糖心TV

Wanqing Jiang, Cecilia Skoug, Ian Rodrigues, Ernesto Ciabatti, Fiona M. Gribble, Frank Reimann, Daniel I. Brierley, Marie K. Holt, Stefan Trapp

Glucagon-like peptide-1 receptor (GLP-1R) activation in the brain strongly reduces appetite, but most brain GLP-1Rs are not accessible for systemically administered GLP-1R agonists. Acute activation of nucleus tractus solitarius (NTS) GLP-1 neurons, known as preproglucagon (PPG) neurons, strongly suppresses food intake separate from GLP-1R agonists. However, it is unknown if chronic stimulation of PPG neurons is a viable strategy for appetite suppression, or if obesity disrupts their function. Here we demonstrate that PPG neurons in the NTS and intermediate reticular nucleus (IRT) determine meal size, and that their total number is inversely correlated with bodyweight gain. We report that PPG^NTS and PPG^IRT neurons receive distinct monosynaptic inputs, but have convergent efferent projection targets throughout the brain, and that combined ablation of both populations delays the onset of physiological satiation to a degree sufficient to promote weight gain under ad libitum chow fed conditions. Crucially, chronic daily chemogenetic activation of PPG^NTS+IRT neurons drives robust and sustained hypophagia and weight loss in obese mice without notable adverse effects, demonstrating their value as targets for obesity pharmacotherapy.

Roisin Murphy, Julia A. Fairbairn, Becca W.A. Baileeves, Phillip J. Stansfeld, Timothy D.H. Bugg

A series of 4-aryl-2-imidazoles containing an ortho-substituted benzyl substituent were designed as a new peptidomimetic scaffold for an Arg-Trp-x-x-Trp motif used by lysis protein E from bacteriophage 蠒X174 to target translocase MraY on the peptidoglycan biosynthesis pathway. The analogues showed antimicrobial activity against a panel of ESKAPE pathogens, with compound 9c (substituent CF₃) showing effective antimicrobial activity against antibiotic-resistant Acinetobacter baumannii 19606 (MIC 8 渭g/mL) and Staphylococcus aureus MRSA USA300 (MIC 8 渭g/mL). The analogues showed 33–47% inhibition of particulate E. coli MraY at 200 渭M concentration, with highest enzyme inhibition shown by compound 9b (substituent F, IC₅₀ 210 渭M). Docking against the structure of E. coli MraY revealed a possible binding site in the 鈥渆lbow鈥� of bent helix 9, close to Phe-288. This work identifies the MraY-protein E interaction site as a possible target for the antimicrobial activity of bromoageliferin, and establishes a new skeleton for design of non-nucleoside MraY inhibitors.

Boltze J., Fisher M

Recanalization therapies for ischemic stroke, in particular endovascular thrombectomy, have revolutionized acute stroke management. Cytoprotective approaches were unsuccessfully tested in the pre-recanalization era but have seen a renaissance in translational research and early clinical trials as a potential intervention to augment the impact of recanalization therapies. The new clinical trial approaches in which cytoprotective therapies are now being applied require refinement of cytoprotective application strategies. This has a profound impact on both preclinical translational and clinical research. This review summarizes current cytoprotection concepts and explains their rationale based on ischemic stroke pathophysiology and provides an overview of cytoprotection approaches currently under clinical assessment. Preclinical assessment of novel cytoprotective paradigms will require advanced in vivo testing in models resembling human stroke patients as much as possible. The review therefore also describes ways to improve preclinical and translational research with respect to comorbidities and other aspects impacting stroke pathophysiology. Moreover, the role of modern brain imaging approaches is discussed including their use as potential biomarkers or patient selection tools. The review further provides detailed considerations of novel clinical trial design features for cytoprotection trials in the context of recanalization therapies and provides an outlook on potential future research approaches.

Ling Cai, Yan Li, Chong Wang, Tim Magnus, Chengye Yao, Xiaoming Hu, Ann M. Stowe, Anna Rosell, Sunghee Cho, Stuart M. Allan, Jieqing Wan, Yulong Ma, Yang Liu, Daniel I. Sessler, Johannes Boltze, Tianlong Wang, Weifeng Yu, Yueman Zhang, Peiying Li,

Ischemic stroke is a major global health burden, leading to considerable mortality and long-term disability. Endovascular thrombectomy and mechanical recanalization have revolutionized acute stroke care. Nonetheless, many patients experience poor long-term neurological outcomes, which are often attributed to the no-reflow phenomenon and activation of inflammatory cascades. The perioperative period of endovascular thrombectomy, managed under either general anesthesia or conscious sedation, represents a critical window where anesthetic strategies may influence recovery through hemodynamic control and possibly immune modulation. This consensus review was generated by an international multidisciplinary expert group and synthesizes preclinical and clinical evidence to evaluate the promise of various immunomodulatory strategies for improving functional outcomes in patients with ischemic stroke following endovascular thrombectomy. Our goal is to provide a foundational reference for future research and development of novel perioperative immune therapies for patients with endovascular thrombectomy.

Matthew J Padgett , Nela Fucelova , Johannes Boltze, Timothy J England , Tuuli Hietamies , Karen Horsburgh , Terence J Quinn , Emily S Sena , Lorraine M Work, Marietta Zille, Rebecca C Trueman, Tracy D Farr

Hypoperfusion via bilateral carotid artery stenosis is the most common mouse model of vascular cognitive impairment, but the literature varies surrounding which behavioural tests are most appropriate to detect cognitive deficits in this model. We aimed to address this via a systematic review and meta-analysis. We also aimed to provide a recommendation that also considers how the tests cover the different cognitive domains. We identified 1714 publications and extracted data from 56. Interestingly, only six cognitive behavioural tests were employed across the literature with the most common being the Morris water and radial arm mazes, followed by the Y maze, novel object recognition, open field, and the Barnes maze. While all examined tests were able to detect cognitive impairments in hypoperfused mice, there was a high degree of heterogeneity across the publications, highlighting that not all research groups consistently observed cognitive deficits in the model. There was also evidence of publication bias, and occasionally some publications with extremely high effect sizes were influential. We recommend all tests, but ideally experiments should be complemented with additional approaches that examine a greater range of cognitive functions.

Amol Mohan Bhandare, Adwoa Boaten, Dylan Dunkwu, Jade Hill, Biborka Balazs, Nicholas Dale

Impaired CO鈧� responsiveness in epilepsy can result in hypoventilation and hypercapnia and these respiratory disturbances are key contributors to Sudden Unexpected Death in Epilepsy (SUDEP). While mild to moderate inflammation is known to modulate respiratory function, its specific role in regulating respiratory responses in the context of epilepsy remains unclear. We studied the effects of lipopolysaccharide (LPS)-induced inflammation and microglial inhibition via minocycline during the acute and chronic phases of epilepsy on hypercapnic ventilatory responses (HCVR) in the intrahippocampal kainic acid model of temporal lobe epilepsy in male C57BL/6 mice. LPS treatment during acute seizures and minocycline during spontaneous seizures in the chronic phase of epilepsy restored the impaired HCVR in mice. Notably, LPS treatment during acute seizures also reduced the frequency of spontaneous seizures. In contrast, minocycline given during acute seizures and LPS administered during chronic epilepsy further exacerbated HCVR impairment. Immunohistochemical analysis of chemosensitive retrotrapezoid nucleus (RTN) revealed varied effects of different treatments in epileptic mice on microglia density, morphology and their expression of triggering receptor expressed on myeloid cells 2 (TREM2), P2Y12 receptor, and astrocytic adenosine 2A receptor (A2AR). Overall, the inflammation during epileptogenic or acute phase preserves HCVR and reduces spontaneous seizure frequency in chronic epilepsy, whereas in chronic phase it worsens HCVR. Although not yet fully validated, changes in microglial and astrocytic receptor expression could contribute to this HCVR impairment and may represent a mechanistic target for preserving HCVR in epilepsy; a dysfunction that could potentially lead to SUDEP.