptic plasticity and social recognition memory in APP/PS1 mice.

Mol Brain 2021 Jul 27;14(1):121. Epub 2021 Jul 27.

Program in Neurosciences and Mental Health, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, ON, M5S 1A8, Canada.

Accumulating evidence indicates that the actin regulator cofilin is overactivated in Alzheimer's Disease (AD), but whether this abnormality contributes to synaptic and cognitive impairments in AD is unclear. In addition, the brain region and cell types involved remain unknown. In this study, we specifically manipulate LIMK1, the key protein kinase that phosphorylates and inactivates cofilin, in the hippocampus of APP/PS1 transgenic mice. Using local injections of the AAV virus containing LIMK1 under the control of the CaMKIIα promoter, we show that expression of LIMK1 in hippocampal excitatory neurons increases cofilin phosphorylation (i.e., decreases cofilin activity), rescues impairments in long-term potentiation, and improves social memory in APP/PS1 mice. Our results suggest that deficits in LIMK1/cofilin signaling in the hippocampal excitatory neurons contribute to AD pathology and that manipulations of LIMK1/cofilin activity provide a potential therapeutic strategy to treat AD.
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http://dx.doi.org/10.1186/s13041-021-00833-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314529PMC
July 2021

Iodine Immobilized Metal-Organic Framework for NIR-Triggered Antibacterial Therapy on Orthopedic Implants.

Small 2021 Jul 26:e2102315. Epub 2021 Jul 26.

Orthopedics Research Institute of Zhejiang University, Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310000, P. R. China.

Iodine has been known as an effective disinfectant with broad-spectrum antimicrobial potency yet without drug resistance risk when used in clinic. However, the exploration of iodine for antibacterial therapy in orthopedics remains sparse due to its volatile nature and poor solubility. Herein, leveraging the superior absorption capability of metal-organic frameworks (MOFs) and their inherent photocatalytic properties, iodine-loaded MOF surface is presented to realize responsive iodine release along with intracellular reactive oxygen species(ROS) oxidation under near-infrared (NIR) exposure to achieve synergistic antibacterial effect. Iodine is successfully loaded using vapor deposition process onto zeolitic imidazolate framework-8(ZIF-8), which is immobilized onto micro arc oxidized titanium via a hydrothermal approach. The combination of NIR-triggered iodine release and ZIF-8 mediated ROS oxidative stress substantially augments the antibacterial efficacy of this approach both in vitro and in vivo. Furthermore, this composite coating also supported osteogenic differentiation of bone marrow stromal cells, as well as improved osseointegration of coated implants using an intramedullary rat model, suggesting improvement of antibacterial efficacy does not impair osteogenic potential of the implants. Altogether, immobilization of iodine via MOF on orthopedic implants with synergistic antibacterial effect can be a promising strategy to combat bacterial infections.
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http://dx.doi.org/10.1002/smll.202102315DOI Listing
July 2021

Early-life inflammation promotes depressive symptoms in adolescence via microglial engulfment of dendritic spines.

Neuron 2021 Jun 26. Epub 2021 Jun 26.

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, China. Electronic address:

Early-life inflammation increases the risk for depression in later life. Here, we demonstrate how early-life inflammation causes adolescent depressive-like symptoms: by altering the long-term neuronal spine engulfment capacity of microglia. For mice exposed to lipopolysaccharide (LPS)-induced inflammation via the Toll-like receptor 4/NF-κB signaling pathway at postnatal day (P) 14, ongoing longitudinal imaging of the living brain revealed that later stress (delivered during adolescence on P45) increases the extent of microglial engulfment around anterior cingulate cortex (ACC) glutamatergic neuronal (ACC) spines. When the ACC microglia of LPS-treated mice were deleted or chemically inhibited, the mice did not exhibit depressive-like behaviors during adolescence. Moreover, we show that the fractalkine receptor CX3CR1 mediates stress-induced engulfment of ACC neuronal spines. Together, our findings establish that early-life inflammation causes dysregulation of microglial engulfment capacity, which encodes long-lasting maladaptation of ACC neurons to stress, thus promoting development of depression-like symptoms during adolescence.
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http://dx.doi.org/10.1016/j.neuron.2021.06.012DOI Listing
June 2021

Service acceptance of HIV non-occupational post-exposure prophylaxis(nPEP) among college students: a cross-sectional study in China.

BMC Public Health 2021 06 24;21(1):1220. Epub 2021 Jun 24.

Beijing YouAn Hospital, Capital Medical University, Beijing, China.

Background: College students were the key group we should pay more attention for acquired immune deficiency syndrome (AIDS) prevention and control in recent years in China. Few studies of HIV non-occupational post-exposure prophylaxis (nPEP) knowledge and service acceptance had been conducted among them in China. This study conducted a cross-sectional survey to understand the service acceptance of nPEP and its influencing factors among college students in the three cities of China.

Methods: A questionnaire survey was conducted to collect information on socio-demographic, behavioral characteristic, HIV/AIDS knowledge, nPEP knowledge, acceptance of nPEP services among the college students in Beijing, Shenzhen, and Kunming of China from March to April of 2019. Each participant completed an anonymous questionnaire on line by computer-assisted or mobile phone-assisted self-interview with informed consent. Multivariable logistic regression analyses identified predictors for service acceptance of nPEP.

Results: A total of 4698 students were surveyed with the average age of 20 years old. 98.0% (4605/4698) of them were undergraduates, 21.8%(1022/4698) had sexual intercourse; 48.6% (2282/4698) heard of nPEP, among which 4.95%(113/2282) received nPEP services. The awareness rate of HIV/AIDS knowledge was 85.6% (5495/4698) with the differences statistically significant between the three cities. The awareness rate of nPEP knowledge was 16.5% (774/4698). There were significant differences in receiving nPEP services among students of different ages, genders, sexual behaviors, and knowledge of HIV/AIDS by univariate analysis. Multivariable analyses indicated that age group of 18 and under (OR = 2.551, 95% CI = 1.153-5.646), male (OR = 3.131, 95% CI = 1.866-5.253), homosexual behavior (OR = 4.661,95%CI = 2.658-8.172), heterosexual behavior (OR = 1.676, 95% CI = 1.040-2.947), no awareness of AIDS knowledge (OR = 3.882, 95% CI = 2.371-6.356) and nPEP (OR = 4.788, 95% CI = 2.50-9.169) knowledge, were associated with the service acceptance of nPEP among the college students.

Conclusion: The low acceptance of nPEP services was mainly affected by low level of nPEP knowledge among the college students. Further publicity and education of nPEP knowledge were necessary, as well as promotion of knowledge of HIV/AIDS prevention and treatment. More attention should be paid to the factors associated with acceptance of nPEP services.
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http://dx.doi.org/10.1186/s12889-021-11286-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228990PMC
June 2021

L-Theanine regulates glutamine metabolism and immune function by binding to cannabinoid receptor 1.

Food Funct 2021 Jul;12(13):5755-5769

Key Lab of Tea Science of Ministry of Education, Hunan Agricultural University, Changsha, Hunan 410128, China. and National Research Center of Engineering Technology for Utilization of Botanical Functional Ingredients, Hunan Agricultural University, Changsha, Hunan 410128, China and Hunan Agricultural University, Co-Innovation Center of Education Ministry for Utilization of Botanical Functional Ingredients, Changsha, Hunan 410128, China.

l-Theanine is a characteristic amino acid in tea with various effects including antioxidant and anti-inflammatory effects. Previously, most studies had reported that l-theanine regulates the immune function in vivo by inhibiting the expression of the inflammatory factors, but how l-theanine regulates the inflammatory factors' pathway is not known. In this study, we innovatively found the binding target of l-theanine in vivo-cannabinoid receptor 1, and demonstrated that l-theanine regulated the immune function and glutamine metabolism by competitively binding cannabinoid receptor 1. Mechanistically, l-theanine competitively binds cannabinoid receptor 1, leading to inhibition of cannabinoid receptor 1 activity, and regulates glutamine metabolism and immune function in normal and E44813-stressed rats. In normal rats, l-theanine inhibits ERK1/2 phosphorylation through Gβy by antagonizing cannabinoid receptor 1, thus affecting GS expression. From the point of view of immune signaling, after LTA antagonizes the activity of cannabinoid receptor 1, it relieves the inhibition of cannabinoid receptor 1 on COX-2 expression, downregulates Pdcd4 expression and NFκB, and ultimately enhances the expression of the anti-inflammatory factor IL-10. In E44813-stressed rats, l-theanine promotes the nuclear translocation of p-ERK1/2 by inhibiting the activity of cannabinoid receptor 1, and finally acts on GS. At the same time, it decreases the expression of the pro-inflammatory factor TNF-α and increases the expression of the anti-inflammatory factor IL-10 in stressed rats through the COX2-Pdcd4-NFκB-IL10 and TNFα pathways. In summary, these results demonstrate that l-theanine regulates glutamine metabolism and immune function by competitively binding to cannabinoid receptor 1.
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http://dx.doi.org/10.1039/d1fo00505gDOI Listing
July 2021

Dosimetric comparison of multiple vs single isocenter technique for linear accelerator-based stereotactic radiosurgery: The Importance of the six degree couch.

J Appl Clin Med Phys 2021 Jun 21;22(6):45-49. Epub 2021 May 21.

Department of Radiation Oncology, City of Hope National Medical Center, Duarte, CA, USA.

Purpose: Single isocenter technique (SIT) for linear accelerator-based stereotactic radiosurgery (SRS) is feasible. However, SIT introduces the potential for rotational error which can lead to geographical miss. Additional planning treatment volume (PTV) margin is required when using SIT. With the six degrees of freedom (6DoF) couch, rotational error can be minimized. We sought to evaluate the effect of the 6DoF couch on the dosimetry of patients with multiple brain metastases treated with SIT.

Materials And Methods: Ten consecutive patients treated with SRS to ≥3 metastases were identified. Original treatments had MIT plans (MITP). The lesions were replanned using SIT. Lesions 5-10 cm from isocenter had an additional 1mm of margin. Patients were replanned with these additional margins to account for inability to correct rotational error (SITPM). Multiple dosimetric variables and time metrics were evaluated. Dosimetry planning time (DPT) and patient treatment time (PTT) were evaluated. Statistics were calculated using the Wilcoxon signed-rank test.

Results: A total of 73 brain metastases receiving SRS, to a median of 6 lesions per patient, were identified. MITPs treated 73 lesions with 63 isocenters. On average, MITPs had a 19.2% higher brain V12 than SITPs (P = 0.017). For creation of SITPM, 30 lesions required 1 mm of additional margin, while none required 2 mm of margin. This increased V12 by 47.8% on average per patient (P = 0.008) from SITP to SITPM. DPT was 5.5 hours for SITP, while median for MITP was 12.5 hours (P = 0.005) PTT was 30 minutes for SITP, while median for MITP was 144 minutes (P = 0.005).

Conclusions: SITPs are comparable to MITPs if rotational error can be corrected with the use of a 6DoF couch. Increasing margin to account for rotational error leads to a nearly 50% increase in V12, which could result in higher rates of radiation necrosis. Time savings are significant using SIT.
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http://dx.doi.org/10.1002/acm2.13286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200442PMC
June 2021

MiRNA-3662 reverses the gemcitabine resistance in pancreatic cancer through regulating the tumor metabolism.

Cancer Chemother Pharmacol 2021 Aug 15;88(2):343-357. Epub 2021 May 15.

Department of Gastrointestinal Surgery, The First People's Hospital of Yueyang, Yueyang, 414000, People's Republic of China.

Objectives: Gemcitabine (Gem) is one of the most commonly used chemotherapeutic drugs in treating patients with pancreatic ductal adenocarcinoma (PDAC). Acquired drug resistance against Gem presents a major clinical challenge in the chemotherapy of PDAC. It has been shown that miRNA-3662 is lowly expressed and implicated with quantities of biological processes in cancer. However, whether miRNA-3662 regulates chemoresistance in PDAC remains largely unknown.

Materials And Methods: The level of miRNA-3662 in PDAC tissues was determined by real-time qPCR (RT-qPCR). Functional experiments were used to investigate the biological role of miRNA-3662 on Gem resistance of PDAC in vitro and in vivo. Fluorescence in situ hybridization (FISH), RT-qPCR, western blotting, bioinformatics analysis and luciferase reporter assay were employed to determine the precise regulation mechanisms.

Results: In this study, it was investigated that miRNA-3662 was down-regulated in PDAC clinical samples as well as cell lines. Functional assays revealed that miRNA-3662 was sufficient to inhibit Gem resistance in PDAC cells both in vitro and in vivo. Mechanistically, hypoxia-inducible factor 1ɑ (HIF-1ɑ) was one of the transcriptional target of miRNA-3662 and was up-regulated in PDAC samples. Importantly, genetic promoting of HIF-1ɑ largely compromised miR-3662-mediated chemosensitive effects. In addition, miR-3662 could impair the aerobic glycolysis in PDAC cells.

Conclusions: This study sheds light on miRNA-3662 inhibits PDAC cell chemoresistance and aerobic glycolysis through a negative feedback loop with HIF-1ɑ. Therefore, the co-delivery of miR-3662 and Gem could be served as a promising therapeutic regimen for PDAC patients.
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http://dx.doi.org/10.1007/s00280-021-04289-zDOI Listing
August 2021

An orthobiologics-free strategy for synergistic photocatalytic antibacterial and osseointegration.

Biomaterials 2021 07 4;274:120853. Epub 2021 May 4.

Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, PR China; Orthopedics Research Institute of Zhejiang University, Hangzhou, Zhejiang Province, PR China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou, Zhejiang Province, PR China. Electronic address:

Tissue damage caused by hyperthermia during photothermal therapy (PTT) has largely limited its clinical applications for implant infection. However, rescue of tissue regeneration by conjugating orthobiologics with PTT has been problematic as they can easily deactivate biologics while eradicating bacteria. Herein, we report an orthobiologics-free strategy to synergistically couple photocatalytic antibacterial with pro-osteogenic capacity via self-assembly of copper sulphide nanoparticle (CuS NP) and reduced graphene oxide (rGO) on implant surface. This strategy not only offers enhanced photothermal effects for bacterial eradiation via near-infrared light (NIR), but also promotes vascularized osseointegration via cooperation of copper ion with rGO. In vitro and in vivo data showed that coupling CuS and rGO synergistically increased antibacterial efficacy of implants by 40 times and successfully destroyed bacterial biofilm upon NIR. Moreover, CuS/rGO decorated surface substantially improved bone marrow stromal cell adhesion, proliferation, as well as subsequent differentiation toward osteoblast. We also revealed that enhanced peri-implant vascularization may be attributed to the sustained release of copper ion from CuS NPs, which further collaborated with rGO to promote vascularized osseointegration. Altogether, this novel orthobiologics-free approach offers a practical alternative to circumvent the intrinsic drawbacks of PTT and endows powerful antibacterial and pro-osteogenic capacities for implant associated infections.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120853DOI Listing
July 2021

Ligustilide Prevents Radiation Enteritis by Targeting Gch1/BH/eNOS to Improve Intestinal Ischemia.

Front Pharmacol 2021 22;12:629125. Epub 2021 Apr 22.

Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, China.

There is a high incidence of radiation enteritis (RE) after abdominal radiotherapy. The occurrence of RE seriously affects the treatment and quality of life of patients; however, its pathogenesis is complex and there are no effective drugs for its prevention or treatment. Intestinal ischemia plays an important role in the occurrence of enteritis. Previous studies have shown that targeting GTP-cyclohydrolase 1 (Gch1) to improve intestinal ischemia could be a new strategy to prevent and treat RE. A high content of the naturally occurring phthalide derivative ligustilide (LIG) has been found in the plant drug Rhizoma Ligustici Chuanxiong for the treatment of cardiovascular diseases. The purpose of this study was to evaluate the protective effects of LIG on RE. Ionizing radiation (IR) rat and endothelial cell models were used to observe and record rat body weights and stool morphologies, measure intestinal blood perfusion by laser Doppler blood flow imaging, determine the diastolic functions of mesenteric arteries, detect the levels of Gch1/BH/eNOS pathway-related proteins and regulatory molecules in the mesenteric arteries and endothelial cells, and predict affinity by molecular docking technology. The results showed that LIG significantly improved the body weights, loose stools, intestinal villi lengths, intestinal perfusion and vasodilatory functions of IR rats. LIG also significantly improved Gch1 protein and BH levels in the mesenteric arteries and endothelial cells after IR, increased the NO content, reduced superoxide accumulation, and improved p-eNOS (Ser1177) levels in endothelial cells. LIG has good affinity for Gch1, which significantly improves its activity. These results indicate that LIG is the preferred compound for the prevention and treatment of RE by improving intestinal ischemia through the Gch1/BH/eNOS pathway. This study provides a theoretical basis and new research ideas for the development of new drugs for RE.
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http://dx.doi.org/10.3389/fphar.2021.629125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100595PMC
April 2021

Late-life sleep duration associated with amnestic mild cognitive impairment.

Int Psychogeriatr 2021 May 10:1-10. Epub 2021 May 10.

Department of Geriatric Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine and Alzheimer's Disease and Related Disorders Center, Shanghai Jiao Tong University, Shanghai, China.

Objective: To examine the association between sleep duration in different stages of life and amnestic mild cognitive impairment (aMCI).

Design, Setting, And Participants: A total of 2472 healthy elderly and 505 patients with aMCI in China were included in this study. The study analyzed the association between aMCI and sleep duration in different stages of life.

Measurements: We compared sleep duration in different stages of life and analyzed the association between Montreal Cognitive Assessment scores and sleep duration by curve estimation. Logistic regression was used to evaluate the association between aMCI and sleep duration.

Results: In the analysis, there were no results proving that sleep duration in youth (P = 0.719, sleep duration < 10 hours; P = 0.999, sleep duration ≥ 10 hours) or midlife (P = 0.898, sleep duration < 9 hours; P = 0.504, sleep duration ≥ 9 hours) had a significant association with aMCI. In the group sleeping less than 7 hours in late life, each hour more of sleep duration was associated with approximately 0.80 of the original risk of aMCI (P = 0.011, odds ratio = 0.80, 95% confidence interval = 0.68-0.95).

Conclusions: Among the elderly sleeping less than 7 hours, there is a decreased risk of aMCI for every additional hour of sleep.
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http://dx.doi.org/10.1017/S1041610221000466DOI Listing
May 2021

ER stress modulates apoptosis in A431 cell subjected to EtNBSe-PDT via the PERK pathway.

Photodiagnosis Photodyn Ther 2021 Jun 24;34:102305. Epub 2021 Apr 24.

Department of Dermatology, Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address:

Photodynamic therapy (PDT) is a promising modality against various cancers including squamous cell carcinoma (SCC) with which the induction of apoptosis is an effective mechanism. Here, we initially describe the preclinical activity of 5-ethylamino-9-diethylaminobenzo [a] phenoselenazinium(EtNBSe)-mediated PDT treatment in SCC. Results of our studies suggest that EtNBSe-PDT provokes a cellular state of endoplasmic reticulum (ER) stress triggering the PERK/ eIF2α signaling pathway and induces the appearance of apoptosis in A431 cells at the meantime. With ER stress inhibitor 4-PBA or eIF2α inhibitor ISRIB, suppressing the EtNBSe-PDT induced ER stress substantially promotes apoptosis of A431 cells. Furthermore, we demonstrate that ATF4, whose expression is ER-stress-inducible and elevated in response to the PERK/eIF2α signaling pathway activation, contributes to cytoprotection against EtNBSe-PDT induced apoptosis. In a mouse model bearing A431 cells, EtNBSe shows intense phototoxicity and when associated with decreased ER stress, EtNBSe-PDT ameliorates tumor growth. Taken together, our study reveals an antagonistic activity of ER stress against EtNBSe-PDT treatment via inhibiting apoptosis in A431 cells. With further development, these results provide a proof-of-concept that downregulation of ER stress response has a therapeutic potential to improve EtNBSe-PDT sensitivity in SCC patients via the promotion of induced apoptosis.
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http://dx.doi.org/10.1016/j.pdpdt.2021.102305DOI Listing
June 2021

Scutellarin ameliorates the stress-induced anxiety-like behaviors in mice by regulating neurotransmitters.

Phytother Res 2021 Jul 15;35(7):3936-3944. Epub 2021 Apr 15.

Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.

Anxiety disorders are a common frequently psychiatric symptom in patients that lead to disruption of daily life. Scutellarin (Scu) is the main component of Erigeron breviscapus, which has been used as a neuroprotective agent against glutamate-induced excitotoxicity. However, the potential effect of Scu on the stress-related neuropsychological disorders has not been clarified. In this study, Anxiety-like behavior was induced by acute restraint stress in mice. Scu were injected intraperitoneally (twice daily, 3 days). Results showed that Scu exhibited good protective activity on mice by decreasing transmitter release levels. Restraint stress caused significant anxiety like behavior in mice. Treatment of Scu could significantly improve the moving time of open arms in Elevated Plus Maze and central time on open field test. Scu treatment suppressed action potential firing frequency, restored excessive presynaptic quantal release, and down-regulated glutamatergic receptor expression levels in the prefrontal cortex (PFC) of stressed mice. GABA Rα1 and GABA γ expression in the brain PFC tissues of mice were nearly abrogated by Scu treatment. In stress-induced anxiety mice, stress can increase the frequency of mini excitatory postsynaptic currents (mEPSC), which can be reversed by Scu treatment. Therefore, Scu has a potent anxiolytic activity and may be valuable for the treatment of stress-induced anxiety disorders.
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http://dx.doi.org/10.1002/ptr.7106DOI Listing
July 2021

Prebiotics enhance the biotransformation and bioavailability of ginsenosides in rats by modulating gut microbiota.

J Ginseng Res 2021 Mar 7;45(2):334-343. Epub 2020 Aug 7.

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

Background: Gut microbiota mainly function in the biotransformation of primary ginsenosides into bioactive metabolites. Herein, we investigated the effects of three prebiotic fibers by targeting gut microbiota on the metabolism of ginsenoside Rb1 .

Methods: Sprague Dawley rats were administered with ginsenoside Rb1 after a two-week prebiotic intervention of fructooligosaccharide, galactooligosaccharide, and fibersol-2, respectively. Pharmacokinetic analysis of ginsenoside Rb1 and its metabolites was performed, whilst the microbial composition and metabolic function of gut microbiota were examined by 16S rRNA gene amplicon and metagenomic shotgun sequencing.

Results: The results showed that peak plasma concentration and area under concentration time curve of ginsenoside Rb1 and its intermediate metabolites, ginsenoside Rd, F2, and compound K (CK), in the prebiotic intervention groups were increased at various degrees compared with those in the control group. Gut microbiota dramatically responded to the prebiotic treatment at both taxonomical and functional levels. The abundance of , which possesses potential function to hydrolyze ginsenoside Rb1 into CK, was significantly elevated in the three prebiotic groups (P < 0.05). The gut metagenomic analysis also revealed the functional gene enrichment for terpenoid/polyketide metabolism, glycolysis, gluconeogenesis, propanoate metabolism, etc.

Conclusion: These findings imply that prebiotics may selectively promote the proliferation of certain bacterial stains with glycoside hydrolysis capacity, thereby, subsequently improving the biotransformation and bioavailability of primary ginsenosides .
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http://dx.doi.org/10.1016/j.jgr.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020290PMC
March 2021

Scrophularia ningpoensis Hemsl: a review of its phytochemistry, pharmacology, quality control and pharmacokinetics.

J Pharm Pharmacol 2021 Mar;73(5):573-600

Laboratory of Traditional Chinese Medicine Chemistry and Quality Evaluation of Traditional Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.

Objectives: Scrophularia ningpoensis Hemsl (SNH) is a commonly used medicinal plant in East Asia. Scrophulariae Radix (SR) is the dried roots of SNH, and is one of the most commonly used medicinal parts of SNH, and is an essential traditional medicine and widely used in East Asia for more than 2000 years. SR is used for clearing away heat and cooling blood, nourishing Yin and reducing fire, detoxicating and resolving a mass. The purpose of this paper is to systematically review the phytochemistry, pharmacology, quality control and pharmacokinetics of SNH based on the surveyed and summarized literature.

Key Findings: Up to now, iridoids, phenolic glycosides, phenolic acids, alkaloids, flavonoids, triterpenes and other compounds have been isolated and identified from SNH. The extract and chemical components of SNH exerts multiple pharmacological effects, such as hepatoprotective effect, anti-inflammatory effect, neuroprotective effect, anti-ventricular remodeling effect and other activities. Various methods have been developed for the quality control of SNH, mainly for SR. Some bioactive compounds in SNH exhibited different pharmacokinetic behaviours and individual metabolic transformation profiles.

Summary: This review will contribute to understanding the correlation between the pharmacological activities and the traditional usage of SNH, and useful to rational use and drug development in the future.
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http://dx.doi.org/10.1093/jpp/rgaa036DOI Listing
March 2021

Neuropsychiatric Adverse Events During 12 Months of Treatment With Efavirenz in Treatment-Naïve HIV-Infected Patients in China: A Prospective Cohort Study.

Front Psychiatry 2021 24;12:579448. Epub 2021 Feb 24.

Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China.

Efavirenz (EFV) is widely used in antiretroviral therapy (ART), but the incidence and risk factors of neuropsychiatric adverse events (NPAEs) after EFV treatment have rarely been studied in Chinese ART naïve patients. This prospective cohort study assessed HIV-infected patients initiating antiretroviral treatment with EFV to determine prevalence of and factors associated with NPAEs over a 12-month follow-up period using the Hospital Anxiety and Depression Scale (HADS) and the Pittsburgh Sleep Quality Index (PSQI). A total of 546 patients were enrolled. Prevalence of anxiety, depression, and sleep disturbances at baseline were 30.4, 22.7, and 68.1%, respectively. Six patients discontinued treatment due to drug related NPAEs. Treatment was associated with improvements in HADS-A, HADS-D, and PSQI scores over the 12-month follow-up, and the frequencies of patients with anxiety, depression, and sleep disturbances significantly decreased after 12 months. Abnormal baseline HADS-A, HADS-D, and PSQI scores and other factors, including high school education or lower income, unemployment, divorce, and WHO III/IV stages, were associated with severe neuropsychiatric disorders over the 12 months. These findings suggested EFV discontinuation due to NAPEs was low, and the HADS-A, HADS-D, and PSQI scores after 12 months of EFV treatment were associated with several risk factors. The clinicians should keep in mind and routinely screen for the risk factors associated with neuropsychiatric disorders in HIV-infected patients.
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http://dx.doi.org/10.3389/fpsyt.2021.579448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943719PMC
February 2021

Distinct thalamocortical circuits underlie allodynia induced by tissue injury and by depression-like states.

Nat Neurosci 2021 04 8;24(4):542-553. Epub 2021 Mar 8.

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, PR China.

In humans, tissue injury and depression can both cause pain hypersensitivity, but whether this involves distinct circuits remains unknown. Here, we identify two discrete glutamatergic neuronal circuits in male mice: a projection from the posterior thalamic nucleus (PO) to primary somatosensory cortex glutamatergic neurons (S1) mediates allodynia from tissue injury, whereas a pathway from the parafascicular thalamic nucleus (PF) to anterior cingulate cortex GABA-containing neurons to glutamatergic neurons (ACC) mediates allodynia associated with a depression-like state. In vivo calcium imaging and multi-tetrode electrophysiological recordings reveal that PO and PF populations undergo different adaptations in the two conditions. Artificial manipulation of each circuit affects allodynia resulting from either tissue injury or depression-like states, but not both. Our study demonstrates that the distinct thalamocortical circuits PO→S1 and PF→ACC subserve allodynia associated with tissue injury and depression-like states, respectively, thus providing insights into the circuit basis of pathological pain resulting from different etiologies.
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http://dx.doi.org/10.1038/s41593-021-00811-xDOI Listing
April 2021

PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation.

Mol Cell 2021 04 3;81(7):1425-1438.e10. Epub 2021 Mar 3.

School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China; Department of Neurology, Affiliated ZhongDa Hospital, Institute of Neuropsychiatry, Southeast University, Nanjing, Jiangsu 210009, China. Electronic address:

Eukaryotic elongation factor 2 (eEF2) mediates translocation of peptidyl-tRNA from the ribosomal A site to the P site to promote translational elongation. Its phosphorylation on Thr56 by its single known kinase eEF2K inactivates it and inhibits translational elongation. Extensive studies have revealed that different signal cascades modulate eEF2K activity, but whether additional factors regulate phosphorylation of eEF2 remains unclear. Here, we find that the X chromosome-linked intellectual disability protein polyglutamine-binding protein 1 (PQBP1) specifically binds to non-phosphorylated eEF2 and suppresses eEF2K-mediated phosphorylation at Thr56. Loss of PQBP1 significantly reduces general protein synthesis by suppressing translational elongation. Moreover, we show that PQBP1 regulates hippocampal metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) and mGluR-LTD-associated behaviors by suppressing eEF2K-mediated phosphorylation. Our results identify PQBP1 as a novel regulator in translational elongation and mGluR-LTD, and this newly revealed regulator in the eEF2K/eEF2 pathway is also an excellent therapeutic target for various disease conditions, such as neural diseases, virus infection, and cancer.
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http://dx.doi.org/10.1016/j.molcel.2021.01.032DOI Listing
April 2021

Gas Chromatography Detection Protocol of Short-chain Fatty Acids in Mice Feces.

Bio Protoc 2020 Jul 5;10(13):e3672. Epub 2020 Jul 5.

Key Laboratory of Ministry of Education Industrial Fermentation Microbiology, Tianjin Key Laboratory of Industrial Microbiology, Tianjin Engineering Research Center of Microbial Metabolism and Fermentation Process Control, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, P. R. China.

Short-chain fatty acids (SCFAs), which are formed mainly by bacteria fermenting undigested carbohydrates in the colon, they are based on the number of carbon atoms in the carbon chain. Organic fatty acids with less than 6 carbon atoms are called short-chain fatty acids. SCFAs are closely related to various aspects of the human body, so more and more researchers concentrate on SCFAs. This protocol describes, a direct injection gas chromatography detection method with a pretreatment method for extracting SCFA from mice feces by combining acidification. The corresponding sample limit of quantization (LOQ) and limit of detection (LOD) are 0.8-1.0 mg/L and 0.5-0.8 mg/L, respectively. The correlation coefficient of calibration curve is greater than 0.999. The recovery rate of the spiked standard is 80%-102%. This method can be used to analyze and determine SCFAs in mice feces. Therefore, this is an economical, effective and reproducible method for SCFAs measurement in mice samples.
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http://dx.doi.org/10.21769/BioProtoc.3672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842300PMC
July 2020

Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy.

Nat Commun 2021 03 1;12(1):1359. Epub 2021 Mar 1.

School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, 511442, PR China.

Modulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an 'adaptor' while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.
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http://dx.doi.org/10.1038/s41467-021-21497-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921676PMC
March 2021

Matrine, as a CaSR agonist promotes intestinal GLP-1 secretion and improves insulin resistance in diabetes mellitus.

Phytomedicine 2021 Apr 14;84:153507. Epub 2021 Feb 14.

Department of Pharmacy, The Second Affiliated Hospital of Air Force Medical University, Xi'an, 710038, PR China.. Electronic address:

Background: Matrine (Mat), a bitter tastes compounds of derived from leguminosae such as Sophora flavescens and S. subprostrata, commonly used to improve obesity and diabetes.

Purpose: Our study to demonstrate bitter substances can stimulate the Bitter taste receptors (TAS2Rs) or Calcium-sensing receptor (CaSR) to stimulate the secretion of GLP-1 to promote blood glucose regulation.

Methods: The diabetic mice and intestinal secretory cell model were established to evaluate the Mat on glucose metabolism, intestinal insulin secretion and GLP-1 secretion related substances. To clarify the mechanism of Mat in regulating GLP-1 secretion by immunofluorescence, calcium labeling, siRNA, and molecular docking.

Results: The results showed that Mat could significantly improve glucose metabolism and increased insulin and GLP-1 secretion in diabetic mice and increased trisphosphate inositol (IP3) levels by affecting the expression of phospholipase C β2 (PLCβ2) and promote an increase in intracellular Ca2 levels in STC-1 cells to subsequently stimulate the secretion of GLP-1. Knockdown of the bitter taste receptors mTas2r108, mTas2r137, and mTas2r138 in STC-1 cells by siRNA did could not affect the role of Mat in regulating GLP-1. However, the secretion of GLP-1 by Mat could be significantly inhibited by administration of a CaSR inhibitor or siRNA CaSR. Molecular docking analysis showed that Mat could embed CaSR protein and bind to the original ligand of the egg white at the same amino acid site to play the role of an agonist.

Conclusion: Matrine is a typical bitter alkaloid could be used as an agonist of CaSR to stimulate the secretion of GLP-1 in the intestine, and it may be used as a potential drug for diabetes treatment.
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http://dx.doi.org/10.1016/j.phymed.2021.153507DOI Listing
April 2021

[Study on quality evaluation method of classical prescription Mahuang Decoction primary standard substances].

Zhongguo Zhong Yao Za Zhi 2020 Dec;45(23):5589-5598

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences Beijing 100700, China.

This study aimed to establish the HPLC characteristic chromatogram and content determination method for index components with the primary standard substances of the classical prescription Mahuang Decoction, and to provide data basis for the establishment of its quality standard and the development and utilization of compound preparations. First, HPLC was used to establish the material reference chromatograms of Mahuang Decoction, and 15 batches of standard samples of Mahuang Decoction were determined. Their similarity was calculated by the median method. Secondly, the content of the standard substances was determined and a simplecontent determination method was established by HPLC. Relevant methodology was investigated, and the extraction ratio, index component transfer rate and moisture content of 15 batches of primary standard samples were calculated. The results showed that the two sets of HPLC methods had their own characteristics. The six chromatographic peaks identified from the 10 common peaks in the former characteristic chromatogram covered all the herbal medicines in the standard substances, which can better indicate the quality characteristics of the standard substances of Mahuang Decoction. The latter method(content determination method) was simple and practical, so it was suitable for establishing the quality standard of its compound preparation. Two sets of methods were jointly used to evaluate the quality of 15 batches of Mahuang Decoction. The results were as follows: the similarity of 15 batches of samples was greater than 0.90; the average extraction ratio was 18.1%; the average moisture content was 9.7%; the average content and transfer rate of the standard ingredients ephedrine hydrochloride and total pseudoephedrine hydrochloride were 2.3% and 26.7% respectively, and the average content and transfer rate of amygdalin were 2.2% and 48.3% respectively. None of the data showed dispersion(beyond 70%-130% of the mean value), which met the application data requirements for the substance standards of ancient classical Chinese herbal compound preparations(draft for comments). Based on the above research, the primary substance quality standard of Mahuang Decoction was established in order to provide reference for the development and research of the compound preparation of Mahuang Decoction.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200908.301DOI Listing
December 2020

Chromosome-Level Genome Assembly and Annotation of a Sciaenid Fish, Argyrosomus japonicus.

Genome Biol Evol 2021 Feb;13(2)

Fishery College, Zhejiang Ocean University, Zhoushan, Zhejiang, China.

Argyrosomus japonicus is an economically and ecologically important fish species in the family Sciaenidae with a wide distribution in the world's oceans. Here, we report a high-quality, chromosome-level genome assembly of A. japonicus based on PacBio and Hi-C sequencing technology. A 673.7-Mb genome containing 282 contigs with an N50 length of 18.4 Mb was obtained based on PacBio long reads. These contigs were further ordered and clustered into 24 chromosome groups based on Hi-C data. In addition, a total of 217.2 Mb (32.24% of the assembled genome) of sequences were identified as repeat elements, and 23,730 protein-coding genes were predicted based on multiple approaches. More than 97% of BUSCO genes were identified in the A. japonicus genome. The high-quality genome assembled in this work not only provides a valuable genomic resource for future population genetics, conservation biology and selective breeding studies of A. japonicus but also lays a solid foundation for the study of Sciaenidae evolution.
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http://dx.doi.org/10.1093/gbe/evaa246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874996PMC
February 2021

Switching of delta opioid receptor subtypes in central amygdala microcircuits is associated with anxiety states in pain.

J Biol Chem 2021 Jan-Jun;296:100277. Epub 2021 Jan 9.

Hefei National Laboratory for Physical Sciences at the Microscale, Department of Biophysics and Neurobiology, University of Science and Technology of China, Hefei, China; Department of Physiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China. Electronic address:

Anxiety is often comorbid with pain. Delta opioid receptors (DORs) are promising targets for the treatment of pain and mental disorders with little addictive potential. However, their roles in anxiety symptoms at different stages of pain are unclear. In the current study, mice with inflammatory pain at the fourth hour following complete Freund's adjuvant (CFA) injection displayed significant anxiety-like behavior, which disappeared at the seventh day. Combining electrophysiology, optogenetics, and pharmacology, we found that activation of delta opioid receptor 1 (DOR1) in the central nucleus amygdala (CeA) inhibited both the anxiolytic excitatory input from the basolateral amygdala (BLA) and the anxiogenic excitatory input from the parabrachial nucleus (PBN). In contrast, activation of delta opioid receptor 2 (DOR2) did not affect CeA excitatory synaptic transmission in normal and 4-h CFA mice but inhibited the excitatory projection from the PBN rather than the BLA in 7-day CFA mice. Furthermore, the function of both DOR1 and DOR2 was downregulated to the point of not being detectable in the CeA of mice at the 21st day following CFA injection. Taken together, these results suggest that functional switching of DOR1 and DOR2 is associated with anxiety states at different stages of pain via modulating the activity of specific pathways (BLA-CeA and PBN-CeA).
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http://dx.doi.org/10.1016/j.jbc.2021.100277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948800PMC
January 2021

Biodegradable intramedullary nail (BIN) with high-strength bioceramics for bone fracture.

J Mater Chem B 2021 01 6;9(4):969-982. Epub 2021 Jan 6.

The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang 310006, China.

About 10 million fractures occur worldwide each year, of which more than 60% are long bone fractures. It is generally agreed that intramedullary nails have significant advantages in rigid fracture fixation. Metal intramedullary nails (INs) can provide strong support but a stress shielding effect can occur that results in nonunion healing in clinic. Nondegradable metals also need to be removed by a second operation. Could INs be biodegradable and used to overcome this issue? As current degradable biomaterials always suffer from low strength and cannot be used in Ins, herein, we report a novel device consisting of biodegradable IN (BIN) made for the first time with bioceramics. These BINs have an extremely high bending strength and stable internal and external structure. Experiments show that the BINs could not only fix and support the tibial fracture model, but also promote osteogenesis and affect the microenvironment of the bone marrow cavity. Therefore, they could be expected to replace traditional metal IN and become a more effective treatment option for tibial fractures.
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http://dx.doi.org/10.1039/d0tb02423fDOI Listing
January 2021

UPLC-Q-TOF/MS-Based Serum Metabolomics Reveals the Anti-Ischemic Stroke Mechanism of Nuciferine in MCAO Rats.

ACS Omega 2020 Dec 15;5(51):33433-33444. Epub 2020 Dec 15.

Key Laboratory of Beijing for Identification and Safety Evaluation of Chinese Medicine, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, No. 16 Nanxiaojie, Dongzhimennei, Beijing 100700, P. R. China.

Nuciferine is an aporphine alkaloid monomer that is extracted from the leaves of the lotus species and Gaertn. Nuciferine was reported to treat cerebrovascular diseases. However, the potential mechanism of the neuroprotective effects of nuciferine at the metabolomics level is still not unclear. The present research used neurological score, infarct volume, cerebral water content, and ultraperformance liquid chromatography to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based serum metabolomics to elucidate the anti-ischemic stroke effect and mechanisms of nuciferine. The results showed that nuciferine significantly improved neurological deficit scores and ameliorated cerebral edema and infarction. Multivariate data analysis methods were used to examine the differences in serum endogenous metabolism between groups, and the biomarkers of nuciferine on ischemic stroke were identified. Approximately 19 metabolites and 7 metabolic pathways associated with nuciferine on treatment of stroke were found, which indicated that nuciferine exerted a positive therapeutic action on cerebral ischemic by regulating metabolism. These results provided some data support for the study of anti-stroke effect of nuciferine from the perspective of metabolomics.
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http://dx.doi.org/10.1021/acsomega.0c05388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774285PMC
December 2020

Responsive hyaluronic acid-gold cluster hybrid nanogel theranostic systems.

Biomater Sci 2021 Feb;9(4):1363-1373

MOE Key Laboratory of High Performance Polymer Materials and Technology, and Department of Polymer Science & Engineering, College of Chemistry & Chemical Engineering, Nanjing University, Nanjing, 210093, P. R. China.

Tumor microenvironment responsive and self-monitored multimodal synergistic theranostic strategies can significantly improve therapeutic efficacy by overcoming biological barriers. Herein, we report a type of smart fluorescent hyaluronic acid nanogel that can respond to the reducing microenvironment and activate tumor targeting with light-traceable monitoring in cancer therapy. First, the derivative of hyaluronic acid (HA) with a vinyl group and cystamine bisacrylamide were used to synthesize bioreducible HA based nanogels via copolymerization in aqueous medium. Then, multifunctional mHA-gold cluster (mHA-GC) hybrid nanogels were successfully prepared by the in situ reduction of gold salt in the HA nanogels. The HA matrix turns the nanogels into a capsule for effective drug loading with excellent colloidal stability. Interestingly, the reducing tumor microenvironment dramatically enhanced the fluorescence signal of gold clusters in the hybrid nanogels. The highly selective cancer cell uptake and efficient intratumoral accumulation of the hybrid nanogels were demonstrated by fluorescence tracking of these nanogels. Responsive disassembly of the hybrid nanogels and drug release were triggered by excess glutathione presence in cancer cells. Moreover, in vivo and in vitro tumor suppression assays revealed that the doxorubicin-loaded hybrid nanogels exhibited significantly superior tumor cell inhibition abilities compared to free DOX. Overall, the mHA-GC hybrid nanogels emerge as a promising theranostic nanoplatform for the targeted delivery and controlled release of antitumor drugs with light-traceable monitoring in cancer treatment.
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http://dx.doi.org/10.1039/d0bm01815eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934158PMC
February 2021

Growth differentiation factor-5-gelatin methacryloyl injectable microspheres laden with adipose-derived stem cells for repair of disc degeneration.

Biofabrication 2020 12 25;13(1):015010. Epub 2020 Dec 25.

Department of Orthopedic Surgery, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou 310009, Zhejiang, People's Republic of China. Department of Orthopedic Research, Institute of Zhejiang University, Hangzhou 310009, Zhejiang, People's Republic of China. These two authors contributed equally to this work.

Nucleus pulposus (NP) degeneration is the major cause of degenerative disc disease (DDD). This condition cannot be treated or attenuated by traditional open or minimally invasive surgical options. However, a combination of stem cells, growth factors (GFs) and biomaterials present a viable option for regeneration. Injectable biomaterials act as carriers for controlled release of GFs and deliver stem cells to target tissues through a minimally invasive approach. In this study, injectable gelatin methacryloyl microspheres (GMs) with controllable, uniform particle sizes were rapidly biosynthesized through a low-cost electrospraying method. The GMs were used as delivery vehicles for cells and GFs, and they exhibited good mechanical properties and biocompatibility and enhanced the in vitro differentiation of laden cells into NP-like phenotypes. Furthermore, this integrated system attenuated the in vivo degeneration of rat intervertebral discs, maintained NP tissue integrity and accelerated the synthesis of extracellular matrix. Therefore, this novel therapeutic system is a promising option for the treatment of DDD.
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http://dx.doi.org/10.1088/1758-5090/abc4d3DOI Listing
December 2020

The bioavailability and excretion of an antitussive compound IAsp-N-Glc in rats by validated UPLC-MS/MS methods.

Pak J Pharm Sci 2020 May;33(3(Special)):1403-1411

Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China.

IAsp-N-Glc is a potential antitussive agent that is first reported to be isolated from Ginkgo Semen, but the bioavailability and excretion of IAsp-N-Glc are unknown. Therefore, we carried out our study to obtain the bioavailability and excretion profiles of IAsp-N-Glc in rats. Rapid, specific, and reliable quantification methods for the measurement of IAsp-N-Glc in rat plasma and fecal samples by using ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry were developed and validated. A C18 column was used for the separation of IAsp-N-Glc and internal standards, and water (containing 0.1% formic acid) and acetonitrile were chosen as the mobile phase for the separation in the flow-gradient mode. In the ranges of 37.5-7500 ng/mL and 120-30000 ng/mL, the calibration curves of IAsp-N-Glc exhibited satisfactory linearity for plasma and fecal samples with each linear correlation coefficient higher than 0.99, respectively. The methods were reproducible and reliable. The analytes were stable, and no apparent matrix effects were observed. The bioanalytical methods were successfully used to study the pharmacokinetics and excretion of IAsp-N-Glc in rats. Oral administration of IAsp-N-Glc exhibited a low absolute oral bioavailability (1.83±0.09%), and 59.63±6.29% of IAsp-N-Glc was excreted in feces. This report is the first to describe the bioavailability and excretion of IAsp-N-Glc in rats and will lay the foundation for the in-depth study and drug development of IAsp-N-Glc.
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May 2020

A trilogy antimicrobial strategy for multiple infections of orthopedic implants throughout their life cycle.

Bioact Mater 2021 Jul 10;6(7):1853-1866. Epub 2020 Dec 10.

Department of Orthopedics, Centre for Orthopaedic Research, Orthopedics Research Institute of Zhejiang University, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310000, PR China.

Bacteria-associated infection represents one of the major threats for orthopedic implants failure during their life cycles. However, ordinary antimicrobial treatments usually failed to combat multiple waves of infections during arthroplasty and prosthesis revisions etc. As these incidents could easily introduce new microbial pathogens in/onto the implants. Herein, we demonstrate that an antimicrobial trilogy strategy incorporating a sophisticated multilayered coating system leveraging multiple ion exchange mechanisms and fine nanotopography tuning, could effectively eradicate bacterial infection at various stages of implantation. Early stage bacteriostatic effect was realized via nano-topological structure of top mineral coating. Antibacterial effect at intermediate stage was mediated by sustained release of zinc ions from doped CaP coating. Strong antibacterial potency was validated at 4 weeks post implantation via an implanted model . Finally, the underlying zinc titanate fiber network enabled a long-term contact and release effect of residual zinc, which maintained a strong antibacterial ability against both and even after the removal of top layer coating. Moreover, sustained release of Sr and Zn during CaP coating degradation substantially promoted implant osseointegration even under an infectious environment by showing more peri-implant new bone formation and substantially improved bone-implant bonding strength.
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http://dx.doi.org/10.1016/j.bioactmat.2020.11.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732879PMC
July 2021

The safety and efficacy of a novel hypo-fractionated total marrow and lymphoid irradiation before allogeneic stem cell transplantation for lymphoma and acute leukemia.

Clin Transl Radiat Oncol 2021 Jan 12;26:42-46. Epub 2020 Nov 12.

Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China.

Purpose: Total body irradiation (TBI) has been widely utilized as part of the conditioning regimen for hematopoietic stem cell transplantation (HSCT), but is associated with significant toxicities. Targeted TBI using helical Tomotherapy allows precise and homogeneous tumor coverage and excellent sparing of organs at risk. The purpose of this study was to evaluate the clinical outcomes of a novel hypo-fractionation strategy for patients receiving total marrow and involved lymphoid irradiation (TMLI) as part of the conditioning regimen before HSCT.

Methods And Materials: 61 patients (7 acute myelogenous leukemia (AML), 33 acute lymphoblastic leukemia (ALL), 18 non-Hodgkin's lymphoma (NHL), 3 mixed acute leukemia (MAL)) received conditioning radiation treatment with TMLI (8 Gy to bone marrow, 10 Gy to involved field in 2 fractions per day) in conjunction with chemotherapy before transplantation.

Results: The median age of 61 patients with TMLI was 24 (4-54) years. The prescribed dose covered the entire bone and involved target volume, and the dose of organs at risk (OAR) was reduced by 28%-78% of the prescription dose. Grade 1-2 nausea and vomiting occurred in 12 patients and grade 1-2 pain in 6 patients during radiotherapy. Fatigue occurred in 16 patients. 2 patients had diarrhea, enteritis, and 1 patient had fever. None of patient had grade 3-4 non-hematologic adverse reactions. Late (30 days after HSCT) grade 2 toxicities including reversible enteritis occurred in 3 patients. 5 patients developed infectious pneumonia. The 2 years progression-free survival (PFS) was 64.1% (95% CI: 0.16-0.22) and overall survival (OS) was 74.7% (95% CI: 0.19-0.24) for the 61 patients who had received their planned HSCT. The 2-year non-relapse mortality was significantly reduced to 5% in this patient cohort.

Conclusions: This study demonstrates that hypo-fractionated TMLI (8 Gy to bone marrow, 10 Gy to involved field in a single day) as a conditioning regimen for lymphoma and acute leukemia was feasible and the clinical outcomes were acceptable.
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http://dx.doi.org/10.1016/j.ctro.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708691PMC
January 2021
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