Low incidence of advanced neurological burden but high incidence of age-related conditions that are dementia risk factors in aging people living with HIV: a data-linkage 10-year follow-up study.

Although increasing research is focusing on age-related comorbidities (ARC) among people living with HIV (PLHIV), no studies have concomitantly assessed non-HIV age-related neurological disorders (e.g., Alzheimer's dementia). A total of 254 PLHIV and 69 HIV-negative controls completed baseline medical history and cognitive testing. ARC data were collected from medical records over the subsequent 9-10 years and included all types of strokes, all types of dementia, mild cognitive impairment, Parkinson's disease, motor neuron disease (grouped into a non-HIV age-related neurological category), cardiovascular disease, chronic kidney disease, chronic liver disease, chronic lung disease, non-AIDS cancers, osteoporosis, and diabetes. Kaplan-Meier curves assessed differences in the incident rates (per 1000 person year) of groups of ARC as defined above and combined ARC (i.e., development of any of the ARC) among younger (baseline age < 50) and older (baseline age ≥ 50) PLHIV and younger and older controls. Cox-proportional hazard models assessed the individual and interaction effects of HIV status and chronological age, in addition to a range of demographic and clinical variables including historical and baseline HIV brain involvement on the risk of developing combined ARC. Older PLHIV had a higher incidence of cardiovascular disease, osteoporosis, and combined ARC compared to other groups (p < 0.05). Incident rate of non-HIV age-related neurological disorders was 2.3 [0.93, 4.79] per 1000 person year. While this incident rate was higher in older PLHIV (5.37 [1.97, 11.92]) than older HIV-negative participants (3.58 [0.18-17.67]), this was not significant. In multivariate analyses, HIV status and chronological age, but not their interaction, and smoking were associated with higher risk of combined ARC (p < 0.05). In analyses focusing on PLHIV, older age and taking abacavir/efavirenz/atazanavir/darunavir containing antiretroviral treatments at the time of diagnosis were associated with greater ARC (p < 0.05). Non-HIV age-related neurological disorders are uncommon in older PLHIV, where the majority were < 70 years of age at the end of follow-up. However, the greater burden of ARC among older PLHIV, most of which are established dementia risk factors, warrants the establishment of commensurate prevention strategies and greater attention to neurocognitive screening.

Retraction Notice to: A Novel Mechanism of Doxorubicin Resistance and Tumorigenesis Mediated by MicroRNA-501-5p-Suppressed BLID.

[This retracts the article DOI: 10.1016/j.omtn.2018.06.011.].

Abnormal cognitive aging in people with HIV: evidence from data integration between two countries' cohort studies.

OBJECTIVES: Previous research has shown inconsistent results on whether cognitive aging is abnormal in people with HIV (PWH) because of low sample size, cross-sectional design, and nonstandard neuropsychological methods. To address these issues, we integrated data from two longitudinal studies: Australian HIV and Brain Ageing Research Program ( N  = 102) and CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study ( N  = 924) and determined the effect of abnormal aging on neurocognitive impairment (NCI) among PWH. METHODS: Both studies used the same neuropsychological test battery. NCI was defined based on demographically corrected global deficit score (≥0.5 = impaired). Both studies also assessed comorbidities, neuropsychiatric conditions and functional status using similar tools. To determine the cross-sectional and longitudinal effects of age on the risk of NCI, a generalized linear mixed-effect model tested main and interaction effects of age group (young, <50 vs. old, ≥50) and time on NCI adjusting the effects of covariates. RESULTS: Older PWH had 83% higher chance of NCI compared with younger PWH [odds ratio (OR) = 1.83 (1.15-2.90), P  < 0.05]. Older participants also had a greater risk of increases in NCI over the follow-up [OR = 1.66 (1.05-2.64), P  < 0.05] than younger participants. Nonwhite ethnicity ( P  < 0.05), having a contributing ( P  < 0.05) or confounding ( P  < 0.001) comorbidity, greater cognitive symptoms ( P  < 0.001), and abnormal creatinine level ( P  < 0.05), plasma viral load greater than 200 copies/ml ( P  < 0.05), being from the Australian cohort ( P  < 0.05) were also associated with a higher risk of NCI. CONCLUSION: Data integration may serve as a strategy to increase sample size and study power to better assess abnormal cognitive aging effect in PWH, which was significant in the current study.

Upregulation of Src Family Tyrosine Kinases in the Rat Striatum by Adenosine A2A Receptors.

Adenosine A2A receptors are Golf-coupled receptors and are predominantly expressed in the striatum of mammalian brains. As a mostly postsynaptic receptor, A2A receptors are implicated in the regulation of a variety of intracellular signaling pathways in striatopallidal output neurons and are linked to the pathogenesis of various neuropsychiatric and neurological disorders. This study investigated the possible role of A2A receptors in the modulation of the Src family kinase (SFK) in the adult rat striatum. In acutely prepared striatal slices, adding the A2A receptor agonist PSB-0777 induced a significant increase in phosphorylation of SFKs at a conserved autophosphorylation site (Y416) in the caudate putamen (CPu). This increase was also seen in the nucleus accumbens (NAc). Another A2A agonist CGS-21680 showed the similar ability to elevate SFK Y416 phosphorylation in the striatum. Treatment with the A2A receptor antagonist KW-6002 blocked the effect of PSB-0777 on SFK Y416 phosphorylation. In addition, PSB-0777 enhanced kinase activity of two key SFK members (Src and Fyn) immunoprecipitated from the striatum. These data demonstrate a positive linkage from A2A receptors to the SFK signaling pathway in striatal neurons. Activation of A2A receptors leads to the upregulation of phosphorylation of SFKs (Src and Fyn) at an activation-associated autophosphorylation site and kinase activity of these SFK members.

Placental-Cadherin, a biomarker for local immune status and poor prognosis among patients with tongue squamous cell carcinoma.

BACKGROUND: The prognostic and clinicopathological value of placental-Cadherin (CDH3) in multiple cancers is controversial. The diagnostic significance and functional mechanism of CDH3 in tongue squamous cell carcinoma (TSCC) have not been thoroughly investigated. This study aims to clarify the potential of CDH3 as biomarker for TSCC. METHODS: Here, meta-analysis, bioinformatics, along wet-lab techniques were employed to evaluate the diagnostic, as well as the prognostic value of CDH3 in diverse types of cancers, especially TSCC. Meta-analysis was used to determine the influence of CDH3 on prognostic and clinicopathological features in numerous cancers. Molecular biology function was used to investigate the role of CDH3 in TSCC cells. The relationship of CDH3 with tumor-infiltrating immune cells (TIICs) in TSCC was assessed using CIBERSORT. Moreover, gene set enrichment analysis (GSEA) was done based on TCGA. Besides, the hub genes and associated cascades were uncovered based on gene co-expression with CDH3. RESULTS: CDH3 upregulation correlated with worse overall survival and disease-free survival in various cancers. CDH3 was validated as an independent risk factor for HNSC and was linked to the onset of tumors, tumor stage, and infiltration depth. CDH3 silencing inhibited cell growth and induced apoptosis of the CAL-27 cell line. CDH3 expression level correlated with infiltration by macrophages, T cells, T cell regulatory cells (Tregs), and plasma cells in TSCC. GSEA revealed that CDH3 influences multiple cancer-associated cascades. Besides, CBX3, CCHCR1, along NFYC were identified as the core hub genes for CDH3. CONCLUSION: We identified CDH3 as a pan-cancer gene with potential prognostic and diagnostic significance in various cancers, particularly in TSCC, where it is tumorigenic.

Roles of adenosine A1 receptors in the regulation of SFK activity in the rat forebrain.

Adenosine A1 receptors are widely expressed in the mammalian brain. Through interacting with Gαi/o -coupled A1 receptors, the neuromodulator adenosine modulates a variety of cellular and synaptic activities. To determine the linkage from A1 receptors to a key intracellular signaling pathway, we investigated the impact of blocking A1 receptors on a subfamily of nonreceptor tyrosine kinases, that is, the Src family kinase (SFK), in different rat brain regions in vivo. We found that pharmacological blockade of A1 receptors by a single systemic injection of the A1 selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) induced an increase in autophosphorylation of SFKs at a consensus activation site, tyrosine 416 (Y416), in the two subdivisions of the striatum, the caudate putamen and nucleus accumbens. DPCPX also increased SFK Y416 phosphorylation in the medial prefrontal cortex (mPFC) but not the hippocampus. The DPCPX-induced Y416 phosphorylation was time dependent and reversible. In immunopurified Fyn and Src proteins from the striatum, DPCPX elevated SFK Y416 phosphorylation and tyrosine kinase activity in Fyn but not in Src proteins. In the mPFC, DPCPX enhanced Y416 phosphorylation and tyrosine kinase activity in both Fyn and Src immunoprecipitates. DPCPX had no effect on expression of total Fyn and Src proteins in the striatum, mPFC, and hippocampus. These results demonstrate a tonic inhibitory linkage from A1 receptors to SFKs in the striatum and mPFC. Blocking this inhibitory tone could significantly enhance constitutive SFK Y416 phosphorylation in the rat brain in a region- and time-dependent manner.

Is There Any Evidence of Premature, Accentuated and Accelerated Aging Effects on Neurocognition in People Living with HIV? A Systematic Review.

Despite evidence of premature, accentuated and accelerated aging for some age-related conditions such as cardiovascular diseases in people living with HIV (PLHIV), the evidence for these abnormal patterns of aging on neurocognition remains unclear. Further, no systematic review has been dedicated to this issue. Using PRISMA guidelines, we searched standard databases (PubMed, EMBASE, CINAHL and PsycINFO). Articles were included if they analyzed and reported the effect of age on neurocognition among PLHIV as one of their major findings, if they were conducted in the combination anti-retroviral therapy era (after 1996) and published in a peer-reviewed journal in English. Quality appraisal was conducted using the Joanna Briggs Institute (JBI) appraisal tools. To systematically target the abnormal patterns of neurocognitive aging, we define premature cognitive aging as significant interaction effect of HIV status and age on cross-sectional neurocognitive test performance covering both the normal and abnormal performance range; accentuated cognitive aging as significant interaction effect of HIV status and age on cross-sectional neurocognitive impairment (NCI) rate, thus covering the abnormal performance range only; accelerated cognitive aging as significant interaction effect of HIV status and age on longitudinal neurocognitive test performance or incidence of NCI. Because these definitions require an age-comparable HIV-negative (HIV-) control group, when no controls were included, we determined the range of the age effect on neurocognitive test performance or NCI among PLHIV. A total of 37 studies originating from the US (26), UK (2), Italy (2), Poland (2), China (2), Japan (1), Australia (1), and Brazil (1) were included. Six studies were longitudinal and 14 included HIV- controls. The quality appraisal showed that 12/37 studies neither used an age-matched HIV- controls nor used demographically corrected cognitive scores. A meta-analysis was not possible because study methods and choice of neurocognitive measurement methods and outcomes were heterogeneous imposing a narrative synthesis. In studies with an HIV- control sample, premature neurocognitive aging was found in 45% of the cross-sectional analyses (9/20), while accelerated neurocognitive aging was found in 75% of the longitudinal analyses (3/4). There was no evidence for accentuated aging, but this was tested only in two studies. In studies without an HIV- control sample, the age effect was always present but wide (NCI OR = 1.18-4.8). While large sample size (> 500) was associated with abnormal patterns of cognitive aging, most of the studies were under powered. Other study characteristics such as longitudinal study design and higher proportion of older participants were also associated with the findings of abnormal cognitive aging. There is some support for premature and accelerated cognitive aging among PLHIV in the existing literature especially among large and longitudinal studies and those with higher proportion of older samples. Future HIV and cognitive aging studies need to harmonize neuropsychological measurement methods and outcomes and use a large sample from collaborative multi-sites to generate more robust evidences.

Estimation of the impact of changing drug-use trend on HIV, hepatitis C and syphilis epidemics among people who use synthetic drug-only, polydrug and heroin-only during 2005-2035 in China: modelling study.

OBJECTIVE: The rapid expansion of the recreational drug market becomes a global health concern. It is worrying that the bacterial and viral infection epidemics linking to drug use may worsen accordingly. This study aimed to estimate the impacts of changing trend and behaviours of using heroin only, synthetic drug (SD) only and polydrug (using SD and heroin concurrently) on HIV, hepatitis C virus (HCV) and syphilis epidemics among people who use drugs in China by 2035. METHODS: We constructed a compartmental model to estimate HIV, HCV and syphilis epidemics in the dynamic drug-use trend by three scenarios: SD-only use, heroin-only use and polydrug use based on Monte Carlo simulations. The parameters for the model were collected from a comprehensive literature search. RESULTS: Our model estimated that polydrug use led to the highest HIV and HCV prevalence among three drug-use patterns. The prevalences were projected to increase from 10.9% (95% CI 10.2% to 11.5%) and 61.7% (95% CI 59.4% to 62.5%) in 2005 to 19.0% (95% CI 17.3% to 20.7%) and 69.1% (95% CI 67.3% to 69.5%), respectively, in 2035 among people using polydrug. Similarly, HIV and HCV prevalence in the SD-only group were projected to increase from 0.4% (95% CI 0.3% to 0.4%) and 19.5% (95% CI 19.4% to 21.7%) to 1.8% (95% CI 1.4 to 2.1%) and 33.7% (95% CI 33.2% to 34.9%) in 2005-2035. Conversely, HIV prevalence in the heroin-only group was projected to decrease from 8.0% (95% CI 7.6% to 8.1%) to 2.2% (95% CI 2.0% to 2.3%) in 2005-2035. Syphilis prevalence was estimated to remain unchanged in all population groups within this time frame. It was projected that the proportion of HIV transmitted by sexual transmission will increase compared with unsafe injection transmission in all people who use drugs from 2005 to 2035. CONCLUSION: Our modelling suggests that polydrug use is projected to lead to the highest HIV and HCV disease burden by 2035, and the proportion of HIV transmitted by sexual transmission will increase. Current HIV intervention among people using heroin seems effective according to our estimation.

High levels of engagement with testing for HIV and sexually transmissible infection among gay Asian men in Sydney and Melbourne: an observational study.

Background Gay and other men who have sex with men of Asian background (GAM) have been identified as a key population in efforts to eradicate HIV in New South Wales. The aims of the present study were to evaluate current levels of engagement with HIV and sexually transmissible infection (STI) testing services, assess knowledge of pre- and post-exposure prophylaxis and to identify factors associated with service engagement in this group. METHODS: A survey of 604 GAM residing in Sydney and Melbourne was undertaken. RESULTS: The data identified that a significant proportion of non-HIV-positive men (i.e. HIV-negative men and men whose HIV status was unknown) surveyed (n = 567; 93.9%) had engaged in frequent HIV testing and comprehensive STI testing in the 12 months prior to the survey (n = 180; 31.7%). There were significant differences (P < 0.05) in sexual practices at the bivariate level between those who reported frequent and comprehensive HIV/STI testing and those who did not. Those who tested regularly were substantially more sexually active, were more likely to have multiple partners (P = 0.001) and were more likely to engage in condomless anal intercourse with both casual (P < 0.001) and regular (P = 0.002) partners. Those who engaged with testing initiatives were more likely to discuss HIV status with both regular (P = 0.008) and casual (P < 0.001) partners, and identified more reasons to test than their counterparts (P < 0.001). The data also highlighted key service venues, with gay men most likely to have used public sexual health clinics (46.9%) as their most recent testing venue. CONCLUSIONS: The data demonstrate an association between high levels of male-to-male sexual activity and engagement in frequent and comprehensive HIV and STI testing. This likely derives from both self-perceived notions of risk and current reliance on established gay community organisations to convey information around testing. Increasing engagement with testing initiatives beyond GAM who self-identify as being at high HIV and STI risk will require the use of novel routes by which to disseminate this information.

Linkage of Non-receptor Tyrosine Kinase Fyn to mGlu5 Receptors in Striatal Neurons in a Depression Model.

The Src family kinase (SFK) is a subfamily of non-receptor tyrosine kinases. The SFK member Fyn is enriched at synaptic sites in the limbic reward circuit and plays a pivotal role in the regulation of glutamate receptors. In this study, we investigated changes in phosphorylation and function of the two key SFK members (Fyn and Src) and SFK interactions with a metabotropic glutamate (mGlu) receptor in the limbic striatum of adult rats in response to chronic passive stress, i.e., prolonged social isolation which is a pre-validated animal paradigm modeling depression in adulthood. In rats that showed typical anhedonic/depression-like behavior after chronic social isolation, phosphorylation of SFKs at a conserved and activation-associated autophosphorylation site (Y416) was not altered in the two subdivisions of the striatum, the nucleus accumbens and caudate putamen. The total level of phosphorylation and kinase activity of individual Fyn and Src immunopurified from the striatum also remained stable after social isolation. Noticeably, Fyn and Src were found to interact with a Gαq-coupled mGlu5 receptor in striatal neurons. The interaction of Fyn with mGlu5 receptors was selectively elevated in socially isolated rats. Moreover, social isolation induced an increase in surface expression of striatal mGlu5 receptors, which was reduced by an SFK inhibitor. These results indicate that Fyn interacts with mGlu5 receptors in striatal neurons. Adulthood social isolation in rats enhances the Fyn-mGlu5 interaction, which appears to be critical for the upregulation of surface mGlu5 receptor expression in striatal neurons.

Increases in HIV Testing Frequency in Australian Gay and Bisexual Men are Concentrated Among PrEP Users: An Analysis of Australian Behavioural Surveillance Data, 2013-2018.

Increasing HIV testing frequency in gay and bisexual men (GBM) is critical to reducing the time between HIV infection and diagnosis. Using anonymous national behavioural surveillance data (2013-2018) from 43,753 surveys of Australian GBM, we examined HIV testing frequency trends and factors differentiating PrEP-users, non-PrEP-users reporting two or more tests in the previous year, and non-PrEP-users reporting less frequent testing. The proportion tested at least annually increased from 64.4% in 2013 to 70.8% in 2018 (p-trend < 0.001), and from 73.9% to 84.6% among the 51.6% of men classified as higher-risk. Among higher-risk men, having two or more tests in the previous year increased from 48.0% to 69.3% (p-trend < 0.001). Among higher-risk non-PrEP-users, it increased from 47.2% to 54.8% (p-trend < 0.001), however, there was a decrease since 2016 (p-trend < 0.001). Among PrEP-users, it increased from 82.1% in 2013 to 97.3% in 2018 (p-trend < 0.001). Non-PrEP-using higher-risk men having less frequent tests reported lower risk than PrEP-users and non-PrEP-using men reporting two or more tests in the previous year. However, recent risk behaviour was not uncommon: nearly half reported condomless sex; one-fifth reported receptive condomless sex with ejaculation; over half reported group sex; one-quarter used drugs for the purposes of sex; and one-fifth had more than ten sex partners. Efforts are needed to encourage frequent testing and PrEP use among non-PrEP-users who are at higher-risk.

Upregulation of AMPA receptor GluA1 phosphorylation by blocking adenosine A1 receptors in the male rat forebrain.

OBJECTIVE: The adenosine A1 receptor is a Gαi/o protein-coupled receptor and inhibits upon activation cAMP formation and protein kinase A (PKA) activity. As a widely expressed receptor in the mammalian brain, A1 receptors are implicated in the modulation of a variety of neuronal and synaptic activities. In this study, we investigated the role of A1 receptors in the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the adult rat brain in vivo. METHODS: Adult male Wistar rats were used in this study. After a systemic injection of the A1 antagonist DPCPX, rats were sacrificed and several forebrain regions were collected for assessing changes in phosphorylation of AMPA receptors using Western blots. RESULTS: A systemic injection of the A1 antagonist DPCPX induced an increase in phosphorylation of AMPA receptor GluA1 subunits at a PKA-dependent site, serine 845 (S845), in the two subdivisions of the striatum, the caudate putamen, and nucleus accumbens. DPCPX also increased S845 phosphorylation in the medial prefrontal cortex (mPFC) and hippocampus. The DPCPX-stimulated S845 phosphorylation was a transient and reversible event. Blockade of Gαs/olf -coupled dopamine D1 receptors with a D1 antagonist SCH23390 abolished the responses of S845 phosphorylation to DPCPX in the striatum, mPFC, and hippocampus. DPCPX had no significant impact on phosphorylation of GluA1 at serine 831 and on expression of total GluA1 proteins in all forebrain regions surveyed. CONCLUSION: These data demonstrate that adenosine A1 receptors maintain an inhibitory tone on GluA1 S845 phosphorylation under normal conditions. Blocking this inhibitory tone leads to the upregulation of GluA1 S845 phosphorylation in the striatum, mPFC, and hippocampus via a D1 -dependent manner.

Which Gay and Bisexual Men Attend Community-Based HIV Testing Services in Australia? An Analysis of Cross-Sectional National Behavioural Surveillance Data.

In Australia, HIV testing services have become increasingly available in non-traditional settings such as peer-led, community-based services to expand access and increase uptake of HIV testing among gay and bisexual men (GBM). This study aimed to compare the socio-demographic and behavioural characteristics of GBM whose last HIV test was conducted at a community-based service to GBM whose last test was at a traditional clinical setting. We analysed behavioural surveillance data collected from 5988 participants in seven states and territories in the period 2016-2017. We found that non-HIV-positive GBM who attended community-based services were largely similar to men attending clinic-based settings, particularly in terms of sexual practice and risk of HIV. However, non-HIV-positive GBM who were younger, born in Asia, more socially engaged with other gay men but who had not recently used PrEP were more likely to attend community-based services for their last HIV test. This study points to the successful establishment of community-based HIV testing services in Australia as a way to attract subgroups of GBM at potentially higher risk of HIV.

Green Tea Polyphenol (-)-Epigallocatechin Gallate (EGCG) Attenuates Neuroinflammation in Palmitic Acid-Stimulated BV-2 Microglia and High-Fat Diet-Induced Obese Mice.

Obesity is closely associated with neuroinflammation in the hypothalamus, which is characterized by over-activated microglia and excessive production of pro-inflammatory cytokines. The present study was aimed at elucidating the effects of (-)-epigallocatechin gallate (EGCG) on palmitic acid-stimulated BV-2 microglia and high-fat-diet-induced obese mice. The results indicated the suppressive effect of EGCG on lipid accumulation, pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) release, and microglial activation in both cellular and high-fat-diet rodent models. These results were associated with lower phosphorylated levels of the janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) signaling pathway. In conclusion, EGCG can attenuate high-fat-induced hypothalamic inflammation via inhibiting the JAK2/STAT3 signaling pathways in microglia.

Role of c-Met expression on prognosis of head and neck cancer: A literature review and meta-analysis.

The prognostic role of c-Met expression in patients with head and neck cancer were controversial among different studies. Thus, we performed a meta-analysis to evaluate the relationships between c-Met expression and survival and clinical parameters of head and neck cancer patients. Summary hazard ratio (HR) and 95% confidence intervals (CIs) were calculated to analyze the correlations between c-Met expression and overall survival (OS), and disease-free survival (DFS). Furthermore, odds ratios (ORs) and 95% CIs were used to describe the relationships between c-Met expression and different clinicopathological parameters. A total of 2417 patients from 19 studies were enrolled in the final analysis. The results showed that patients with higher c-Met expression had a poor OS (HR, 1.65; 95% CI, 1.20-2.27) and DFS (HR, 1.48; 95% CI, 0.99-2.20). In addition, c-Met expression was associated with the N classification of patients with head and neck cancer. These results suggested that c-Met expression was a risk factor for head and neck cancer, and increased c-Met expression would be a predictor of a poorer prognosis for the patients.

Changes in ERK1/2 phosphorylation in the rat striatum and medial prefrontal cortex following administration of the adenosine A1 receptor agonist and antagonist.

The extracellular signal-regulated kinase (ERK) is enriched in the central nervous system, including the dopamine responsive regions such as the striatum and medial prefrontal cortex (mPFC). The kinase is sensitive to changing cellular and synaptic input and is implicated in the regulation of synaptic transmission and plasticity. In this study, the role of a Gαi/o protein-coupled adenosine A1 receptor in the regulation of ERK1/2 was investigated in the rat brain in vivo. We found that an A1 agonist CPA after an intraperitoneal injection reduced ERK1/2 phosphorylation in the nucleus accumbens (NAc) and mPFC. In contrast, a single dose of an A1 antagonist DPCPX induced a rapid and transient increase in ERK1/2 phosphorylation in the caudate putamen (CPu), NAc, and mPFC. Pretreatment with a dopamine D1 receptor antagonist SCH23390 abolished the DPCPX-induced ERK1/2 phosphorylation in the striatum and mPFC. Coadministration of DPCPX and a D1 agonist SKF81297 at a low dose induced a greater elevation of ERK1/2 phosphorylation. Activation or blockade of A1 receptors had no effect on total ERK1/2 expression in the striatum and mPFC. These results reveal an existence of an inhibitory linkage from adenosine A1 receptors to ERK1/2 in striatal and mPFC neurons. This inhibitory linkage seems to form a dynamic balance with positive dopamine D1 receptor signaling to control the ERK1/2 pathway.

Estimates of the national trend of drugs use during 2000-2030 in China: A population-based mathematical model.

BACKGROUND: The use of synthetic drugs has exceeded heroin to become a major public health concern in China. We aimed to estimate the trend of heroin-only, synthetic drug-only and poly-drug (heroin and synthetic drug) use during 2000-2030 period in China using existing data. METHODS: We used data from the Annual Report on Drug Control in China and peer-reviewed publications. We constructed a mathematical model to estimate the drug use trend based on Monte Carlo simulations. RESULTS: The best calibrated model estimated that the number of drug users would increase from 0.86 million to 3,120,059 (95% CI 2,669,214-3,570,904) during 2000-2030 period. The proportion of heroin-only users among the total drug users will decrease from 96.8% (95% CI, 96.6-97.1%) in 2000 to 36.9% (30.1-40.8%) in 2030, while the proportion of synthetic drug-only users will increase from 1.1% (0.9-1.3%) in 2000 to 57.7% (51.7-65.6%) in 2030. In contrast, the proportion of poly-drug users shared an increasing trend during 2000-2016 (from 2.1% (1.5-2.8%) to 15.1 (13.8-17.1%)) but declined to 5.5% (3.4-7.2%) in 2030. Estimated 46,370 (41,634-51,106) heroin-only users and 3767 (3481-4053) synthetic drug only users initiated poly-drug use in 2000. We observed a cross-over in 2012 where more synthetic drug-only users were initiating heroin use than heroin-only users initiating synthetic drug use. There will be estimated 2,094,052 (1,819,830-2,368,274) synthetic drug-only users and poly-drug users 211,407 (177,150-245,664) in 2030. CONCLUSIONS: Synthetic drug use will become dominant in drug users in China, but poly-drug use of both heroin and synthetic drugs will remain substantial.

Amphetamine activates non-receptor tyrosine kinase Fyn and stimulates ERK phosphorylation in the rat striatum in vivo.

The psychostimulant amphetamine (AMPH) has an impact on a variety of cellular activities in striatal neurons, although underlying signaling mechanisms are incompletely understood. The Src family kinase (SFK) is among key signaling molecules enriched in striatal neurons and is involved in the regulation of a set of discrete downstream targets. Given the likelihood that AMPH may regulate SFKs, we investigated and characterized the effect of AMPH on SFK phosphorylation and enzymatic activity in rat striatal neurons in vivo. We found that AMPH elevated SFK Y416 phosphorylation in striatal slices and the adult rat striatum. This elevation was concentration- and time-dependent and occurred in all subdivisions of the striatum, including the caudate putamen and nucleus accumbens (core and shell). The dopamine D1 receptor antagonist SCH23390 blocked the effect of AMPH. Between Fyn and Src, AMPH elevated phosphorylation of immunoprecipitated Fyn but not Src and increased Fyn kinase activity in the striatum. In parallel with SFKs, striatal ERK phosphorylation was increased by AMPH. This increase in ERK phosphorylation was reduced by the SFK inhibitor PP2. These results demonstrate that AMPH is able to activate SFKs (mainly Fyn) in striatal neurons via a D1 receptor-dependent mechanism. Activated SFKs participate in processing the concomitant ERK response to AMPH.

Effects of (-)-Epigallocatechin Gallate (EGCG) on Energy Expenditure and Microglia-Mediated Hypothalamic Inflammation in Mice Fed a High-Fat Diet.

Obesity is an escalating global epidemic caused by an imbalance between energy intake and expenditure. (-)-Epigallocatechin-3-gallate (EGCG), the major polyphenol in green tea, has been reported to be conducive to preventing obesity and alleviating obesity-related chronic diseases. However, the role of EGCG in energy metabolism disorders and central nervous system dysfunction induced by a high-fat diet (HFD) remains to be elucidated. The aim of this study was to evaluate the effects of EGCG on brown adipose tissue (BAT) thermogenesis and neuroinflammation in HFD-induced obese C57BL/6J mice. Mice were randomly divided into four groups with different diets: normal chow diet (NCD), normal chow diet supplemented with 1% EGCG (NCD + EGCG), high-fat diet (HFD), and high-fat diet supplemented with 1% EGCG (HFD + EGCG). Investigations based on a four-week experiment were carried out including the BAT activity, energy consumption, mRNA expression of major inflammatory cytokines in the hypothalamus, nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) phosphorylation, and immunofluorescence staining of microglial marker Iba1 in hypothalamic arcuate nucleus (ARC). Experimental results demonstrated that dietary supplementation of EGCG significantly inhibited HFD-induced obesity by enhancing BAT thermogenesis, and attenuated the hypothalamic inflammation and microglia overactivation by regulating the NF-κB and STAT3 signaling pathways.

Suppressing glucose metabolism with epigallocatechin-3-gallate (EGCG) reduces breast cancer cell growth in preclinical models.

Numerous studies propose that epigallocatechin-3-gallate (EGCG), an abundant polyphenol in green tea, has anti-cancer properties. However, its mechanism of action in breast cancer remains unclear. This study investigated the capacity of EGCG to suppress breast cancer cell growth in vitro and in vivo, characterizing the underlying mechanisms, focusing on the effect of EGCG on glucose metabolism. EGCG reduced breast cancer 4T1 cell growth in a concentration- (10-320 µM) and time- (12-48 h) dependent manner. EGCG induced breast cancer apoptotic cell death at 24 h, as evidenced by annexin V/PI, caspase 3, caspase 8 and caspase 9 activation. Furthermore, EGCG affected the expression of 16 apoptosis-related genes, and promoted mitochondrial depolarization. EGCG induced autophagy concentration-dependently in 4T1 cells by modulating the levels of the autophagy-related proteins Beclin1, ATG5 and LC3B. Moreover, EGCG affected glucose, lactate and ATP levels. Mechanistically, EGCG significantly inhibited the activities and mRNA levels of the glycolytic enzymes hexokinase (HK), phosphofructokinase (PFK), and lactic dehydrogenase (LDH), and to a lesser extent the activity of pyruvate kinase (PK). In addition, EGCG decreased the expression of hypoxia-inducible factor 1α (HIF1α) and glucose transporter 1 (GLUT1), critical players in regulating glycolysis. In vivo, EGCG reduced breast tumor weight in a dose-dependent manner, reduced glucose and lactic acid levels and reduced the expression of the vascular endothelial growth factor (VEGF). In conclusion, EGCG exerts an anti-tumor effect through the inhibition of key enzymes that participate in the glycolytic pathway and the suppression of glucose metabolism.