Studies have shown that there were associations between endocrine disrupting chemicals (EDCs) and anxiety. Nonylphenol (NP) is an EDC with weak estrogen activity. This study aimed to clarify whether subchronic exposure of NP at environmental concentrations induces anxiety-like behavior, and effects of NP on the regulators (NMDAR2B, PSD-95, Synapsin1) expressions of synaptic plasticity in vivo and in vitro experiments. In vivo, 40 male SD rats were randomly divided into 4 groups (each with 10 rats): low dose (0.4 mg/kg/day, L-NP), middle-dose (4 mg/kg/day, M - NP), high-dose (40 mg/kg/day, H-NP) and corn oil (Control) groups. In vitro, HT22 cells were divided into a control group (Control), NP group (NP, 20 μM), glutamine acid receptor inhibitor group (MK-801, 10 μM) and MK-801 + NP group. The concentration of NP in the hippocampus rised with the increase of NP exposure concentration in the treatment groups (F = 7.542, P = 0.001). Compared with the control group, the residence time in the dark box after NP exposure had extended (F = 117.927, P < 0.01). The duration (F = 112.054, P < 0.01) and the number of times (F = 13.514, P < 0.01) to enter the closed arm in the NP exposure group significantly increased. There were more neurons degeneration and nuclear shrinkage in the M - and H- NP groups, while the average number of shrinked neurons increased with the increasing dose of NP exposure. The protein expressions of PSD-95 (F = 97.723, P < 0.01), Synapsin1 (F = 41.797, P < 0.01) and NMDAR2B (F = 3.440, P = 0.036) in the NP group were lower than those of the control. Simultaneously, the expressions of PSD-95, Synapsin1 and NMDAR2B in the hippocampus were down-regulated; the mRNA expression of PSD-95 (F = 19.950, P < 0.01), Synapsin1 (F = 3.498, P = 0.035) and NMDAR2B (F = 9.293, P < 0.01) genes in the hippocampus decreased in the M - and H-NP groups. In vitro, the trend of the fluorescence intensity expressed by PSD-95 (F = 2.606, P = 0.124) and Synapsin1 (F = 20.573, P < 0.01) among the groups was: MK-801 + NP group < MK-801 < NP group. The protein expressions of PSD-95 (F = 5.699, P = 0.022), Synapsin1 (F = 10.820, P = 0.003) and NMDAR2B (F = 6.041, P = 0.019) were down-regulated. These results suggested that subchronic exposure to environmental concentrations of NP induced anxiety, and reduced the protein and/or mRNA expressions of regulators of synaptic plasticity (PSD-95, Synapsin1, NMDAR2B).

01 Nov 2021·International Journal of Drug PolicyQ2 · MEDICINE

Pharmacotherapies for cannabis use disorder: A systematic review and network meta-analysis

Q2 · MEDICINE

Review

Author: Tibbo, Philip G ; Bahji, Anees ; Hawken, Emily R ; Meyyappan, Arthi Chinna

OBJECTIVEThis study aimed to determine the efficacy and acceptability of pharmacotherapies for cannabis use disorder (CUD).METHODSWe conducted a systematic review and frequentist network meta-analysis, searching five electronic databases for randomized placebo-controlled trials of individuals diagnosed with CUD receiving pharmacotherapy with or without concomitant psychotherapy. Primary outcomes were the reduction in cannabis use and retention in treatment. Secondary outcomes were adverse events, discontinuation due to adverse events, total abstinence, withdrawal symptoms, cravings, and CUD severity. We applied a frequentist, random-effects Network Meta-Analysis model to pool effect sizes across trials using standardized mean differences (SMD, g) and rate ratios (RR) with their 95% confidence intervals.RESULTSWe identified a total of 24 trials (n=1912, 74.9% male, mean age 30.2 years). Nabilone (d=-4.47 [-8.15; -0.79]), topiramate (d=-3.80 [-7.06; -0.54]), and fatty-acid amyl hydroxylase inhibitors (d=-2.30 [-4.75; 0.15]) reduced cannabis use relative to placebo. Dronabinol improved retention in treatment (RR=1.27 [1.02; 1.57]), while topiramate worsened treatment retention (RR=0.62 [0.42; 0.91]). Gabapentin reduced cannabis cravings (d=-2.42 [-3.53; -1.32], while vilazodone worsened craving severity (d=1.69 [0.71; 2.66]. Buspirone (RR=1.14 [1.00; 1.29]), venlafaxine (RR=1.78 [1.40; 2.26]), and topiramate (RR=9.10 [1.27; 65.11]) caused more adverse events, while topiramate caused more dropouts due to adverse events.CONCLUSIONSBased on this review, some medications appeared to show promise for treating individual aspects of CUD. However, there is a lack of robust evidence to support any particular pharmacological treatment. There is a need for additional studies to expand the evidence base for CUD pharmacotherapy. While medication strategies may become an integral component for CUD treatment one day, psychosocial interventions should remain the first line given the limitations in the available evidence.

01 Oct 2019·Molecular Cancer Therapeutics

Leelamine Is a Novel Lipogenesis Inhibitor in Prostate Cancer Cells In Vitro and In Vivo

Article

Author: Hahm, Eun-Ryeong ; Singh, Shivendra V. ; Singh, Krishna B. ; Pore, Subrata K.

AbstractIncreased de novo synthesis of fatty acids is implicated in the pathogenesis of human prostate cancer, but a safe and effective clinical inhibitor of this metabolic pathway is still lacking. We have shown previously that leelamine (LLM) suppresses transcriptional activity of androgen receptor, which is known to regulate fatty acid synthesis. Therefore, the current study was designed to investigate the effect of LLM on fatty acid synthesis. Exposure of 22Rv1, LNCaP, and PC-3 prostate cancer cells, but not RWPE-1 normal prostate epithelial cell line, to LLM resulted in a decrease in intracellular levels of neutral lipids or total free fatty acids. LLM was superior to another fatty acid synthesis inhibitor (cerulenin) for suppression of total free fatty acid levels. LLM treatment downregulated protein and/or mRNA expression of key fatty acid synthesis enzymes, including ATP citrate lyase, acetyl-CoA carboxylase 1, fatty acid synthase, and sterol regulatory element-binding protein 1 (SREBP1) in each cell line. Consistent with these in vitro findings, we also observed a significant decrease in ATP citrate lyase and SREBP1 protein expression as well as number of neutral lipid droplets in vivo in 22Rv1 tumor sections of LLM-treated mice when compared with that of controls. LLM-mediated suppression of intracellular levels of total free fatty acids and neutral lipids was partly attenuated by overexpression of SREBP1. In conclusion, these results indicate that LLM is a novel inhibitor of SREBP1-regulated fatty acid/lipid synthesis in prostate cancer cells that is not affected by androgen receptor status.

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Preclinical	US	Arkansas State University	20 Sep 2023

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