Publications by authors named "Li-Jun Xu"

225 Publications

TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc.

Mol Psychiatry 2022 Jan 25. Epub 2022 Jan 25.

Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, USA.

Relapse remains a major challenge to the treatment of cocaine addiction. Recent studies suggested that the trace amine-associated receptor 1 (TAAR1) could be a promising target to treat cocaine addiction and relapse; however, the underlying mechanism remains unclear. Here, we aimed to investigate the neural mechanism underlying the role of TAAR1 in the drug priming-induced reinstatement of cocaine-seeking behavior in rats, an animal model of cocaine relapse. We focused on the shell subregion of nucleus accumbens (NAc), a key brain region of the brain reward system. We found that activation of TAAR1 by systemic and intra-NAc shell administration of the selective TAAR1 agonist RO5166017 attenuated drug-induced reinstatement of cocaine-seeking and prevented drug priming-induced CaMKIIα activity in the NAc shell. Activation of TAAR1 dampened the CaMKIIα/GluR1 signaling pathway in the NAc shell and reduced AMPAR-EPSCs on the NAc slice. Microinjection of the selective TAAR1 antagonist EPPTB into the NAc shell enhanced drug-induced reinstatement as well as potentiated CaMKIIα activity in the NAc shell. Furthermore, viral-mediated expression of CaMKIIα in the NAc shell prevented the behavioral effects of TAAR1 activation. Taken together, our findings indicate that TAAR1 regulates drug-induced reinstatement of cocaine-seeking by negatively regulating CaMKIIα activity in the NAc. Our findings elucidate a novel mechanism of TAAR1 in regulating drug-induced reinstatement of cocaine-seeking and further suggests that TAAR1 is a promising target for the treatment of cocaine relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-022-01448-3DOI Listing
January 2022

Interleukin-1 receptor-associated kinase 4 (IRAK4) in the nucleus accumbens regulates opioid-seeking behavior in male rats.

Brain Behav Immun 2021 Dec 24;101:37-48. Epub 2021 Dec 24.

Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, United States. Electronic address:

Opioid addiction remains a severe health problem. While substantial insights underlying opioid addiction have been yielded from neuron-centric studies, the contribution of non-neuronal mechanisms to opioid-related behavioral adaptations has begun to be recognized. Toll-like receptor 4 (TLR4), a pattern recognition receptor, has been widely suggested in opioid-related behaviors. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a kinase essential for TLR4 responses, However, the potential role of IRAK4 in opioid-related responses has not been examined. Here, we explored the role of IRAK4 in cue-induced opioid-seeking behavior in male rats. We found that morphine self-administration increased the phosphorylation level of IRAK4 in the nucleus accumbens (NAc) in rats; the IRAK4 signaling remained activated after morphine extinction and cue-induced reinstatement test. Both systemic and local inhibition of IRAK4 in the NAc core attenuated cue-induced morphine-seeking behavior without affecting the locomotor activity and cue-induced sucrose-seeking. In addition, inhibition of IRAK4 also reduced the cue-induced reinstatement of fentanyl-seeking. Our findings suggest an important role of IRAK4 in opioid relapse-like behaviors and provide novel evidence in the association between innate immunity and drug addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbi.2021.12.014DOI Listing
December 2021

Development of 3-(4-Chlorophenyl)-1-(phenethyl)urea Analogues as Allosteric Modulators of the Cannabinoid Type-1 Receptor: RTICBM-189 is Brain Penetrant and Attenuates Reinstatement of Cocaine-Seeking Behavior.

J Med Chem 2022 Jan 20;65(1):257-270. Epub 2021 Dec 20.

Research Triangle Institute, Research Triangle Park, Research Triangle Park, North Carolina 27709, United States.

We have shown that CB receptor negative allosteric modulators (NAMs) attenuated the reinstatement of cocaine-seeking behaviors in rats. In an effort to further define the structure-activity relationships and assess the druglike properties of the 3-(4-chlorophenyl)-1-(phenethyl)urea-based CB NAMs that we recently reported, we introduced substituents of different electronic properties and sizes to the phenethyl group and evaluated their potency in CB calcium mobilization, cAMP, and GTPγS assays. We found that 3-position substitutions such as Cl, F, and Me afforded enhanced CB potency, whereas 4-position analogues were generally less potent. The 3-chloro analogue (, RTICBM-189) showed no activity at >50 protein targets and excellent brain permeation but relatively low metabolic stability in rat liver microsomes. Pharmacokinetic studies in rats confirmed the excellent brain exposure of with a brain/plasma ratio of 2.0. Importantly, intraperitoneal administration of significantly and selectively attenuated the reinstatement of the cocaine-seeking behavior in rats without affecting locomotion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.1c01432DOI Listing
January 2022

A Fischer-Type Ruthenium Carbene Complex as a Metathesis Catalyst for the Synthesis of Enol Ethers.

J Org Chem 2021 Dec 30;86(24):17629-17639. Epub 2021 Nov 30.

Department of Chemistry, National Taiwan University, Taipei 10617, Taiwan.

The Grubbs G-I or G-II catalyst gives the ruthenium ethoxy carbene complex, which catalyzes ring-opening cross metathesis (ROCM) of a strained cyclic alkene to give a diene where one of the two alkene moieties in the product contains an ethoxy substituent. No polymeric products are detected. Hydrocarbons such as parent norbornene or substituted cyclopropenes can proceed with the reaction smoothly. Tertiary amines, -alkylimides, esters, and aryl or alkyl bromides remain intact under the reaction conditions. In addition to vinyl ethers, vinylic esters can also be used. The time required to reach a 50% yield of the ROCM product varies from 0.01 to 140 h depending on the strain and nucleophilicity of the double bond. Anchimeric participation of an electron-rich group would result in significant enhancement of the reactivity, and the could be as short as several minutes. A similar substrate without such a neighboring group shows a much slower rate. An -norborne derivative reacts much faster than the corresponding -isomer. Alkenes with poor nucleophilicity are less favored for the ROCM process, so is less strained cyclooctene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.1c01741DOI Listing
December 2021

Effect of natural garlic essential oil on chickens with artificially infected Eimeria tenella.

Vet Parasitol 2021 Dec 3;300:109614. Epub 2021 Nov 3.

College of Animal Science and Technology, Hebei Agricultural University, Baoding, Hebei 071001, China. Electronic address:

Chicken coccidiosis is a kind of parasitic protozoosis caused by Eimeria parasitizing in the chicken intestinal epithelial cells. Eimeria tenella is considered as a significantly virulent and harmful parasite. At present, drug resistance remains a major problem and a large number of drug residues have been found to be produced in the treatment of the disease. Hence, novel strategies are needed to avoid the harmful effects caused by the generation of various chemical drug residues to the human body and also reduce the economic loss caused by coccidiosis to the chicken industry. In this study, natural garlic essential oil was used to control Eimeria tenella infection. The anticoccidial index (ACI) was calculated according to the clinical symptoms, body weight gain, oocyst excretion and cecal lesions. The immune organ index and serum biochemical indexes were measured to verify the possible anticoccidial effects. The results showed that: compared with the infected group, continuous feeding of different doses of natural garlic essential oil could significantly reduce the clinical symptoms, cecal lesions, the number of oocysts, but increase the weight of sick chickens, and effectively improve the intestinal functions. Moreover, compared with diclazuril control group, 0.06 mL/L garlic essential oil exhibited similar anticoccidial index. The content of immune organ index, serum biochemical index IgM, IgG and IgA in 0.06 mL/L garlic essential oil group was the highest, which indicated that garlic essential oil had a significant tendency to improve the immune function of the chickens. This study also showed that the natural garlic essential oil exhibited the same beneficial effects as that of diclazuril on chicken coccidiosis, and the anti-coccidiosis index of 0.06 mL/L garlic essential oil was favorable. Thus based on the above evidences and its relatively low cost, garlic essential oil can be potentially be used as an efficient anti parasitic drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vetpar.2021.109614DOI Listing
December 2021

Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders.

Authors:
Ruyan Wu Jun-Xu Li

CNS Drugs 2021 Dec 12;35(12):1239-1248. Epub 2021 Nov 12.

Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York, 955 Main Street, Buffalo, NY, 14214, USA.

Trace amines, including β-phenylethylamine (β-PEA), p-tyramine (TYR), tryptamine (TRP), and p-octopamine (OCT), represent a group of amines expressed at low levels in the mammalian brain. Given the close structural similarities to traditional monoamines, links between trace amines and the monoaminergic system have long been suspected. Trace amine-associated receptor 1 (TAAR1), the most well characterized receptor in the TAAR family, has been shown to be potently activated by trace amines such as TYR and PEA. Further, catecholamine metabolites and amphetamine analogs are also potent agonists of TAAR1, implicating the receptor in mediating the monoaminergic system and in substance use disorders. In the central nervous system, TAAR1 is expressed in brain regions involved in dopaminergic, serotonergic, and glutamatergic transmission, and genetic animal models and electrophysiological studies have revealed that TAAR1 is a potent modulator of the monoaminergic system. Selective and potent engineered TAAR1 ligands, including full (RO5166017 and RO5256390) and partial (RO5203648, RO5263397 and RO5073012) agonists and the antagonist EPPTB (N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl) benzamide, RO5212773), serve as invaluable tools for the investigation of TAAR1 functions and display significant potential for the development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. Despite a number of advances that have been made, more clinical studies are warranted in order to test the potential and efficacy of TAAR1 ligands in the treatment of psychiatric disorders, including substance use disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40263-021-00871-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8787759PMC
December 2021

Discovery of new genetic loci for male sexual orientation in Han population.

Cell Discov 2021 Oct 31;7(1):103. Epub 2021 Oct 31.

Department of Psychiatry, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, P = 8.36 × 10, OR = 1.29; rs7259428, 19q12, ZNF536, P = 7.58 × 10, OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, P = 1.95 × 10; rs2414487, 15q21.3, LOC145783, P = 4.53 × 10; rs2106525, 7q31.1, MDFIC, P = 6.24 × 10). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41421-021-00341-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558329PMC
October 2021

WTD Attenuating Rheumatoid Arthritis Suppressing Angiogenesis and Modulating the PI3K/AKT/mTOR/HIF-1α Pathway.

Front Pharmacol 2021 27;12:696802. Epub 2021 Sep 27.

Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Wutou Decoction (WTD), as a classic prescription, has been generally used to treat rheumatoid arthritis (RA) for two thousand years in China. However, the potential protective effects of WTD on rheumatoid arthritis and its possible mechanism have rarely been reported. The aim of this study was to explore the possible mechanism of WTD against RA and a promising alternative candidate for RA therapy. A model of collagen-induced arthritis (CIA) was constructed in rats to assess the therapeutic effects of WTD. Histopathological staining, immunofluorescence, and western blotting of synovial sections were conducted to detect the antiangiogenic effects of WTD. Then, cell viability assays, flow cytometry, scratch healing assays, and invasion assays were conducted to explore the effects of WTD on MH7A human fibroblast-like synoviocyte (FLS) cell proliferation, apoptosis, migration, and invasion . The ability of WTD to induce blood vessel formation after MH7A cell and human umbilical vein endothelial cell line (HUVEC) coculture with WTD intervention was detected by a tube formation assay. The mechanisms of WTD were screened by network pharmacology and confirmed by and experiments. WTD ameliorated the symptoms and synovial pannus hyperplasia of CIA rats. Treatment with WTD inhibited MH7A cell proliferation, migration, and invasion and promoted MH7A apoptosis. WTD could inhibit MH7A cell expression of proangiogenic factors, including VEGF and ANGI, to induce HUVEC tube formation. Furthermore, the PI3K-AKT-mTOR-HIF-1α pathway was enriched as a potential target of WTD for the treatment of RA through network pharmacology enrichment analysis. Finally, it was confirmed and that WTD inhibits angiogenesis in RA by interrupting the PI3K-AKT-mTOR-HIF-1α pathway. WTD can inhibit synovial hyperplasia and angiogenesis, presumably by inhibiting the migration and invasion of MH7A cells and blocking the production of proangiogenic effectors in MH7A cells. The possible underlying mechanism by which WTD ameliorates angiogenesis in RA is the PI3K-AKT-mTOR-HIF-1α pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2021.696802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502817PMC
September 2021

The selective TAAR1 partial agonist RO5263397 promoted novelty recognition memory in mice.

Psychopharmacology (Berl) 2021 Nov 22;238(11):3221-3228. Epub 2021 Jul 22.

Department of Pharmacology and Toxicology, University At Buffalo, The State University of New York, 955 Main Street, Buffalo, NY, 14214, USA.

Rationale: Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that has a particular role in regulating dopaminergic, serotonergic, and glutamatergic transmission. TAAR1 agonists have shown pro-cognitive activities. However, it remains largely unknown of the effects of TAAR1 agonists on memory performance.

Objectives: Here, by using the mice novel object recognition (NOR) test, we examined the effects of the selective TAAR1 partial agonist RO5263397 on recognition memory.

Results: We found that RO5263397 significantly enhanced the retrieval of short-term memory (STM; 20 min after training) both in male and female mice. RO5263397 promoted the retrieval of STM in the wild-type (WT) littermates but not TAAR1-KO mice, indicating that the effects of RO5263397 were dependent on TAAR1. Interestingly, compared to their WT litters, TAAR1-KO mice showed similar levels of STM, suggesting that genetic deletion of taar1 gene did not affect the STM retrieval. Furthermore, RO5263397 also promoted the retrieval of long-term NOR memory (24 h after training).

Conclusions: These results indicate that TAAR1 activation promotes NOR memory retrieval. Consistent with previous studies, our finding further suggests that TAAR1 agonists have pro-cognitive properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00213-021-05937-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605990PMC
November 2021

Activation of trace amine-associated receptor 1 attenuates nicotine withdrawal-related effects.

Addict Biol 2022 Jan 25;27(1):e13075. Epub 2021 Jun 25.

Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.

Nicotine addiction is a leading avoidable brain disorder globally. Although nicotine induces a modest reinforcing effect, which is important for the initial drug use, the transition from nicotine use to nicotine addiction involves the mechanisms responsible for the negative consequences of drug abstinence. Recent study suggested that trace amine-associated receptor 1 (TAAR1) is a promising pharmacological target for the modulation of positive reinforcing effects of nicotine. However, whether TAAR1 plays a part in the negative reinforcement of nicotine withdrawal remains to be determined. Here, using a long-access (LA) self-administration model, we investigated whether LA rats show increased nicotine intake and withdrawal symptoms in comparison with saline and ShA rats and then tested the effect of TAAR1 partial agonist RO5263397 on nicotine withdrawal effects. We found that rats from long-access group showed significant abstinence-induced anxiety-like behaviour, mechanic hypersensitivity, increased number of precipitated withdrawal signs and higher motivation for the drug, while rats from short-access did not differ from saline group. TAAR1 partial agonist RO5263397 significantly reduced the physical and motivational withdrawal effects of nicotine in LA rats, as reflected by increased time spent on the open arm in the elevated plus maze (EPM) test, normalized paw withdrawal threshold, decreased withdrawal signs and motivation to self-administer nicotine. This study indicates that activation of TAAR1 attenuates the negative-reinforcing effects of nicotine withdrawal and further suggests TAAR1 as a promising target to treat nicotine addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/adb.13075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8709869PMC
January 2022

Increasing the height of the anterior lip on a tibial insert in a posterior stabilized knee prosthesis has little effect on the wear rate.

Med Eng Phys 2021 05 27;91:48-53. Epub 2021 Mar 27.

School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China; School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China; Beijing Advanced Innovation Center for Biomedical Engineering, Beihang University, Beijing 100083, China. Electronic address:

A high anterior lip on a total knee prosthesis is an effective way of reducing anterior translation, but the effect on joint wear is unclear. Using finite element analysis (FEA), this study quantitatively compared wear rates and anterior contact stresses in three posterior stabilized knee prostheses with different heights for the anterior lip during six daily activities (walking, stair ascent, stair descent, sit-to-stand, pivot turn and crossover turn). The wear rate and location of maximum wear depth were similar for the three lip heights tested, but the knee with the highest anterior lip also showed slight anterior wear scaring due to articular contact stress during swing phase, which was highly dependent on the shape of the contact interface. This study illustrates that tibial inserts with a high anterior lip maintain a wear rate similar to moderate and low lip posterior stabilized designs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.medengphy.2021.03.007DOI Listing
May 2021

Emergence of Invasive Serotype Ib Sequence Type 10 Group B Streptococcus Disease in Chinese Infants Is Driven by a Tetracycline-Sensitive Clone.

Front Cell Infect Microbiol 2021 14;11:642455. Epub 2021 May 14.

Department of Clinical Laboratory, Shanxi Children's Hospital Shanxi Maternal and Child Health Hospital, Taiyuan, China.

Background: Group B streptococcus (GBS) is a leading cause of serious infections in infants. The extensive use of tetracycline has led to the selection of specific resistant and infectious GBS clones. The sequence type (ST) 10 GBS strain, causing invasive infections in infants, is becoming prevalent in China. We aimed to understand the clinical and microbiological characteristics of this GBS strain.

Methods: We conducted a retrospective study on infants with invasive GBS disease from the largest women's and children's medical center in Shanxi and collected data between January 2017 and October 2020. GBS isolates were analyzed by capsule serotyping, genotyping, antibiotic resistance, and surface protein genes.

Results: All ST10 isolates belonged to serotype Ib; type Ib/ST10 strains were responsible for 66.7% (14/21, < 0.05) of infant invasive GBS infections during the period and all resulted in late-onset (LOD) and late LOD disease (14/14). Infants with type Ib/ST10 GBS disease had significantly higher rates of meningitis (9/14, 64.3%, p < 0.05) and clinical complications (5/14, 35.7%, p < 0.05). The Ib/ST10 GBS isolates had limited genetic diversity, clustered in the CC10/bca/PI-1 + PI-2a genetic lineage, showed resistance to erythromycin, lincomycin, and fluoroquinolones and sensitivity to tetracycline, and possessed genes , , and amino acid changes in and .

Conclusions: The probable clonal expansion can result in severe infections in infants and ongoing emergence of multi-drug resistant isolates. Continued monitoring for type Ib/ST10 GBS infections is warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fcimb.2021.642455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162377PMC
July 2021

The Effect of TCM-Induced HAMP on Key Enzymes in the Hydrolysis of AD Model Cells.

Neurochem Res 2021 May 8;46(5):1068-1080. Epub 2021 Mar 8.

Hebei Key Laboratory of Chinese Medicine Research on Cardio-cerebrovascular Disease, Hebei University of Chinese Medicine, Shijiazhuang, 050200, China.

Alzheimer's disease (AD) process is characterized classically by two hallmark pathologies: β-amyloid (Aβ) plaque deposition and neurofibrillary tangles of hyperphosphorylated tau. Aβ peptides play an important role in AD, but despite much effort the molecular mechanisms of how Aβ contributes to AD remain unclear. The present study evaluated the effects of the active components of Epimedium, Astragalus and Radix Puerariae induced HAMP on key enzymes in the hydrolysis of APP in HT22 cells. The active components of Epimedium, Astragalus and Radix Puerariae could effectively up-regulate the expression of HAMP, alleviate the iron overload in the brain tissues of mice, significantly improve the learning and memory ability of AD, down-regulate the expression of Aβ and reduce the deposition of SP in an APPswe/PS1 transgenic mouse model of AD. HAMP and Aβ induced HT22 cells are used as AD cell models in this study to investigate the effect of the compound consisting of the effective components of Epimedium, Astragalus and Pueraria on the key enzymes in the hydrolysis of APP. After the administration of traditional Chinese medicine (TCM), the expression levels of ADAM10 and ADAM17 were increased while the expression level of BACE1 decreased. This indicates that TCM can promote the expression level of ADAM10 and ADAM17, inhibit the expression level of BACE1, thus further inhibiting the production of amyloid protein and reducing the production of Aβ and SP. Compared with RNAi group, the expression level of ADAM10 and ADAM17 in Aβ + RNAi group was decreased while the expression level of BACE1 increased. Compared with the Aβ + RNAi group the expression level of ADAM10 and ADAM17 in the Aβ + RNAi + TCM group was increased while the expression level of BACE1 was decreased. The present study indicated the effects of the active components of Epimedium, Astragalus and Radix Puerariae may alleviate AD by up-regulating the expression of HAMP, thus reducing brain iron overload, promoting the expression of ADAM10 and ADAM17, inhibiting the expression of BACE1, and reducing the deposition of Aβ.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11064-021-03235-yDOI Listing
May 2021

Protective Effects of Hu-Lu-Ba-Wan () against Oxidative Stress in Testis of Diabetic Rats through PKCα/NAPDH Oxidase Signaling Pathway.

Chin J Integr Med 2021 Jun 15;27(6):432-439. Epub 2021 Jan 15.

Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Objective: To explore the protective effect and the underlying mechanism of Hu-Lu-Ba-Wan (, HLBW) on the testis of diabetic rats.

Methods: Twenty-four male Wistar rats (160-180 g) were randomly divided into 3 groups according to a random number table, including a control group (n=8), diabetic group (n=8), and HLBW group (n=8). Diabetic rat model was established by high-fat-diet administration and single intravenous injection of streptozotocin (26 mg/kg). Then HLBW granule was administrated for 12 weeks. Fasting blood glucose and insulin levels as well as serum total testosterone level and testicular testosterone content were examined. Oxidative stress markers in both serum and testis were tested. Meanwhile, testicular morphology was observed under hematoxylin and eosin (HE) and the ultrastructure of Leydig cell was observed by electron microscope. The superoxide anion level was detected by DHE, and TUNEL-positive cells of testis was evaluated by TUNEL assay. The gene and protein expression of protein kinase C (PKCα), phosphorylated PKCα (P-PKCα) and P47phox in testicular tissues were determined by quantitative RT-PCR analysis and Western bolt analysis.

Results: Compared with the diabetic group, HLBW treatment significantly reduced the fasting glucose levels and increased the levels of fasting insulin and testosterone in serum (P<0.01). HLBW administration also reduced the levels of reactive oxygen species (ROS) in plasma and alleviated the damage of oxidative stress in the testis of diabetic rats. Additionally, HLBW down-regulated the protein and mRNA levels of PKCα, P-PKCα and P47phox in testicular tissues.

Conclusion: HLBW may attenuate the oxidative stress in the testis of diabetic rats via PKCα /NAPDH oxidase signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11655-021-2863-2DOI Listing
June 2021

Toll-Like Receptor 4 Signaling and Drug Addiction.

Authors:
Ruyan Wu Jun-Xu Li

Front Pharmacol 2020 24;11:603445. Epub 2020 Nov 24.

Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, United States.

The emphasis of neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction. Recent studies have begun to appreciate the role of innate immune system, especially toll-like receptor 4 (TLR4) signaling in drug reward-associated behaviors and physiology. Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction. Inhibition of TLR4 or its downstream effectors attenuated the reinforcing effects of opioids, alcohol and psychostimulants, and this effect is also involved in the withdrawal and relapse-like behaviors of different drug classes. However, conflicting results also argue that TLR4-related immune response may play a minimal part in drug addiction. This review discussed the preclinical evidence that whether TLR4 signaling is involved in multiple drug classes action and the possible mechanisms underlying this effect. Moreover, clinical studies which examined the potential efficacy of immune-base pharmacotherapies in treating drug addiction are also discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.603445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793839PMC
November 2020

Blockade of α1 subtype GABAA receptors attenuates the development of tolerance to the antinociceptive effects of midazolam in rats.

Behav Pharmacol 2021 06;32(4):345-350

Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.

Benzodiazepines bind to and act on α1-3 and α5-containing GABAA receptors. Previous studies suggest that different GABAA receptor α-subtypes mediate the various behavioral effects of benzodiazepines, which raises the possibility of combining benzodiazepines with subtype-selective GABAA receptor antagonists to improve the therapeutic profiles of benzodiazepines. This study examined the GABAA receptor subtype mediation of the tolerance to midazolam-induced antinociception in rats. Midazolam (3.2 mg/kg) significantly reduced the locomotion in rats which was prevented by the selective α1-preferring GABAA receptor antagonist β-carboline-3-carboxylate-t-butyl ester (βCCt) (3.2 mg/kg). Midazolam increased the paw withdrawal threshold as tested by the von Frey filament assay in the complete Freund's adjuvant-induced inflammatory pain model in rats, and this effect was not altered by βCCt or another α1-preferring GABAA receptor antagonist 3-propoxy-β-carboline hydrochloride (3PBC). Repeated treatment with midazolam in combination with vehicle, βCCt or 3PBC (twice daily) for 7 days led to a progressive increase of the ED50 values in the midazolam- and vehicle-treated rats, but not in other rats, suggesting the development of tolerance to midazolam but not to the combination of midazolam with α1-preferring GABAA receptor antagonists. These results suggest the essential role of the α1-subtype of GABAA receptors in mediating the development of tolerance to midazolam-induced antinociceptive effects and raise the possibility of increasing therapeutic profiles of benzodiazepines by selectively blocking specific α-subtypes of GABAA receptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FBP.0000000000000614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119291PMC
June 2021

Sequencing and analysis of John Cunningham polyomavirus DNA from acquired immunodeficiency syndrome patients with progressive multifocal leukoencephalopathy.

Chin Med J (Engl) 2020 Dec;133(23):2887-2889

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, China.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CM9.0000000000001225DOI Listing
December 2020

Activation of trace amine-associated receptor 1 selectively attenuates the reinforcing effects of morphine.

Br J Pharmacol 2021 02 4;178(4):933-945. Epub 2021 Jan 4.

Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.

Background And Purpose: Trace amine-associated TA receptors play critical roles in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of TA receptors modulates addiction-like behaviours associated with psychostimulants. However, little is known about whether TA receptor modulation would regulate the behavioural effects of opioids.

Experimental Approach: Effects of the selective TA receptor partial agonist RO5263397 on the addiction-related and antinociceptive effects of morphine were systematically assessed in male rats and mice.

Key Results: RO5263397 attenuated the expression of morphine-induced behavioural sensitization in wildtype but not TA receptor knockout mice. RO5263397 shifted the dose-effect curve of morphine self-administration downward and reduced the breakpoint in a progressive ratio schedule of reinforcement but did not affect food self-administration in rats. RO5263397 decreased the cue- and drug-induced reinstatement of morphine-seeking behaviour in rats. RO5263397 alone did not trigger reinstatement of morphine-seeking behaviour or change locomotor activity in rats with a history of morphine self-administration. However, RO5263397 did not affect the expression of morphine-induced conditioned place preference in mice or rats. RO5263397 did not affect naltrexone-precipitated jumping behaviour or naltrexone-induced conditioned place aversion in morphine-dependent mice. Furthermore, RO5263397 did not affect the analgesic effects of morphine in an acute nociception model in mice and a chronic pain model in rats.

Conclusion And Implications: These results indicated that TA receptor activation selectively attenuated the reinforcing, but not withdrawal or antinociceptive effects of morphine, suggesting that selective TA receptor agonists might be useful to combat opioid addiction, while sparing the analgesic effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.15335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8758336PMC
February 2021

Spectral-domain optical coherence tomography finding in cytomegalovirus retinitis in AIDS patients.

Int J Ophthalmol 2020 18;13(11):1800-1807. Epub 2020 Nov 18.

Department of Infectious Disease, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China.

Aim: To observe the findings of spectral domain optical coherence tomography (SD-OCT) scan in cytomegalovirus retinitis (CMVR).

Methods: Forty-six eyes of 33 patients with acquired immunodeficiency syndrome and CMVR were enrolled in the study. Complete ophthalmologic examinations, color fundus photography, SD-OCT and fundus autofluorescence (FAF) were performed for all patients at the first visit and each follow-up visit. Retinal necrosis in CMVR was analyzed on SD-OCT and classified into two types, the typical type and the atypical type.

Results: Forty-one eyes of active CMVR and 4 eyes of recurrent CMVR were classified into typical type, and 4 eyes with graying retinal lesion without hemorrhage or only punctate hemorrhage were classified into atypical type. In active stage of CMVR, the retina in typical type was significant thickened with hyperreflective lesion and full-thickness disruption of retinal architecture with enlarged vessel; while in atypical type, the retina was also destroyed in all layers but without thickening or slightly thinned. The choroid, vitreous and retinal vessels were not significantly involved. In healed stage, the retina was thin with destroyed layers in both types. In typical type, FAF showed mottled hypofluorescence mixed with punctuate hyperfluorescence. In atypical type, the retina showed some "cavity" in outer nuclear layer, and FAF showed mild hyperfluorescence.

Conclusion: SD-OCT show different changes in the retina in typical type and atypical type of CMVR, which should be useful in assisting diagnosis and follow-up management of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18240/ijo.2020.11.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590866PMC
November 2020

Tetramethylpyrazine Ameliorates Lipopolysaccharide-Induced Sepsis in Rats Protecting Blood-Brain Barrier, Impairing Inflammation and Nitrous Oxide Systems.

Front Pharmacol 2020 2;11:562084. Epub 2020 Oct 2.

Department of Anesthesiology, Ningbo Ninth Hospital, Ningbo, China.

The aim of this study was to assess the underlying impact of Tetramethylpyrazine (TMP), which is the main activity compound of Hort, on the blood-brain barrier, inflammatory and nitrous oxide systems in a rat model of lipopolysaccharide (LPS)-induced sepsis. The SD rats were divided into control group, LPS treatment group, and LPS + TMP treatment group. TMP administered by tail vein injection. The mortality of experimental rats was recorded during the experiment. Rats were sacrificed after 14 days. Peripheral blood was collected and the expression levels of inflammatory factors TNF-α, IL-1β, and IL-6 were detected by ELISA. The integrity of blood-brain barrier was detected by sodium fluorescein staining. Lung and brain tissues were taken to detect the infiltration of immune cells. Immunohistochemistry was performed to detect the expression of tight junctions related proteins and oxidative stress-related proteins. The results showed that TMP treatment for 14 days significantly decreased the weight loss and increased the survival rate of the septic rats significantly. TMP decreased the infiltration of inflammatory cells and alleviated the sepsis-induced damage in both the lung and brain tissues. The inflammatory cytokines TNF-α, IL-1β, and IL-6, were significantly decreased post-TMP treatment. Histopathological analysis with sodium fluorescein staining density showed that TMP had a protective effect on the basal lamina and cerebral cortex. Also, TMP significantly increased expression of the tight junction-related proteins claudin-5 and occludin in the brain tissue and increased the expression of the , , and genes, indicating alleviated the degree of blood-brain barrier destruction. Furthermore, immunohistochemistry (IHC) and immunoblotting confirmed that TMP could inhibit the indicators of the nitrous oxide system, iNOS and eNOS; in addition, TMP significantly decreased the levels of MDA and NO. The findings showed that TMP treatment during sepsis was associated with the protection of the blood-brain barrier and the suppression of inflammatory reactions and the nitrous oxide system. This study reveals a promising protective role of TMP in septic encephalopathy and may suggest a therapeutic approach for fighting the deadly disease of sepsis in the clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.562084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566283PMC
October 2020

Molecular characterization of pathogenic group B streptococcus from a tertiary hospital in Shanxi, China: High incidence of sequence type 10 strains in infants/pregnant women.

J Microbiol Immunol Infect 2021 Dec 11;54(6):1094-1100. Epub 2020 Aug 11.

Department of Clinical Laboratory, Shanxi Children's Hospital Shanxi Maternal and Child Health Hospital, Taiyuan, China.

Background: Group B streptococcus (GBS) is a leading cause of serious infection in infants. Understanding its regional molecular epidemiology is helpful for regulating efficient prevention practice.

Methods: A retrospective study was conducted to collected data from infants and pregnant women with culture-proven GBS disease in the largest women and children's medical center in Shanxi between January 2017 and September 2019. All GBS isolates were analyzed by multi-locus sequence typing (MLST) as well as distribution of pilus island (PI) genes.

Results: A total of 54 GBS isolates were obtained from 36 (66.7%) pregnant women and 18 (33.3%) infants with invasive disease. Among invasive GBS strains, the most common sequence type was ST10 (72.2%, P < 0.05), followed by ST23 and ST19. The ST10 strain was also the leading sequence type in colonizing pregnant women (44.4%, P < 0.05). All of the isolates carried at least one pilus island. The most frequently detected pilus island was PI-1+PI-2a (85.2%, P < 0.05), followed in turn by PI-2a and PI-2b.

Conclusions: Our study demonstrates that one hypervirulent clone, sequence type 10, accounts for a large proportion of invasive GBS disease in infants and colonizing pregnant women, and the PI-1+PI-2a sub-lineages should be noted in infant infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmii.2020.07.018DOI Listing
December 2021

Long non-coding RNA uc.80- overexpression promotes M2 polarization of microglias to ameliorate depression in rats.

IUBMB Life 2020 10 11;72(10):2194-2203. Epub 2020 Aug 11.

Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.

Microglia polarization is associated with the pathogenesis of depression. A previous study shows that long non-coding RNA uc.80- is down-regulated in the hippocampus of depressed rats. Thus, this article aims to investigate the role of uc.80- in microglia polarization in depression. We first established depression model rats by chronic unpredictable mild stress (CUMS) regiment. We found that hippocampus of depressed rats exhibited an increase of M1 microglias and a decrease of M2 microglias. uc.80- was down-regulated in hippocampus of depressed rats. Furthermore, the detection of behaviouristics of depressed rats showed that uc.80- overexpression alleviated depression of rats. In addition, uc.80- overexpression promoted M2 polarization of microglias in vivo and in vitro. uc.80- overexpression led to a decrease in apoptosis of hippocampal neurons in vivo and in vitro. In conclusion, our study confirms that lncRNA uc.80- overexpression ameliorates depression in rats by promoting M2 polarization of microglias. Thus, our work suggests that uc.80- may be a target gene for depression treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/iub.2353DOI Listing
October 2020

Berberine Inhibits Gluconeogenesis in Skeletal Muscles and Adipose Tissues in Streptozotocin-induced Diabetic Rats via LKB1-AMPK-TORC2 Signaling Pathway.

Curr Med Sci 2020 Jun 17;40(3):530-538. Epub 2020 Jul 17.

Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

The effect and potential molecular mechanisms of berberine on gluconeogenesis in skeletal muscles and adipose tissues were investigated. After adaptive feeding for one week, 8 rats were randomly selected as the normal group and fed on a standard diet. The remaining 32 rats were fed on a high-fat diet and given an intravenous injection of streptozotocin (STZ) for 2 weeks to induce the diabetic models. The diabetic rat models were confirmed by oral glucose tolerance test (OGTT) and randomly divided into 4 groups (n=8 each), which were all fed on a high-fat diet. Berberine (3 g/kg per day) or metformin (183 mg/kg per day) was intragastrically administered to the diabetic rats for 12 weeks, serving as berberine group and metformin group respectively. 5-aminoimidazole-4-carboxamide1-β-D-ribofuranoside [AICAR, an agonist of AMP-activated protein kinase (AMPK), 0.5 mg/kg per day] was subcutaneously injected to the diabetic rats for 12 weeks, serving as AICAR group. The remaining 8 diabetic rats served as the model group, which was given a 0.5% carboxyl methylcellulose solution by oral gavage. Fasting serum insulin (FINS), OGTT as well as lipid parameters were tested by commercial kit. The protein levels of liver kinase B1 (LKB1), AMPK, phosphorylated AMP-activated protein kinase (p-AMPK), transducer of regulated CREB activity 2 (TORC2), phosphorylated transducer of regulated CREB activity 2 (p-TORC2), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pase) in skeletal muscles and adipose tissues were examined by Western blotting. The results showed that berberine significantly decreased the body weight, plasma glucose, insulin levels, and homeostatic model assessment for insulin resistance (HOMA-IR) of diabetic rats compared with those in the model group. Meanwhile, the serum total triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels were markedly decreased and high-density lipoprotein cholesterol (HDL-C) level was significantly increased after the treatment with berberine. In addition, we found that berberine significantly increased the expression of p-AMPK and LKB1, while decreasing the p-TORC2 levels in skeletal muscles and adipose tissues. Moreover, the expression of PEPCK and G6Pase was significantly down-regulated after the treatment with berberine compared to the model group. It was suggested that the mechanism by which berberine inhibited peripheral tissue gluconeogenesis may be attributed to the activation of the LKB1-AMPK-TORC2 signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11596-020-2210-4DOI Listing
June 2020

Neuropeptide FF and Its Receptors: Therapeutic Applications and Ligand Development.

J Med Chem 2020 11 31;63(21):12387-12402. Epub 2020 Jul 31.

Center for Drug Discovery, Research Triangle Institute, 3040 East Cornwallis Road, Research Triangle Park, North Carolina 27709, United States.

The endogenous neuropeptide FF (NPFF) and its two cognate G protein-coupled receptors, Neuropeptide FF Receptors 1 and 2 (NPFFR1 and NPFFR2), represent a relatively new target system for many therapeutic applications including pain regulation, modulation of opioid side effects, drug reward, anxiety, cardiovascular conditions, and other peripheral effects. Since the cloning of NPFFR1 and NPFFR2 in 2000, significant progress has been made to understand their pharmacological roles and interactions with other receptor systems, notably the opioid receptors. A variety of NPFFR ligands with different mechanisms of action (agonists or antagonists) have been discovered although with limited subtype selectivities. Differential pharmacological effects have been observed for many of these NPFFR ligands, depending on assays/models employed and routes of administration. In this Perspective, we highlight the therapeutic potentials, current knowledge gaps, and latest updates of the development of peptidic and small molecule NPFFR ligands as tool compounds and therapeutic candidates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c00643DOI Listing
November 2020

New role for ceramide in hypoxia and insulin resistance.

World J Gastroenterol 2020 May;26(18):2177-2186

Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.

Ceramides are significant metabolic products of sphingolipids in lipid metabolism and are associated with insulin resistance and hepatic steatosis. In chronic inflammatory pathological conditions, hypoxia occurs, the metabolism of ceramide changes, and insulin resistance arises. Hypoxia-inducible factors (HIFs) are a family of transcription factors activated by hypoxia. In hypoxic adipocytes, HIF-1α upregulates (a novel HIF-1α target gene) gene expression to activate the NLRP3 inflammasome pathway and stimulate insulin resistance, and adipocyte-specific knockout can ameliorate homocysteine-induced insulin resistance in mice. The study on the HIF-2α-NEU3-ceramide pathway also reveals the role of ceramide in hypoxia and insulin resistance in obese mice. Under obesity-induced intestinal hypoxia, HIF-2α increases the production of ceramide by promoting the expression of the gene encoding sialidase 3, which is a key enzyme in ceramide synthesis, resulting in insulin resistance in high-fat diet-induced obese mice. Moreover, genetic and pathophysiologic inhibition of the HIF-2α-NEU3-ceramide pathway can alleviate insulin resistance, suggesting that these could be potential drug targets for the treatment of metabolic diseases. Herein, the effects of hypoxia and ceramide, especially in the intestine, on metabolic diseases are summarized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3748/wjg.v26.i18.2177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235208PMC
May 2020

Effects of a trace amine-associated receptor 1 agonist RO 5263397 on ethanol-induced behavioral sensitization.

Behav Brain Res 2020 07 12;390:112641. Epub 2020 May 12.

Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, NY, United States. Electronic address:

Background: Alcohol dependence is a chronic and severe health problem which puts a heavy burden on society. Alcohol activates mesolimbic dopamine circuity to achieve its reinforcing effect. While TAAR1 is critically involved in the modulation of dopamine, there is little evidence indicating that TAAR1 could play a role in behavioral effects of ethanol.

Methods: By using the animal model of behavioral sensitization induced by ethanol in mice, the present study was performed to investigate whether the activation of TAAR1 would affect the behavioral plasticity of ethanol.

Results: Repeated administration with ethanol induced a significant increased locomotion in WT mice with females showing higher level of sensitization to ethanol than male mice. The TAAR1 agonist RO5263397 significantly decreased the expression of ethanol-induced behavioral sensitization both in male and female WT mice (0.1 and 0.32 mg/kg). Repeated RO5263397 exposure also prevented the development of behavioral sensitization to ethanol both in male and female WT mice. Moreover, while TAAR1-KO mice developed normal levels of ethanol-induced behavioral sensitization, RO5263397 did not affect this behavior in TAAR1-KO mice.

Conclusions: These results indicated that the TAAR1 agonist RO5263397 negatively regulated the expression and development of ethanol-elicited behavioral sensitization in WT but not in TAAR1-KO mice. The present study suggests that TAAR1 is probably involved in certain addiction-like effects of alcohol and could be a useful drug target for the development of new medications to treat alcohol dependence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2020.112641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286772PMC
July 2020

The therapeutic value of SC66 in human renal cell carcinoma cells.

Cell Death Dis 2020 05 11;11(5):353. Epub 2020 May 11.

Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China.

The PI3K-AKT-mTOR cascade is required for renal cell carcinoma (RCC) progression. SC66 is novel AKT inhibitor. We found that SC66 inhibited viability, proliferation, migration and invasion of RCC cell lines (786-O and A498) and patient-derived primary RCC cells. Although SC66blocked AKT-mTORC1/2 activation in RCC cells, it remained cytotoxic in AKT-inhibited/-silenced RCC cells. In RCC cells, SC66 cytotoxicity appears to occur via reactive oxygen species (ROS) production, sphingosine kinase 1inhibition, ceramide accumulation and JNK activation, independent of AKT inhibition. The ROS scavenger N-acetylcysteine, the JNK inhibitor (JNKi) and the anti-ceramide sphingolipid sphingosine-1-phosphate all attenuated SC66-induced cytotoxicity in 786-O cells. In vivo, oral administration of SC66 potently inhibited subcutaneous 786-O xenograft growth in SCID mice. AKT-mTOR inhibition, SphK1 inhibition, ceramide accumulation and JNK activation were detected in SC66-treated 786-O xenograft tumors, indicating that SC66 inhibits RCC cell progression through AKT-dependent and AKT-independent mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41419-020-2566-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214466PMC
May 2020

Effects of hourly levels of ambient air pollution on ambulance emergency call-outs in Shenzhen, China.

Environ Sci Pollut Res Int 2020 Jul 27;27(20):24880-24888. Epub 2020 Apr 27.

Department of Biostatistics, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, 510515, Guangdong, China.

Some researches have shown the associations between air pollution and hospital-based emergency department visits, while the evidence about the acute effects of air pollution on emergency ambulance dispatches for the whole population is rarely available, especially on an hourly time scale. This paper aimed to investigate the effects of hourly concentrations of ambient air pollution on hourly number of ambulance emergency call-outs (AECOs) in Shenzhen, China. AECO data were collected from Shenzhen Emergency Center from January 2013 to December 2016. A time-stratified case-crossover design with conditional Poisson regression was performed to fit the relationship between hourly air pollution and AECOs. The distributed lag model was applied to determine lag structure of the effects of air pollutants. There were a total of 502,862 AECOs during the study period. The significant detrimental effects of SO, PM, and PM appeared immediately with a following harvesting effect after 5 h and the effects lasted for about 96 h. The cumulative effect estimates of four pollutants over 0-96 h were 13.99% (95% CI 7.52-20.85%), 2.07% (95% CI 0.72-3.43%), 1.20% (95% CI 0.54-1.87%), and 2.46% (95% CI 1.63-3.29%), respectively. We did not observe significant effects of O. This population-based study quantifies the adverse effects of air pollution on ambulance dispatches and provides evidence of the lag structure of the effects on an hourly time scale.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11356-020-08416-wDOI Listing
July 2020

TAAR1 agonists attenuate extended-access cocaine self-administration and yohimbine-induced reinstatement of cocaine-seeking.

Br J Pharmacol 2020 08 5;177(15):3403-3414. Epub 2020 May 5.

Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.

Background And Purpose: The trace amine-associated receptor 1 (TAAR1) negatively modulates dopamine transmission. Our previous studies demonstrated that TAAR1 agonists attenuated cue- and drug-induced cocaine-seeking and increased the elasticity of the cocaine demand curve, in the short-access cocaine self-administration model. Compulsive use of cocaine, which is an essential criterion of cocaine use disorder, can be induced by extended access to cocaine self-administration.

Experimental Approach: To characterize the role of TAAR1 in compulsive cocaine use, we evaluated the effects of activation of TAAR1 on cocaine intake, cocaine binge and cue-induced cocaine-seeking using the extended-access cocaine self-administration model in adult male Sprague-Dawley rats. We also investigated the role of TAAR1 in stress-triggered cocaine relapse by using the α -adrenoceptor antagonist yohimbine-induced reinstatement of cocaine-seeking.

Key Results: The selective TAAR1 partial agonist RO5263397 attenuated cocaine intake and did not develop tolerance during the 10-day extended-access cocaine self-administration. RO5263397 reduced a 12-h binge intake of cocaine after forced abstinence. RO5263397 also decreased cue-induced cocaine-seeking after prolonged abstinence from extended-access cocaine self-administration. Furthermore, RO5263397 and the selective TAAR1 full agonist RO5166017 reduced yohimbine-induced reinstatement of cocaine-seeking behaviour.

Conclusion And Implications: Activation of TAAR1 attenuated extended-access cocaine self-administration and stress-induced cocaine reinstatement. These results suggest that TAAR1 agonists are promising pharmacological interventions to treat cocaine use disorder and relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bph.15061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348092PMC
August 2020
-->