A common thalamic hub for general and defensive arousal control.

The expression of defensive responses to alerting sensory cues requires both general arousal and a specific arousal state associated with defensive emotions. However, it remains unclear whether these two forms of arousal can be regulated by common brain regions. We discovered that the medial sector of the auditory thalamus (ATm) in mice is a thalamic hub controlling both general and defensive arousal. The spontaneous activity of VGluT2-expressing ATm (ATmVGluT2+) neurons was correlated with and causally contributed to wakefulness. In sleeping mice, sustained ATmVGluT2+ population responses were predictive of sensory-induced arousal, the likelihood of which was markedly decreased by inhibiting ATmVGluT2+ neurons or multiple downstream pathways. In awake mice, ATmVGluT2+ activation led to heightened arousal accompanied by excessive anxiety and avoidance behavior. Notably, blocking their neurotransmission abolished alerting stimuli-induced defensive behaviors. These findings may shed light on the comorbidity of sleep disturbances and abnormal sensory sensitivity in specific brain disorders.

Preclinical Dose-Escalation Study of ZSJ-0228, a Polymeric Dexamethasone Prodrug, in the Treatment of Murine Lupus Nephritis.

Glucocorticoids (GCs) are widely used in the clinical management of lupus nephritis (LN). Their long-term use, however, is associated with the risk of significant systemic side effects. We have developed a poly(ethylene glycol) (PEG)-based dexamethasone (Dex) prodrug (i.e., ZSJ-0228) and in a previous study, demonstrated its potential therapeutic efficacy in mice with established LN, while avoiding systemic GC-associated toxicity. In the present study, we have employed a dose-escalation design to establish the optimal dose-response relationships for ZSJ-0228 in treating LN and further investigated the safety of ZSJ-0228 in lupus-prone NZB/W F1 mice with established nephritis. ZSJ-0228 was intravenously (i.v.) administered monthly at four levels: 0.5 (L1), 1.0 (L2), 3.0 (L3), and 8.0 (L4) mg/kg/day Dex equivalent. For controls, mice were treated with i.v. saline every 4 weeks. In addition, a group of mice received intraperitoneal injections (i.p.) of Dex every day or i.v. injections of Dex every four weeks. Treatment of mice with LN with ZSJ-0228 dosed at L1 resulted in the resolution of proteinuria in 14% of the mice. Mice treated with ZSJ-0228 dosed at L2 and L3 levels resulted in the resolution of proteinuria in ∼60% of the mice in both groups. Treatment with ZSJ-0228 dosed at L4 resulted in the resolution of proteinuria in 30% of the mice. The reduction and/or resolution of the proteinuria, improvement in renal histological scores, and survival data indicate that the most effective dose range for ZSJ-0228 in treating LN in NZB/W F1 mice is between 1.0 and 3.0 mg/kg/day Dex equivalent. Typical GC-associated side effects (e.g., osteopenia, adrenal glands atrophy, etc.) were not observed in any of the ZSJ-0228 treatment groups, confirming its excellent safety profile.

Low-dose PPI to prevent bleeding after ESD: A multicenter randomized controlled study.

BACKGROUND: Although proton pump inhibitors (PPIs) are widely used in the prevention of gastric bleeding caused by endoscopic submucosal dissection (ESD), there is no consensus on the optimal regimen for these patients. Therefore, we aim to investigate whether intermittent use of low-dose PPI is sufficient to prevent post-ESD bleeding. METHODS: This multicenter, non-inferiority, randomized controlled trial was conducted at 9 hospitals in China. Consecutive eligible patients with a diagnosis of gastric mucosal lesions after ESD treatment were randomly assigned (1:1) to receive either intermittent low-dose or continuous high-dose PPIs treatment. After three days, all patients administered orally esomeprazole 40 mg once a day for 8 weeks. The primary endpoint was post-ESD bleeding within 7 days. Analysis was done according to the intention-to-treat principle with the non-inferiority margin (Δ) of 5%. RESULTS: 526 consecutive patients were assessed for eligibility from 30 September 2017 to 30 July 2019, of whom 414 were randomly assigned to low-dose (n = 209) or high-dose (n = 205) esomeprazole treatment group without dropouts within7 days. The total post-ESD bleeding is occurred in 13 (6.2 %, 95 % CI 3.3-9.6) of 209 within 7 days in the intermittent low-dose group, and 12 (5.9 %, 95 % CI 2.9-9.3) of 205 in the continuous high-dose group. The absolute risk reduction (ARR) was 0.4 % (-4.2, 4.9). One month after ESD, There are 44 patients (21.1 %, 95 % CI 15.8, 26.8) and 39 patients (19.0 % 95 % CI 13.7, 24.4) in scar stage respectively in low-dose group and high-dose group (P = 0.875).The hospital costs in the low-dose PPI group was lower than high -dose group (P = 0.005). CONCLUSION: The intermittent use of low-dose PPIs is sufficient to prevent post-ESD bleeding. It might be applied in clinical practice to prevent post-ESD bleeding and reduce the costs related to PPIs.

6-Gingerol, an active pungent component of ginger, inhibits L-type Ca2+ current, contractility, and Ca2+ transients in isolated rat ventricular myocytes.

Ginger has been widely used as a flavor, food, and traditional medicine for centuries. 6-Gingerol (6-Gin) is the active components of ginger and offers some beneficial effects on cardiovascular diseases. Here, the effects of 6-Gin on L-type Ca2+ current (ICa-L), contractility, and the Ca2+ transients of rat cardiomyocytes, were investigated via patch-clamp technique and the Ion Optix system. The 6-Gin decreased the ICa-L of normal and ischemic ventricular myocytes by 58.17 ± 1.05% and 55.22 ± 1.34%, respectively. 6-Gin decreased ICa-L in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 31.25 µmol/L. At 300 µmol/L, 6-Gin reduced the cell shortening by 48.87 ± 5.44% and the transients by 42.5 ± 9.79%. The results indicate that the molecular mechanisms underlying the cardio-protective effects of 6-Gin may because of a decreasing of intracellular Ca2+ via the inhibition of ICa-L and contractility in rat cardiomyocytes.

Characterization and comparison of the pungent components in commercial Zanthoxylum bungeanum oil and Zanthoxylum schinifolium oil.

In the present study, the characterization and comparison of the pungent components in commercial Z. bungeanum oils and Z. schinifolium oils were investigated. By high-performance liquid chromatography (HPLC)-mass spectrometry (MS/MS) analysis, the major alkylamides in Z. bungeanum and Z. schinifolium oils were identified as hydroxy-ε-sanshool, hydroxy-α-sanshool, hydroxy-ß-sanshool, hydroxy-γ-sanshool, hydroxy-γ-isosanshool, bungeanool, isobungeanool, and tetrahydrobungeanool, respectively. Hydroxy-α-sanshool was found to be the most abundant alkylamide in all oils. The levels of hydroxy-ε-sanshool and hydroxy-ß-sanshool in Z. bungeanum oils were comparable to that in Z. schinifolium oils, whereas Z. bungeanum oils contained significantly (P less than 0.05) higher levels of hydroxy-γ-isosanshool, bungeanool, isobungeanool, and tetrahydrobungeanool, compared with Z. schinifolium oils. Furthermore, principal component analysis (PCA) indicated that Z. bungeanum oil and Z. schinifolium oil were clearly classified by HPLC fingerprinting profiles and concentrations of alkylamides. In addition, the results of PCA suggested that alkylamides, such as hydroxy-γ-sanshool and bungeanool, could be potential markers to distinguish Z. bungeanum oil and Z. schinifolium oil. The results from this study could be used to discriminate the different flavor characterization and control the quality of commercial Z. bungeanum oil and Z. schinifolium oil.

Intestinal alpha-glucosidase inhibitory activity and toxicological evaluation of Nymphaea stellata flowers extract.

AIM OF THE STUDY: Nymphaea stellata willd. flowers (NSF) are used as a traditional medicine in India and Nepal to treat diabetic disease. Different works have demonstrated that NSF extract showed antihyperglycemic effect on alloxan-induced diabetic rats. In the present work we evaluated in vitro intestinal alpha-glucosidase inhibition as the possible mode of action of NSF extract on suppressing postprandial hyperglycemia for curing diabetic mellitus. In addition, NSF extract was studied to assess its possible acute oral toxicity and genotoxicity. MATERIALS AND METHODS: Rat intestinal crude enzyme preparation and Caco-2 monolayer were used to evaluate alpha-glucosidase inhibitory activity of NSF extract. The main alpha-glucosidase inhibitors were detected by HPLC. For acute toxicity test, NSF extract was administered at doses of 2000, 5000 and 10,000 mg/kg body to three groups of 10 ICR mice each, and then clinical symptoms including mortality, clinical sign and gross findings were observed once a day for 14 days. In Ames test, histidine-dependent auxotrophic mutants of Salmonella typhimurium (strains TA97, TA98, TA100, TA102 and TA1535) were used and incubated in the presence and absence of S9 metabolic activation using NSF extract with concentrations of 150-5000 microg/plate. The chromosome aberration test was conducted with Chinese hamster lung (CHL) cells treated with NSF extract at doses of 150-5000 microg/ml in the presence and absence of S9 metabolic activation. In the in vivo mouse micronucleus assay, 9-week-old male and female ICR mice (n=90, 25-30 g) were administered daily by oral gavage at doses of 2.5, 5.0 and 10.0 g/kg body for 1 or 2 days. Bone marrow smears were prepared from each treatment group 24h after last administration and then polychromatic erythrocytes (PCEs) and normochromatic erythrocytes (NCEs) were identified. RESULTS: NSF extract showed potent rat intestinal alpha-glucosidase inhibitory activity for maltose hydrolysis with ED(50) value of 0.1 mg/ml. In Caco-2 monolayer, alpha-glucosidase activity for the maltose hydrolysis was down-regulated by NSF extract at a concentration of 0.05 mg/well level, showing 74% inhibition compared to the saline treated control. NSF was rich in phenol contents and the main alpha-glucosidase inhibitor, 1,2,3,4,6-penta-O-galloyl-beta-D-glucose, was identified together with two phenolic compounds of gallic acid and corilagin. In acute toxicity test, NSF extract did not produce any toxic signs or deaths and the LD(50) value of this extract could be greater than 10,000 mg/kg body weight. These results of genotoxicity assessment showed that NSF extract did not cause genotoxic effects in Ames test, in the in vitro chromosomal aberration assay and in the in vivo micronucleus assay. CONCLUSION: The current study shows that the extract from Nymphaea stellata flowers exhibits significant intestinal alpha-glucosidase inhibitory activity, without showing any acute toxicity or genotoxicity, which may be useful in suppressing postprandial hyperglycemia in diabetics. The results presented here suggest that the use of NSF in folk medicine as a natural antidiabetic treatment could be safe as well as beneficial.