Late-life anxiety has a high prevalence and usually co-morbidity with cerebral-and cardiovascular diseases which in turn increases the disability and mortality in old people.The pathology of late-life anxiety is difference from adult with the character of GABAergic neuroplasticity dysfunction.The therapeutic strategy presently can only alleviate the anxious symptom but not ameliorate the neuroplasticity.Brain-derived neurotrophic factor (BDNF) is a critical signaling molecule which regulates the GABAergic neuroplasticity,reduction of BDNF along with aging can induce GABAergic dysfunction which contributes to late-life anxiety.BDNF may exert anxiolytic effects by restoring the GABAergic plasticity and can be a potential therapeutic strategy of late-life anxiety.

OBJECTIVETo observe the effect of total flavonoids from Scutellaria amoena on the experimental arrhythmia.

METHODExperimental animals anesthetized with 10% chloral hydrate were evenly randomized into control group, positive control group, and low-dose, middle-dose and high-dose total flavonoids groups. The experimental arrhythmia ouabain-induced in guinea pigs and barium chloride or calcium chloride-induced in rats were observed and detected respectively. The result was converted into cumulative dosage of ouabain, in guinea pig model. In rat model, the duration of arrhythmia were detected.

RESULThold dosage of ventricular premature heat (VP) and ventricular fibrillation( VF) ouabain-induced in guinea pigs was markedly elevated, and the duration of ventricular tachycardia (VT) barium chloride-induced and VF calcium chloride-induced in rats was postponed by total flavonoids from S. amoena.

CONCLUSIONTotal flavonoids from S. amoena has obvious protective effect on drug-induced arrhythmia.

Animals ; Anti-Arrhythmia Agents ; administration & dosage ; Arrhythmias, Cardiac ; drug therapy ; Disease Models, Animal ; Female ; Flavonoids ; administration & dosage ; Guinea Pigs ; Humans ; Male ; Plant Extracts ; administration & dosage ; Rats ; Rats, Sprague-Dawley ; Scutellaria ; chemistry

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.