Enhancing the therapeutic potential of isoliensinine for hypertension through PEG-PLGA nanoparticle delivery: A comprehensive in vivo and in vitro study.

BACKGROUND: Hypertension, a highly prevalent chronic disease, is known to inflict severe damage upon blood vessels. In our previous study, isoliensinine, a kind of bibenzyl isoquinoline alkaloid which isolated from a TCM named Lotus Plumule (Nelumbo nucifera Gaertn), exhibits antihypertensive and vascular smooth muscle proliferation-inhibiting effects, but its application is limited due to poor water solubility and low bioavailability. In this study, we proposed to prepare isoliensinine loaded by PEG-PLGA polymer nanoparticles to increase its efficacy METHOD: We synthesized and thoroughly characterized PEG-PLGA nanoparticles loaded with isoliensinine using a nanoprecipitation method, denoted as, PEG-PLGA@Isoliensinine. Additionally, we conducted comprehensive investigations into the stability of PEG-PLGA@Isoliensinine, in vitro drug release profiles, and in vivo pharmacokinetics. Furthermore, we assessed the antihypertensive efficacy of this nano-system through in vitro experiments on A7R5 cells and in vivo studies using AngII-induced mice. RESULT: The findings reveal that PEG-PLGA@Isoliensinine significantly improves isoliensinine absorption by A7R5 cells and enhances targeted in vivo distribution. This translates to a more effective reduction of AngII-induced hypertension and vascular smooth muscle proliferation. CONCLUSION: In this study, we successfully prepared PEG-PLGA@Isoliensinine by nano-precipitation, and we confirmed that PEG-PLGA@Isoliensinine surpasses free isoliensinine in its effectiveness for the treatment of hypertension, as demonstrated through both in vivo and in vitro experiments. SIGNIFICANCE: This study lays the foundation for isoliensinine's clinical use in hypertension treatment and vascular lesion protection, offering new insights for enhancing the bioavailability of traditional Chinese medicine components. Importantly, no toxicity was observed, affirming the successful implementation of this innovative drug delivery system in vivo and offers a promising strategy for enhancing the effectiveness of Isoliensinine and propose an innovative avenue for developing novel formulations of traditional Chinese medicine monomers.

Sanguinarine improved nutrient digestibility, hepatic health indices and productive performance in laying hens fed low crude protein diets.

A major mean to minimize feeding costs and faecal nitrogen excretion on poultry farms is to decrease the supplied dietary protein content. This, however, is associated with the declines in productive performance and systemic health indices. Sanguinarine may improve protein efficiency via decreasing the intestinal amino acid decarboxylation and stimulating the tryptophan-serotonin pathway. The present study was carried out to investigate the effects of dietary supplementation of sanguinarine on the performance, egg yolk biochemical parameters, serum enzyme activities, nutrient digestibility, ovarian follicles, and hepatic health indices in laying hens fed decremental levels of crude protein (CP). For this purpose, 180 laying hens were allocated into nine dietary treatments with four replicates of five birds each. The experimental treatments consisted of three levels of CP (85.0%, 92.5%, and 100% of Hy-Line W-36 manual recommendation) and three levels of sanguinarine (0.00, 3.75, and 7.50 mg/kg) in a 3 × 3 factorial arrangement administered during a 70-day feeding trial. Results showed that the decremental levels of CP led to significant increases in serum aspartate aminotransferase (p < .05), alanine aminotransferase, and alkaline phosphatase (p < .01) activities, egg yolk cholesterol concentration (p = .064), and hepatic fat and malondialdehyde (MDA) contents (p < .05). It also caused the significant declines in ileal dry matter (DM) digestibility (p < .05) and eggshell strength (p < .05), and also tended to decrease CP digestibility (p = .071), Haugh unit (p = .057) and egg production percentage (p = .062). The interaction effects of the experimental factors indicated that dietary supplementation of sanguinarine, especially at 7.50 mg/kg, led to significant improvements in serum aspartate aminotransferase and alanine aminotransferase activities (p < .01), egg yolk cholesterol (p < .001) and triglyceride (p < .05) concentrations, eggshell strength (p < .001), Haugh unit (p < .05), hepatic fat (p < .001) and MDA (p = .059) contents, ileal DM and CP digestibility (p < .01) as well as egg production, egg mass and feed conversion ratio (FCR; p < .05) in birds receiving decremental levels of CP. Taken together, the results indicate that dietary administration of sanguinarine could enhance productive performance via improving nutrient digestibility, hepatic health indices and fortifying systemic antioxidant capacity in laying hens fed low-CP diets.

Effects of plant-derived isoquinoline alkaloids on growth performance and intestinal function of broiler chickens under heat stress.

Broiler chickens reared under heat stress (HS) conditions have decreased growth performance and show metabolic and immunologic alterations. This study aimed to evaluate the effect of supplementation with a standardized blend of plant-derived isoquinoline alkaloids (IQ) on the growth performance, protein catabolism, intestinal barrier function, and inflammatory status of HS-treated chickens. Three hundred sixty 0-day-old Ross 308 male broiler chickens were randomly distributed into 2 treatment groups: control diet (no additives) or diet supplemented with 100 ppm IQ. At day 14, the chicks in each diet group were further divided into 2 groups, each of which was reared under thermoneutral (TN) (22.4°C) or constant HS (33.0°C) conditions until day 42. Each group consisted of 6 replicates with 15 birds per replicate, and chickens were provided ad libitum access to water and feed. During days 15-21, the body weight gain (BWG) and feed intake (FI) were significantly lower in the HS treatment group than in the TN group, and feed conversion ratio was higher (P < 0.05); these factors were not alleviated by IQ supplementation. During days 22-42, the final BW, BWG, and FI of the HS birds were better among those administered IQ than those that were not (P < 0.05). HS treatment increased plasma lipid peroxide, corticosterone, and uric acid concentrations as well as serum fluorescein isothiocyanate-dextran, a marker of intestinal barrier function, and decreased plasma total protein content (P < 0.05). These changes were not observed in the IQ group, suggesting that IQ supplementation improved oxidative damage, protein catabolism, and intestinal barrier function of chickens under HS. Isoquinoline alkaloid supplementation inhibited the expression of intestinal inflammatory factors, IL-6, tumor necrosis factor-like factor 1A, and inducible nitric oxide synthase under HS treatment (P < 0.05). These results suggest that IQ supplementation can improve the growth performance of broiler chickens under HS conditions, which may be associated with amelioration of oxidative damage, protein catabolism, intestinal barrier function, and inflammation.

Sanguinarine modulate gut microbiome and intestinal morphology to enhance growth performance in broilers.

Sanguinarine is a bioactive compound as a quaternary benzophenanthridine alkaloid from plant of the Macleaya cordata, Papaveraceae family. The present study was conducted to investigate the effects of dietary sanguinarine supplementation on growth performance, serum biochemistry parameters, intestinal mucosal morphology and gut microbiome in yellow feathered broilers. Two hundred and seventy 1-d-old female broilers were randomly assigned to 3 treatments ① Basal diet (NG); ② Basal diet containing bacitracin methylene disalicylate (50mg/Kg diet) (ANT); ③ Basal diet containing sanguinarine (0.7 mg/ kg of feed) (SAG). The statistical results showed that dietary sanguinarine supplementation enhanced growth performance and decreased glucose, uric acid as well as urea nitrogen levels of broilers at 28d of age (P<0.05). The 16S rRNA gene sequence analysis revealed that sanguinarine significantly decreased the species from the phyla Bacteroidetes, and increased the species from phyla Firmicutes. Moreover, dietary sanguinarine supplementation improved mucosal morphology to achieve higher ratio of intestinal villus height to crypt depth (P < 0.05), and decreased the concentrations of TNF-α and IL-4 in jejunum mucosal. This study demonstrated that sanguinarine supplementation in the diet of yellow feathered broilers improved intestinal morphology and microbiota community structure to promote growth performance on 1-28d.

Duvelisib for the treatment of chronic lymphocytic leukemia.

INTRODUCTION: Duvelisib, a first in class, oral, dual PI3 k-delta/gamma inhibitor recently received FDA approval for previously treated CLL (chronic lymphocytic leukemia)/SLL (small lymphocytic lymphoma) and follicular lymphoma. Data coming from the phase III 'DUO' trial, in fact, showed a superior progression-free survival (PFS) in CLL patients treated with duvelisib compared to ofatumumab. AREAS COVERED: This review provides analysis of the mechanism of action of duvelisib and includes the rationale for the use of double inhibition. The authors also give their clinical experience with duvelisib. Overall, despite the high efficacy of the drug, some concern remains on duvelisib-related adverse events leading to treatment interruption in a significant proportion of patients. EXPERT OPINION: Considering the unmet need of salvage therapies in patients failing BTK and/or Bcl2 inhibitors, treatment with duvelisib represents a new valid option in the CLL therapeutic armamentarium. Therefore, the correct management of adverse events with early treatment suspension, dose reductions and prompt supportive treatment could help to manage treatment, thus improving patient outcome. Finally, the association of duvelisib with other targeted therapies, such as ibrutinib or venetoclax, could allow clinicians to capitalize on the synergistic activity of these agents.

Tumor-targeted delivery of silibinin and IPI-549 synergistically inhibit breast cancer by remodeling the microenvironment.

We induced changes in the tumor microenvironment (TME) through the synergistic actions of two drugs used in breast cancer therapy. The anti-fibrotic drug silibinin (SLB) targets tumor-associated fibroblasts and exerts immune-mediated anti-cancer effects. IPI-549, an efficient and highly selective phosphoinositide-3-kinase-gamma (PI3Kγ) inhibitor, was applied to alter the balance of immunosuppressive cells by inhibiting PI3Kγ molecules; it also promotes anti-tumor immunity. We developed nanoparticle formulations to encapsulate both drugs into the targeting carrier aminoethyl anisamide-polyethylene glycol-polycaprolactone (AEAA-PEG-PCL) respectively. The drugs were intravenously delivered in mice and resulted in an increase in anti-tumor efficacy and apoptotic tumor tissue compared with either IPI-549 or SLB alone in 4T1 breast cancer cell-derived tumors. Furthermore, a significant reduction in regulatory T (Treg) cells and myeloid suppressor cells (MDSCs) was observed. A normalized TME structure was also observed, including angiogenesis suppression, antifibrotic effects and the inhibition of collagen formation in the tumor tissue, significantly enhancing the anti-tumor effects. In summary, this combination strategy may offer an alternative treatment for breast cancer.

Effects of orally active hypoxia inducible factor alpha prolyl hydroxylase inhibitor, FG4592 on renal fibrogenic potential in mouse unilateral ureteral obstruction model.

Orally active hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors that stabilize HIF protein and stimulate the production of erythropoietin have been approved to treat renal anemia. Our previous report suggested that HIF-1α dependent fibrogenic mechanisms are operating at the early onset of renal fibrosis and its contribution declines with the progression in mouse unilateral ureteral obstruction (UUO) model. The aim of the study is to evaluate the renal fibrogenic potential of FG4592, a recently approved orally active HIF prolyl hydroxylase inhibitor in mouse UUO model. Male C57BL/6J mice orally given FG-4592 (12.5 mg/kg/day and 50 mg/kg/day) were subjected to UUO. Neither dose of FG-4592 affected renal fibrosis or macrophage infiltration. FG-4592 had no effects on increased mRNA of collagen I, collagen III or transforming growth factor-ß1. At 3 days after UUO, higher dose of FG-4592 potentiated the increased mRNA expression of profibrogenic molecules, plasminogen activator inhibitor 1 (Pai-1) and connective tissue growth factor (Ctgf) but such potentiation disappeared at 7 days after UUO. It is suggested that FG-4592 used in the present study had little effects on renal fibrosis even though high dose of FG-4592 used in the present study transiently potentiated gene expression of Pai-1 and Ctgf in the UUO kidney.

7-Deoxy-trans-dihydronarciclasine Isolated from Lycoris chejuensis Inhibits Neuroinflammation in Experimental Models.

Overactivated microglia and persistent neuroinflammation hold an important role in the pathophysiology of neurodegenerative diseases. The extract of Lycoris chejuensis (CJ) and its active compound, 7-deoxy-trans-dihydronarciclasine (named E144), attenuated expressions of pro-inflammatory factors, including nitric oxide, prostaglandin E2, inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), and interleukin 6, secreted by lipopolysaccharide-activated BV-2 microglial cells, as measured by an enzyme-linked immunosorbent assay or western blotting. In contrast, CJ extract and E144 promoted the secretion of the anti-inflammatory cytokine, interleukin 10. Moreover, we found that E144 attenuated the expression of TNF-α and COX-2 in the cerebral cortex of lipopolysaccharide-treated mice and/or T2576 transgenic mice as well as reduced the reactive immune cells visualized by ionized calcium-binding adaptor molecule 1. Our results suggest the possibility of E144 to serve as a potential anti-neuroinflammatory agent by preventing excess production of pro-inflammatory factors.

BU10038 as a safe opioid analgesic with fewer side-effects after systemic and intrathecal administration in primates.

BACKGROUND: The marked increase in mis-use of prescription opioids has greatly affected our society. One potential solution is to develop improved analgesics which have agonist action at both mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) receptors. BU10038 is a recently identified bifunctional MOP/NOP partial agonist. The aim of this study was to determine the functional profile of systemic or spinal delivery of BU10038 in primates after acute and chronic administration. METHODS: A series of behavioural and physiological assays have been established specifically to reflect the therapeutic (analgesia) and side-effects (abuse potential, respiratory depression, itch, physical dependence, and tolerance) of opioid analgesics in rhesus monkeys. RESULTS: After systemic administration, BU10038 (0.001-0.01 mg kg-1) dose-dependently produced long-lasting antinociceptive and antihypersensitive effects. Unlike the MOP agonist oxycodone, BU10038 lacked reinforcing effects (i.e. little or no abuse liability), and BU10038 did not compromise the physiological functions of primates including respiration, cardiovascular activities, and body temperature at antinociceptive doses and a 10-30-fold higher dose (0.01-0.1 mg kg-1). After intrathecal administration, BU10038 (3 µg) exerted morphine-comparable antinociception and antihypersensitivity without itch scratching responses. Unlike morphine, BU10038 did not cause the development of physical dependence and tolerance after repeated and chronic administration. CONCLUSIONS: These in vivo findings demonstrate the translational potential of bifunctional MOP/NOP receptor agonists such as BU10038 as a safe, non-addictive analgesic with fewer side-effects in primates. This study strongly supports that bifunctional MOP/NOP agonists may provide improved analgesics and an alternative solution for the ongoing prescription opioid crisis.

Pharmacokinetics of sanguinarine, chelerythrine, and their metabolites in broiler chickens following oral and intravenous administration.

Sanguinarine (SA) and chelerythrine (CHE) are the main active components of the phytogenic livestock feed additive, Sangrovit®. However, little information is available on the pharmacokinetics of Sangrovit® in poultry. The goal of this work was to study the pharmacokinetics of SA, CHE, and their metabolites, dihydrosanguinarine (DHSA) and dihydrochelerythrine (DHCHE), in 10 healthy female broiler chickens following oral (p.o.) administration of Sangrovit® and intravenous (i.v.) administration of a mixture of SA and CHE. The plasma samples were processed using two different simple protein precipitation methods because the parent drugs and metabolites are stable under different pH conditions. The absorption and metabolism of SA following p.o. administration were fast, with half-life (t1/2 ) values of 1.05 ± 0.18 hr and 0.83 ± 0.10 hr for SA and DHSA, respectively. The maximum concentration (Cmax ) of DHSA (2.49 ± 1.4 µg/L) was higher that of SA (1.89 ± 0.8 µg/L). The area under the concentration vs. time curve (AUC) values for SA and DHSA were 9.92 ± 5.4 and 6.08 ± 3.49 ng/ml hr, respectively. Following i.v. administration, the clearance (CL) of SA was 6.79 ± 0.63 (L·h-1 ·kg-1 ) with a t1/2 of 0.34 ± 0.13 hr. The AUC values for DHSA and DHCHE were 7.48 ± 1.05 and 0.52 ± 0.09 (ng/ml hr), respectively. These data suggested that Sangrovit® had low absorption and bioavailability in broiler chickens. The work reported here provides useful information on the pharmacokinetic behavior of Sangrovit® after p.o. and i.v. administration in broiler chickens, which is important for the evaluation of its use in poultry.

Effects of natural dietary supplementation with Macleaya cordata extract containing sanguinarine on growth performance and gut health of early-weaned piglets.

This study was conducted to investigate the effects of dietary supplementation with Sangrovit® (SAG; minimum of 1.5% sanguinarine, a quaternary benzo[c]phenanthridine alkaloid extracted from Macleaya cordata) on growth performance, intestinal morphology, intestinal microflora and its metabolites of early-weaned piglets. A total of 20 healthy weaned piglets (Duroc× [Large White×Landrace]), weaned at 21 days of age with an average body weight (BW) of 6.52 ± 0.23 kg, were randomly assigned to receive either a corn-soybean meal basal diet (CTR) or a basal diet supplemented with 50 mg/kg SAG (SAG). During the 21-days trial, we collected and analysed intestinal tissues and the luminal digesta for their morphology and populations of gut microbiota, as well as for measuring the concentrations of short-chain fatty acids (SCFAs) and ammonia. Compared with the CTR group, supplementation with SAG improved average daily gains (p = 0.011) and average daily feed intake (p = 0.037). Piglets fed the SAG diet had an average lower value for crypt depth of the jejunum (p = 0.011) and greater values for villus height in the ileum (p = 0.015) and ratios of villus height to crypt depth in the jejunum (p < 0.01) and in the ileum (p = 0.027) than did animals receiving the CTR diet. The addition of SAG increased the amounts of Lactobacillus in the ileum (p = 0.033) and caecum (p < 0.01), and tended to increase the amounts of Bifidobacterium (p = 0.058) in the caecum, while decreasing the amounts of Escherichia coli (p = 0.046) and Salmonella spp. (p = 0.035) in the ileum, as well as Salmonella spp. (p = 0.029) in the caecum. Dietary supplementation with SAG enhanced (p < 0.05) the concentrations of acetate, propionate, butyrate and total SCFAs, and also tended to increase the level of valerate (p = 0.055 and p = 0.052) in the ileal and caecal contents when compared with the CTR group. Concentrations of ammonia also declined in the caecal (p = 0.037) and ileal (p = 0.046) digesta in response to SAG. These results indicate that feeding early-weaned piglets a SAG-supplemented diet can potentially improve their growth performance and intestinal morphology, and can modify the intestinal luminal environment in a beneficial manner.

The preventive and therapeutic implication for renal fibrosis by targetting TGF-ß/Smad3 signaling.

It is well established that Smad3 is a key downstream effector of transforming growth factor-ß (TGF-ß) signaling in tissue fibrogenesis. We reported here that targetting Smad3 specifically with a Smad3 inhibitor SIS3 is able to prevent or halt the progression of renal fibrosis in a mouse model of unilateral ureteral obstructive nephropathy (UUO). We found that preventive treatment with SIS3 at the time of disease induction largely suppressed progressive renal fibrosis by inhibiting α-smooth muscle actin (α-SMA) + myofibroblast accumulation and extracellular matrix (collagen I (Col.I) and fibronectin (FN)) production. Importantly, we also found that treatment with SIS3 on established mouse model of UUO from day 4 after UUO nephropathy halted the progression of renal fibrosis. Mechanistically, the preventive and therapeutic effects of SIS3 on renal fibrosis were associated with the inactivation of Smad3 signaling and inhibition of TGF-ß1 expression in the UUO kidney. In conclusion, results from the present study suggest that targetting Smad3 may be a specific and effective therapy for renal fibrosis.

Phosphodiesterase 4 inhibition reduces lung fibrosis following targeted type II alveolar epithelial cell injury.

Fibrosis of the lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the antifibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary fibrosis by augmenting the activity of endogenous antifibrotic mediators that signal through cyclic AMP. In this study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of lung fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the antifibrotic activity of PDE4 inhibition to the two therapies that are FDA-approved for idiopathic pulmonary fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0-21) and therapeutic (day 11-21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in lung fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in lung fibrosis, and an in vitro inhibition of fibroblast profibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic lung disease.

Gastrodin causes vasodilation by activating KATP channels in vascular smooth muscles via PKA-dependent signaling pathway.

Gastrodin, one of the major components extracted from the Chinese herb Gastrodia elata Bl., has been widely used as an anticonvulsant, sedative, analgesic and hypotensive. In our study, we aimed to investigate the effects and possible mechanisms of gastrodin on vascular KATP channels. Tension experiments were used on rat mesenteric artery rings without an endothelium. Patch clamp experiments were executed to investigate the influences of gastrodin on the membrane current in mesenteric artery smooth muscle cells. Gastrodin induced vasorelaxation in a concentration dependent manner when rat mesenteric artery rings were pre-contracted with Phenylephrine. The vasorelaxation effect was partially diminished by pre-treating with a KATP channel inhibitor, or a PKA inhibitor. With whole-cell patch-clamp recording techniques, we found that gastrodin is a activator of KATP in rat mesenteric artery smooth muscle cells, and this effect was eliminate by pre-treating with H89or PKI, PKA inhibitor. In addition, when rat vascular smooth muscle cells were treated with 100 µM gastrodin for 24 h, maximum KATP current density increased by 28.1%. The results indicate that gastrodin exerts vasorelaxation effect through activation of PKA and subsequent opening of smooth muscle KATP channels.

Inhibition of exendin-4-induced steatosis by protein kinase A in cultured HepG2 human hepatoma cells.

Nonalcoholic fatty liver is characterized by the abnormal accumulation of triglycerides within hepatocytes, resulting in a steatotic liver. Glucagon-like peptide 1 and its analog exendin-4 can ameliorate certain aspects of this syndrome by inducing weight loss and reducing hepatic triglyceride accumulation, but it is unclear whether these effects result from the effects of glucagon-like peptide 1 on the pancreas, or from direct action on the liver. This study investigated the direct action and putative cellular mechanism of exendin-4 on steatotic hepatocytes in culture. Steatosis was induced in cultured HepG2 human hepatoma cells by incubation in media supplemented with 2 mM each of linoleic acid and oleic acid. Steatotic hepatocytes were then pre-incubated in the protein kinase A inhibitor H89 for 30 min, then treated with exendin-4 over a period of 24 h. Cell viability and triglyceride content were characterized by a TUNEL assay and AdipoRed staining, respectively. Our results showed that steatotic cells maintained high levels of intracellular triglycerides (80%) compared to lean controls (25%). Exendin-4 treatment caused a significant reduction in intracellular triglyceride content after 12 h that persisted through 24 h, while protein kinase A inhibitors abolished the effects of exendin-4. The results demonstrate the exendin-4 induces a partial reduction in triglycerides in steatotic hepatocytes within 12 h via the GLP-1 receptor-mediated activation of protein kinase A. Thus, the reduction in hepatocyte triglyceride accumulation is likely driven primarily by downregulation of lipogenesis and upregulation of ß-oxidation of free fatty acids.

Activity of Isoliensinine in Improving the Symptoms of Type 2 Diabetic Mice via Activation of AMP-Activated Kinase and Regulation of PPARγ.

This study was designed to explore the effects and mechanism of isoliensinine (isolie) from embryos of Nelumbo nucifera on type 2 diabetes and dyslipidemia in vivo and in vitro. The in vitro study showed that isolie increased the GLUT4 translocation by 2.5-fold in L6 cells. Furthermore, after 4 weeks of treatment, the in vivo biochemical study indexes revealed that isolie had a positive effect on decreasing serum insulin level (42.2 ± 5.10 vs 55.7 ± 6.33 mU/L, P < 0.05) and reducing fast blood glucose (9.4 ± 1.5 vs 18.7 ± 2.3 mmol/L, P < 0.001) and body weight (37.8 ± 2.9 vs 46.9 ± 5.4 g, P < 0.05) compared with the KK-Ay model mice. Isolie treatment led to significant increases in GLUT4 proteins (∼2.7-fold in skeletal muscle and ∼2.4-fold in WAT) and phosphorylated AMP-activated protein kinase (∼1.4-fold in skeletal muscle, ∼3.1-fold in WAT, and ∼2.3-fold in liver). However, isolie caused a significant decrease in lipogenesis protein expressions of PPARγ and SREBP-1c, and decreased the activity of ACC by increasing the phospho-ACC level. Our findings showed that isolie has the potential to alleviate type 2 diabetes associated with hyperlipidemia in KK-Ay mice. Regulation of GLUT4, SREBP-1c, PPARγ, AMPK phosphorylation, and ACC phosphorylation is implicated in the antidiabetic effects of isolie.

Hypothalamic dopamine is required for salsolinol-induced prolactin secretion in goats.

The aim of the present study was to clarify the relationship between hypothalamic dopamine (DA) and salsolinol (SAL) for the secretion of prolactin (PRL) in goats. SAL or thyrotropin-releasing hormone (TRH) was intravenously injected into female goats treated with or without the D2 DA receptor antagonist haloperidol (Hal), which crosses the blood-brain barrier, and the PRL-releasing response to SAL was compared with that to TRH. PRL-releasing responses to SAL, Hal, and Hal plus SAL were also examined after a pretreatment to augment central DA using carbidopa (Carbi) and L-dopa. The PRL-releasing response to Hal alone was greater than that to SAL or TRH alone. The PRL-releasing response to Hal plus SAL was similar to that of Hal alone. In contrast, the PRL-releasing response to Hal plus TRH was greater than that to TRH or Hal alone. The treatment with Carbi plus L-dopa inhibited SAL- and Hal-induced PRL secretion. The inhibition of the PRL-releasing response to SAL disappeared when SAL was injected with Hal. These results indicate that the mechanisms underlying the SAL-induced PRL response differ from those of TRH, and suggest that hypothalamic DA and its synthesis is associated in part with SAL-induced PRL secretion in goats.

Mechanisms Underlying the Antidepressant Response of Acupuncture via PKA/CREB Signaling Pathway.

Protein kinase A (PKA)/cAMP response element-binding (CREB) protein signaling pathway, contributing to impaired neurogenesis parallel to depressive-like behaviors, has been identified as the crucial factor involved in the antidepressant response of acupuncture. However, the molecular mechanisms associated with antidepressant response of acupuncture, neurogenesis, and depressive-like behaviors ameliorating remain unexplored. The objective was to identify the mechanisms underlying the antidepressant response of acupuncture through PKA signaling pathway in depression rats by employing the PKA signaling pathway inhibitor H89 in in vivo experiments. Our results indicated that the expression of hippocampal PKA-α and p-CREB was significantly downregulated by chronic unpredicted mild stress (CUMS) procedures. Importantly, acupuncture reversed the downregulation of PKA-α and p-CREB. The expression of PKA-α was upregulated by fluoxetine, but not p-CREB. No significant difference was found between Acu and FLX groups on the expression of PKA-α and p-CREB. Interestingly, H89 inhibited the effects of acupuncture or fluoxetine on upregulating the expression of p-CREB, but not PKA-α. There was no significant difference in expression of CREB among the groups. Conclusively, our findings further support the hypothesis that acupuncture could ameliorate depressive-like behaviors by regulating PKA/CREB signaling pathway, which might be mainly mediated by regulating the phosphorylation level of CREB.

Facial eschar following a single application of black salve.

A previously healthy 86-year-old male was transported by ambulance to the trauma bay of the emergency department (ED) for profuse bleeding from the left temple. The ambulance crew raised concern that the volume and force of the bleed may suggest arterial involvement. The patient reported having applied a natural topical remedy to a mole two weeks prior at the recommendation of a naturopath. The patient described progressive blackening and swelling of the area in the days following the single application of the product. After gaining control of the bleeding in the ED, the area was found to have a raised, 2 cm eschar.

Protective effect of Berberis aristata against peritonitis induced by carbapenem-resistant Escherichia coli in a mammalian model.

OBJECTIVES: Berberis aristata is known to contain a variety of phenolic compounds contributing to its holistic capability of mitigating bacterial multidrug resistance. METHODS: B. aristata stem bark extract was prepared and was characterised using liquid chromatography-mass spectrometry (LC-MS). The antimicrobial efficacy of the extract against carbapenem-resistant Escherichia coli was assessed in vivo in an animal model using Sprague Dawley rats. Microbial counts in blood and urine, physical health status, haematological and biochemical analysis of blood, and histopathology of the kidney were assessed as the study endpoints. RESULTS: An aquo-alcoholic extract of B. aristata (PTRC-2111-A) was found to effectively manage peritonitis induced by carbapenem-resistant E. coli in a rat model at a single post-exposure prophylactic dose of 0.5mg/kg body weight (BW). The extract was also found to show a no observed adverse effect level (NOAEL) up to a dose of 2000mg/kg BW. Physical, immunological, haematological, biochemical and histopathological aberrations were found to be restored to normal in the herbal-treated group at a dose of 0.5mg/kg BW. CONCLUSIONS: The antimicrobial and hepatorenal protective ability of PTRC-2111-A could be attributed to the presence of isoquinoline alkaloids.