With this issue we begin print publishing the responses received in our call for Medical Education Adaptations: Lessons learned from educators' experiences rapidly transforming practice on account of ...COVID‐19 related disruption.
Orexins are associated with drug relapse in rodents. Here, we show that acute restraint stress in mice activates lateral hypothalamic (LH) orexin neurons, increases levels of orexin A and ...2-arachidonoylglycerol (2-AG) in the ventral tegmental area (VTA), and reinstates extinguished cocaine-conditioned place preference (CPP). This stress-induced reinstatement of cocaine CPP depends on type 1 orexin receptors (OX1Rs), type 1 cannabinoid receptors (CB1Rs) and diacylglycerol lipase (DAGL) in the VTA. In dopaminergic neurons of VTA slices, orexin A presynaptically inhibits GABAergic transmission. This effect is prevented by internal GDP-β-S or inhibiting OX1Rs, CB1Rs, phospholipase C or DAGL, and potentiated by inhibiting 2-AG degradation. These results suggest that restraint stress activates LH orexin neurons, releasing orexins into the VTA to activate postsynaptic OX1Rs of dopaminergic neurons and generate 2-AG through a Gq-protein-phospholipase C-DAGL cascade. 2-AG retrogradely inhibits GABA release through presynaptic CB1Rs, leading to VTA dopaminergic disinhibition and reinstatement of cocaine CPP.
Abstract Selective laser trabeculoplasty (SLT) is a relatively new type of laser used in treating open-angle glaucoma (OAG) and is reported to be equally efficacious to a first-line medication and ...argon laser trabeculoplasty (ALT). We summarize available evidence for considering SLT as an alternative treatment in OAG through systematic review and meta-analysis. Among OAG patients who range from newly diagnosed to those on maximally tolerated medical therapy, SLT results in a 6.9–35.9% intraocular pressure (IOP) reduction. Complications are rare and include an IOP spike requiring surgery, persistent macular edema, and corneal haze and thinning. Meta-analysis of randomized, controlled trials shows that SLT is non-inferior to ALT and medication in IOP reduction and also in achieving treatment success. Number of medications reduction is similar between SLT and ALT. More robust evidence is needed to determine its efficacy as a repeated procedure.
Objective
Caveolin‐1 (Cav‐1) is expressed abundantly in adipose tissue and involved in many physiological processes. While Cav‐1 has been reported to be secreted in pancreatic acinar cells and LNCaP ...prostate cancer cells, its secretion from adipose tissue awaits investigation.
Methods
Cav‐1 secretion from 3T3‐L1 adipocytes and fat tissues from normal chow diet‐ and high‐fat diet (HFD)‐fed mice was measured. Functions and uptake of secreted Cav‐1 proteins were assessed by adding Cav‐1 back to preadipocytes and LNCaP cells.
Results
Cav‐1 secretion was evident in adipose tissues and were substantially promoted in HFD‐fed mice. Cav‐1 was detectable in the conditioned media of 3T3‐L1 adipocytes but not preadipocytes. Hypertrophied adipocytes induced by glucose and fatty acids secreted more Cav‐1, suggesting that hypertrophied adipocytes were responsible for enhanced Cav‐1 secretion in obese mice. Secreted Cav‐1 was taken up by preadipocytes and LNCaP cells. 3T3‐L1 preadipocytes overexpressing Cav‐1 were better differentiated, suggesting that secreted Cav‐1 may promote adipogenesis. Hypertrophied 3T3‐L1 adipocytes enhanced ERK1/2 activation, and the attenuation of ERK1/2 activity by PD98059 inhibited Cav‐1 secretion.
Conclusions
Cav‐1 is actively secreted from adipocytes as a putative adipogenesis enhancer. Hypertrophied adipocytes secrete Cav‐1 via ERK1/2‐dependent mechanisms to promote adipogenesis, thus establishing a vicious cycle.
Leptin is an adipokine predominantly secreted by adipocytes and has many physiological roles, including in energy homeostasis. We identified that AM630, a cannabinoid receptor 2 (CB2) antagonist, ...down-regulated leptin expression in mature adipocytes differentiated from either stromal vascular fractions isolated from inguinal fat pads of C57BL/6J mice or 3T3-L1 preadipocytes. However, the leptin-suppressive effects of AM630 preserved in CB2-deficient adipocytes indicated the off-target activity of AM630 in leptin expression. Pharmacological and genetic studies, cheminformatics, and docking simulation were applied to identify the potential protein target of AM630 that modulates leptin expression in differentiated primary preadipocytes. Screening of the reported off-targets of AM630 identified a synthetic cannabinoid WIN55212-2 exerting the same function. Target deconvolution and docking simulation suggested that AM630 and WIN55212-2 were both inhibitors of lipocalin-type prostaglandin D2 synthase (L-PGDS). Further studies showed that L-PGDS positively regulates leptin expression. Although glucocorticoid and aldosterone were previously reported to induce expression of both L-PGDS and leptin, our data demonstrated that L-PGDS mediates only glucocorticoid-induced leptin expression in differentiated primary preadipocytes. No effect was observed after aldosterone treatment. This newly discovered glucocorticoid – L-PGDS – leptin pathway may provide insights into current clinical use of glucocorticoid and management of their undesired effects such as obesity.
The benefits of physical exercise on health and well‐being have been studied in a wide range of systemic and ocular diseases, including glaucoma, a progressive optic neuropathy characterized by ...accelerated apoptosis of retinal ganglion cells (RGCs). Elevated intraocular pressure (IOP) and insufficient ocular perfusion have been postulated to be the two main theories in glaucoma development and progression. The effects of exercise in these two aspects have been demonstrated by numerous researches. A review in 2009 focusing on these two theories concluded that exercise results in transient IOP reduction but an inconsistent elevation in ocular perfusion. However, the majority of the studies had been conducted in healthy subjects. Over the past decade, technological advancement has brought forth new and more detailed evidence regarding the effects of exercise. Moreover, the neuroprotective effect of exercise by upregulation of neurotrophin and enhancement of mitochondrial function has been a focus of interest. Apart from visual impairment, the mental health issues in patients with glaucoma, which include anxiety and depression, should also be addressed. In this review, we mainly focus on publications from the recent years, so as to provide a comprehensive review on the impact of physical exercise on IOP, ocular perfusion, neuroprotection and mental health in patients with glaucoma.
Indoleamine 2,3-dioxygenase 1 (IDO1), promoting immune escape of tumors, is a therapeutic target for the cancer immunotherapy. A number of IDO1 inhibitors have been identified, but only limited ...structural biology studies of IDO1 inhibitors are available to provide insights on the binding mechanism of IDO1. In this study, we present the structure of IDO1 in complex with 24, a NLG919 analogue with potent activity. The complex structure revealed the imidazole nitrogen atom of 24 to coordinate with the heme iron, and the imidazoleisoindole core situated in pocket A with the 1-cyclohexylethanol moiety extended to pocket B to interact with the surrounding residues. Most interestingly, 24 formed an extensive hydrogen bond network with IDO1, which is a distinct feature of IDO1/24 complex structure and is not observed in the other IDO1 complex structures. Further structure–activity relationship, UV spectra, and structural biology studies of several analogues of 24 demonstrated that extensive hydrophobic interactions and the unique hydrogen bonding network contribute to the great potency of imidazoleisoindole derivatives. These results are expected to facilitate the structure-based drug design of new IDO inhibitors.
Adequate pain management remains an unmet medical need. We previously revealed an opioid-independent analgesic mechanism mediated by orexin 1 receptor (OX1R)-initiated 2-arachidonoylglycerol (2-AG) ...signaling in the ventrolateral periaqueductal gray (vlPAG). Here, we found that low-frequency median nerve stimulation (MNS) through acupuncture needles at the PC6 (Neiguan) acupoint (MNS-PC6) induced an antinociceptive effect that engaged this mechanism. In mice, MNS-PC6 reduced acute thermal nociceptive responses and neuropathy-induced mechanical allodynia, increased the number of c-Fos–immunoreactive hypothalamic orexin neurons, and led to higher orexin A and lower GABA levels in the vlPAG. Such responses were not seen in mice with PC6 needle insertion only or electrical stimulation of the lateral deltoid, a nonmedian nerve-innervated location. Directly stimulating the surgically exposed median nerve also increased vlPAG orexin A levels. MNS-PC6–induced antinociception (MNS-PC6-IA) was prevented by proximal block of themedian nerve with lidocaine as well as by systemic or intravlPAG injection of an antagonist of OX1Rs or cannabinoid 1 receptors (CB1Rs) but not by opioid receptor antagonists. Systemic blockade of OX1Rs or CB1Rs also restored vlPAG GABA levels after MNS-PC6. A cannabinoid (2-AG)-dependent mechanism was also implicated by the observations that MNS-PC6-IA was prevented by intravlPAG inhibition of 2-AG synthesis and was attenuated in Cnr1
−/− mice. These findings suggest that PC6-targeting low-frequency MNS activates hypothalamic orexin neurons, releasing orexins to induce analgesia through a CB1R-dependent cascade mediated by OX1R-initiated 2-AG retrograde disinhibition in the vlPAG. The opioid-independent characteristic of MNS-PC6–induced analgesia may provide a strategy for pain management in opioid-tolerant patients.
A structure-based virtual screening strategy, comprising homology modeling, ligand–support binding site optimization, virtual screening, and structure clustering analysis, was developed and used to ...identify novel tryptophan 2,3-dioxygenase (TDO) inhibitors. Compound 1 (IC50 = 711 nM), selected by virtual screening, showed inhibitory activity toward TDO and was subjected to structural modifications and molecular docking studies. This resulted in the identification of a potent TDO selective inhibitor (11e, IC50 = 30 nM), making it a potential compound for further investigation as a cancer therapeutic and other TDO-related targeted therapy.
Broadband photosensors have been widely studied in various kinds of materials. Experimental results have revealed strong wavelength-dependent photoresponses in all previous reports. This limits the ...potential application of broadband photosensors. Therefore, finding a wavelength-insensitive photosensor is imperative in this application. Photocurrent measurements were performed in Sb2Te3 flakes at various wavelengths ranging from visible to near IR light. The measured photocurrent change was insensitive to wavelengths from 300 to 1000 nm. The observed wavelength response deviation was lower than that in all previous reports. Our results show that the corresponding energies of these photocurrent peaks are consistent with the energy difference of the density of state peaks between conduction and valence bands. This suggests that the observed photocurrent originates from these band structure peak transitions under light illumination. Contrary to the most common explanation that observed broadband photocurrent carrier is mainly from the surface state in low-dimensional materials, our experimental result suggests that bulk state band structure is the main source of the observed photocurrent and dominates the broadband photocurrent.
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