Disposition of asciminib, a potent BCR-ABL1 tyrosine kinase inhibitor, in healthy male subjects.

Asciminib is a potent, specific BCR-ABL1 inhibitor being developed for the treatment of patients with chronic myelogenous leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL).Here, we present the results of human oral absorption, distribution, metabolism, excretion (ADME) and in vitro studies that together provide an overall understanding of the metabolism, distribution and clearance of asciminib in humans.Asciminib was rapidly absorbed with a maximum plasma concentration at two hours post-dose. Total radioactivity and asciminib showed similar terminal half-lives in plasma.Oral asciminib absorption ranged between a minimum of 33%, and a maximum of 57% based on the metabolite profiles of late time-point feces collections.Asciminib was eliminated mainly through feces via unchanged asciminib excretion and metabolism.Direct glucuronidation and oxidation were major metabolic pathways in human that were catalyzed predominantly by UDP-glucuronosyltransferase (UGT)2B7 and cytochrome P450 (CYP)3A4, respectively.The relative contribution of the glucuronidation pathway to the total clearance of asciminib via metabolism is estimated to range ∼28-58%, whereas the relative contribution of the oxidative pathway is estimated to range ∼37-64%, based upon the maximum oral absorption in humans.

Comparison of the Kinase Profile of Midostaurin (Rydapt) with That of Its Predominant Metabolites and the Potential Relevance of Some Newly Identified Targets to Leukemia Therapy.

The multitargeted protein kinase inhibitor midostaurin is approved for the treatment of both newly diagnosed FLT3-mutated acute myeloid leukemia (AML) and KIT-driven advanced systemic mastocytosis. AML is a heterogeneous malignancy, and investigational drugs targeting FLT3 have shown disparate effects in patients with FLT3-mutated AML, probably as a result of their inhibiting different targets and pathways at the administered doses. However, the efficacy and side effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound but are often comprised of complex cooperative effects between the properties of the parent and active metabolites. Following chronic dosing, two midostaurin metabolites attain steady-state plasma trough levels greater than that of the parent drug. In this study, we characterized these metabolites and determined their profiles as kinase inhibitors using radiometric transphosphorylation assays. Like midostaurin, the metabolites potently inhibit mutant forms of FLT3 and KIT and several additional kinases that either are directly involved in the deregulated signaling pathways or have been implicated as playing a role in AML via stromal support, such as IGF1R, LYN, PDPK1, RET, SYK, TRKA, and VEGFR2. Consequently, a complex interplay between the kinase activities of midostaurin and its metabolites is likely to contribute to the efficacy of midostaurin in AML and helps to engender the distinctive effects of the drug compared to those of other FLT3 inhibitors in this malignancy.

Lactones from the pericarps of Litsea japonica and their anti-inflammatory activities.

Five new lactones, litsenolide F1 (1), lisealactone H1 (10), lisealactone H2 (11), akolactone D (13), and akolactone E (14), along with thirteen known compounds were isolated from the pericarps of Litsea japonica (Thunb.) Jussieu. Their chemical structures were elucidated by extensive spectroscopic analyses, including 1D and 2D NMR, HRMS, and chemical methods. The isolated compounds were evaluated for their inhibitory effects on NO production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Among them, 2-alkylidene-3-hydroxy-4-methylbutanolide derivatives (compounds 1-9) exhibited the most potent activity, with IC50 values in the range of 2.9-12.8 µM. In additon, compounds 1, 3, 4, and 6 showed inhibition of iNOS and COX-2 expression in concentration-dependent manner. Compound 3 suppresses mRNA expression of iNOS, COX-2, IL-6, and TNF-α in LPS-stimulated RAW264.7 cells. Based on these evidence, the isolated lactones from L. japonica could be promissing candidates for the development of new anti-inflammatory agents.

Transport properties of valsartan, sacubitril and its active metabolite (LBQ657) as determinants of disposition.

1. The potential for drug-drug interactions of LCZ696 (a novel, crystalline complex comprising sacubitril and valsartan) was investigated in vitro. 2. Sacubitril was shown to be a highly permeable P-glycoprotein (P-gp) substrate and was hydrolyzed to the active anionic metabolite LBQ657 by human carboxylesterase 1 (CES1b and 1c). The multidrug resistance-associated protein 2 (MRP2) was shown to be capable of LBQ657 and valsartan transport that contributes to the elimination of either compound. 3. LBQ657 and valsartan were transported by OAT1, OAT3, OATP1B1 and OATP1B3, whereas no OAT- or OATP-mediated sacubitril transport was observed. 4. The contribution of OATP1B3 to valsartan transport (73%) was appreciably higher than that by OATP1B1 (27%), Alternatively, OATP1B1 contribution to the hepatic uptake of LBQ657 (∼70%) was higher than that by OATP1B3 (∼30%). 5. None of the compounds inhibited OCT1/OCT2, MATE1/MATE2-K, P-gp, or BCRP. Sacubitril and LBQ657 inhibited OAT3 but not OAT1, and valsartan inhibited the activity of both OAT1 and OAT3. Sacubitril and valsartan inhibited OATP1B1 and OATP1B3, whereas LBQ657 weakly inhibited OATP1B1 but not OATP1B3. 6. Drug interactions due to the inhibition of transporters are unlikely due to the redundancy of the available transport pathways (LBQ657: OATP1B1/OAT1/3 and valsartan: OATP1B3/OAT1/3) and the low therapeutic concentration of the LCZ696 analytes.

Midostaurin, a Novel Protein Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia: Insights from Human Absorption, Metabolism, and Excretion Studies of a BDDCS II Drug.

The absorption, metabolism, and excretion of midostaurin, a potent class III tyrosine protein kinase inhibitor for acute myelogenous leukemia, were evaluated in healthy subjects. A microemulsion formulation was chosen to optimize absorption. After a 50-mg [14C]midostaurin dose, oral absorption was high (>90%) and relatively rapid. In plasma, the major circulating components were midostaurin (22%), CGP52421 (32.7%), and CGP62221 (27.7%). Long plasma half-lives were observed for midostaurin (20.3 hours), CGP52421 (495 hours), and CGP62221 (33.4 hours). Through careful mass-balance study design, the recovery achieved was good (81.6%), despite the long radioactivity half-lives. Most of the radioactive dose was recovered in feces (77.6%) mainly as metabolites, because only 3.43% was unchanged, suggesting mainly hepatic metabolism. Renal elimination was minor (4%). Midostaurin metabolism pathways involved hydroxylation, O-demethylation, amide hydrolysis, and N-demethylation. High plasma CGP52421 and CGP62221 exposures in humans, along with relatively potent cell-based IC50 for FMS-like tyrosine kinase 3-internal tandem duplications inhibition, suggested that the antileukemic activity in AML patients may also be maintained by the metabolites. Very high plasma protein binding (>99%) required equilibrium gel filtration to identify differences between humans and animals. Because midostaurin, CGP52421, and CGP62221 are metabolized mainly by CYP3A4 and are inhibitors/inducers for CYP3A, potential drug-drug interactions with mainly CYP3A4 modulators/CYP3A substrates could be expected. Given its low aqueous solubility, high oral absorption and extensive metabolism (>90%), midostaurin is a Biopharmaceutics Classification System/Biopharmaceutics Drug Disposition Classification System (BDDCS) class II drug in human, consistent with rat BDDCS in vivo data showing high absorption (>90%) and extensive metabolism (>90%).

Pradigastat disposition in humans: in vivo and in vitro investigations.

1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides (TG) in healthy human subjects and fasting TG in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18.4), catalyzed mainly by UDP-glucuronosyltransferases (UGT) 1A1, UGT1A3 and UGT2B7. M18.4 was observed at very low levels in human plasma. 4. In the human AME study, pradigastat was recovered in the feces as parent drug, confounding the assessment of pradigastat absorption and the important routes of elimination. However, considering pradigastat exposure after oral and intravenous dosing, this data suggests that pradigastat was completely bioavailable in the radiolabeled AME study and therefore completely absorbed. 5. Pradigastat is eliminated very slowly into the feces, presumably via the bile. Renal excretion is negligible. Oxidative metabolism is minimal. The extent to which pradigastat is eliminated via metabolism to M18.4 could not be established from these studies due to the inherent instability of glucuronides in the gastrointestinal tract.

A Rare Presentation of Indirect Hyperbilirubinemia: Coexistence of Multiple UGT1A1 Gene Variants.

Indirect hyperbilirubinemia is a common clinical finding and rarely can be attributed to Crigler-Najjar syndrome type 2 or Gilbert syndrome. This case displays a rare presentation of indirect hyperbilirubinemia in a patient with multiple UGT1A1 gene variants. We aim to discuss the complexity of multiple UGT1A1 gene variants and its effect on the degree of observed hyperbilirubinemia.

The Impact of a Paracentesis Clinic on Internal Medicine Resident Procedural Competency.

Background: Competency in paracentesis is an important procedural skill for health care practitioners caring for patients with decompensated cirrhosis. It is estimated that 97,577 paracentesis procedures were performed between 2010 and 2012 across 120 academic medical centers and 290 affiliated hospitals. Methods: Due to limitations of resources at the Central Texas Veterans Affairs Hospital, a paracentesis clinic was created to give patients improved access to this procedure which is staffed by a supervising physician and internal medicine residents. We evaluated resident competency via survey and change in the number of paracentesis procedures performed with the utilization of this clinic. Results: Thirty-three residents completed the survey. The total mean number of paracentesis sessions participated in was 4.8. It was found that during training, 79% met conditional independence in performing this procedure with a high level of comfort by rotating through this clinic. It was also found that the number of procedures performed by internal medicine residents significantly increased with the addition of this clinic. Conclusions: A dedicated paracentesis clinic with internal medicine resident involvement can increase resident paracentesis procedural independence, the number of procedures available and performed, and procedural comfort level by the end of training.

A Case of Breast Cancer Metastasizing to the Ampulla of Vater.

Secondary tumors of the ampulla of Vater are exceedingly rare and associated with relatively poor prognosis. Tumors of the ampulla are classified into four distinct subtypes based on the location and involvement of surrounding structures. Most reported cases are of renal cell or malignant skin melanoma primary with only five previously reported cases of breast primary found in a literature review. We present a 72-year-old woman with metastatic breast cancer to the ampulla of Vater as well as multiple bones. She had a history of breast cancer status post bilateral mastectomy and chemo 27 years prior. She presented to the hospital with altered mental status and was found to have an acute liver injury. Magnetic resonance cholangiopancreatography revealed a distended gallbladder and an indeterminate left retroperitoneal mass concerning for cystic or necrotic lymphadenopathy. Endoscopy then showed an edematous and erythematous periampullary region, which was biopsied and returned positive for carcinoma. Immunohistochemical staining of the retroperitoneal mass returned positive for keratin, estrogen receptor, GATA3, and MOC31 and negative for progesterone receptor, WT1, calretinin, and E-cadherin. The periampullary region's immunohistochemistry returned positive for pankeratin (AE1/AE3) and CD138 and negative for CD45 and S100, supporting a diagnosis of primary breast carcinoma. The average time from diagnosis of breast cancer to metastasis was found to be 2.5 years. Endoscopic visual presentation of metastatic cancer to the ampulla is indistinguishable from that of primary cancers. Thus, a biopsy with cytology and immunohistochemical analysis is necessary for diagnosis. Management of secondary ampullary tumors requires a multidisciplinary team, including gastroenterology, surgery, oncology, and often palliative care. Secondary tumors have been found to be treated by any combination of Whipple's resections, chemotherapy, drainage/stenting, and endoscopic ampullectomy.

Close outpatient follow-up associated with reduced readmission rates in patients with inflammatory bowel disease.

Background: Few studies have shown the effects of prompt outpatient follow-up in relation to reducing readmission rates in patients hospitalized with inflammatory bowel disease (IBD). Our study evaluated whether postdischarge follow-up was associated with fewer IBD-related readmissions. Methods: This single-center retrospective study included 477 patients with Crohn's disease (CD) or ulcerative colitis (UC) who were readmitted to our tertiary care hospital from January 1, 2016, to June 1, 2022. Rehospitalization admissions were defined as admissions that occurred within 90 days after discharge date. We used a chi-square or Fisher's exact test to test for bivariate comparisons to determine if there was an association in patients readmitted for IBD and primary care or gastroenterology follow-up at 1, 2, 3, and 4 weeks versus no follow-up. Results: In UC patients, there were 118 admissions from 2016 to 2022; 36/118 (31%) and 41/118 (34.7%) of the patients were readmitted at 30 days and 90 days, respectively. In the CD group, there were 101 (36.73%) readmissions among 277 patients, with 174 nonreadmissions (63.27%). Conclusions: Gastroenterology follow-up within 1 month was associated with reduced rates of admission in both groups (P < 0.05). This study highlights the importance of close gastroenterology follow-up for IBD-related hospitalizations.

Cholecystitis: A Rare Presentation for Diffuse Eosinophilic Granulomatosis With Polyangiitis.

Eosinophilic granulomatosis with polyangiitis is a rare disorder of small- to medium-sized vessel vasculitis that can affect a multitude of organ systems. It typically presents as asthma, with 50% of cases having some gastrointestinal involvement, but involvement of the gallbladder is very rare. We present a unique case report of a patient who presented for nonspecific symptoms, ultimately leading to a cholecystectomy, which officially histologically diagnosed them with eosinophilic granulomatosis with polyangiitis.

Factors that affect lip changes following incisor retraction in Vietnamese adults with a convex facial profile.

OBJECTIVE: This study aimed to evaluate the factors that influence lip change through the results of tooth anterior retraction by fixed orthodontic treatment in Vietnamese adult patients with a convex facial profile. MATERIALS AND METHODS: This prospective study included 32 Vietnamese adults who have convex facial profiles. Digital software measurements according to Arnett's analysis and the superimposition method were performed to evaluate the changes in dentoskeletal structures, and soft tissue variables included lip change. A multiple logistic regression model was applied with various explanatory variables to analyze the correlation. RESULTS: The study revealed a strong correlation of lip change at the site of the cervical point and incisal edge of the upper incisors, and the cervical position demonstrated a stronger correlation. The ratio between lip change and incisor retraction in patients is approximately 1:2.3 at the incisal edge and 1:1.3 at the cervical point. CONCLUSION: Lip change was associated with incisor retraction at the cervical and incisal edge, but it did not correlate with the rotation axis of the upper incisors.

Development of an inexpensive matrix-assisted laser desorption-time of flight mass spectrometry method for the identification of endophytes and rhizobacteria cultured from the microbiome associated with maize.

Many endophytes and rhizobacteria associated with plants support the growth and health of their hosts. The vast majority of these potentially beneficial bacteria have yet to be characterized, in part because of the cost of identifying bacterial isolates. Matrix-assisted laser desorption-time of flight (MALDI-TOF) has enabled culturomic studies of host-associated microbiomes but analysis of mass spectra generated from plant-associated bacteria requires optimization. In this study, we aligned mass spectra generated from endophytes and rhizobacteria isolated from heritage and sweet varieties of Zea mays. Multiple iterations of alignment attempts identified a set of parameters that sorted 114 isolates into 60 coherent MALDI-TOF taxonomic units (MTUs). These MTUs corresponded to strains with practically identical (>99%) 16S rRNA gene sequences. Mass spectra were used to train a machine learning algorithm that classified 100% of the isolates into 60 MTUs. These MTUs provided >70% coverage of aerobic, heterotrophic bacteria readily cultured with nutrient rich media from the maize microbiome and allowed prediction of the total diversity recoverable with that particular cultivation method. Acidovorax sp., Pseudomonas sp. and Cellulosimicrobium sp. dominated the library generated from the rhizoplane. Relative to the sweet variety, the heritage variety c ontained a high number of MTUs. The ability to detect these differences in libraries, suggests a rapid and inexpensive method of describing the diversity of bacteria cultured from the endosphere and rhizosphere of maize.

Stress cardiomyopathy in hospitalized patients with cancer: machine learning analysis by primary malignancy type.

AIMS: Previous studies have shown that patients with stress (Takotsubo) cardiomyopathy (SC) and cancer have higher in-hospital mortality than patients with SC alone. No studies have examined outcomes in patients with active cancer and SC compared to patients with active cancer without SC. We aimed to assess the potential association between primary malignancy type and SC and their shared interaction with inpatient mortality. METHODS AND RESULTS: We analysed SC by primary malignancy type with propensity score adjusted multivariable regression and machine learning analysis using the 2016 United States National Inpatient Sample. Of 30 195 722 adult hospitalized patients, 4 719 591 had active cancer, of whom 568 239 had SC. The mean age of patients with cancer and SC was 69.1, of which 74.7% were women. Among patients with cancer, those with SC were more likely to be female and have white race, Medicare insurance, hypertension, heart failure with reduced ejection fraction, obesity, cerebrovascular disease, anaemia, and chronic obstructive pulmonary disease (P < 0.003 for all). In machine learning-augmented, propensity score multivariable regression adjusted for age, race, and income, only lung cancer [OR 1.25; 95% CI: 1.08-1.46; P = 0.003] and breast cancer [OR 1.81; 95% CI: 1.62-2.02; P < 0.001] were associated with a significantly increased likelihood of SC. Neither SC alone nor having both SC and cancer was significantly associated with in-hospital mortality. The presence of concomitant SC and breast cancer was significantly associated with reduced mortality (OR 0.48; 95% CI: 0.25-0.94; P = 0.032). CONCLUSIONS: This analysis demonstrates that primary malignancy type influences the likelihood of developing SC. Further studies will be necessary to delineate characteristics in patients with lung cancer and breast cancer which contribute to development of SC. Additional investigation should confirm lower mortality in patients with SC and breast cancer and determine possible explanations and protective factors.

5-HT2A receptor-mediated PKCδ phosphorylation is critical for serotonergic impairments induced by p-chloroamphetamine in mice.

p-Chloroamphetamine (PCA), an amphetamine derivative, has been shown to induce serotonergic toxicity. However, the precise mechanism of serotonergic toxicity induced by PCA remains unclear. In this study, PCA treatment (20 mg/kg, i.p.) did not significantly change 5-HT1A receptor gene expression, but significantly increased 5-HT2A receptor gene expression. Furthermore, 5-HT2A receptor antagonist MDL11939, but not 5-HT1A receptor antagonist WAY100635, significantly attenuated PCA-induced serotonergic impairments. We investigated whether PCA activated a specific isoform of protein kinase C (PKC), since previous evidence indicated the involvement of PKC in neurotoxicity induced by amphetamines. We observed that PCA treatment significantly increased the expression levels of PKCδ among all PKC isoforms. MDL11939 treatment significantly attenuated PCA-induced phosphorylation of PKCδ. However, PCA-induced increase in 5-HT2A receptor gene expression was not altered by rottlerin (a pharmacological inhibitor of PKCδ) in mice, suggesting that 5-HT2A receptor is an upstream molecule for the activation of PKCδ. Rottlerin or PKCδ knockout significantly attenuated serotonergic behaviors. However, MDL11939 did not show any additional effects against the attenuation caused by PKCδ knockout in mice, suggesting that PKCδ gene is a molecular target for 5-HT2A receptor-mediated serotonergic effects. Our results suggest that 5-HT2A receptor mediates PCA-induced serotonergic impairments via activation of PKC.δ.

Disposition of vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in rats and dogs.

The pharmacokinetics, absorption, metabolism, and excretion of vildagliptin, a potent and orally active inhibitor of dipeptidyl peptidase 4, were evaluated in male rats and dogs. Vildagliptin was rapidly absorbed with peak plasma concentrations occurring between 0.5 and 1.5 h. Moderate to high bioavailability was observed in both species (45-100%). The distribution and elimination half-lives of vildagliptin were short: 0.57 h [82% of area under the plasma drug concentration-time curve (AUC)] and 8.8 h in the rat and 0.05 and 0.89 h (87% of AUC) in the dog, respectively. The volume of distribution was 1.6 and 8.6 l/kg in dogs and rats, respectively, indicating moderate to high tissue distribution. The plasma clearance of vildagliptin was relatively high for the rat (2.9 l/h/kg) and dog (1.3 l/h/kg) compared with their hepatic blood flow. The major circulating components in plasma after an intravenous or oral dose were the parent compound (rat and dog), a carboxylic acid metabolite from the hydrolysis of the amide bond M15.3 (dog), and a carboxylic acid metabolite from the hydrolysis of the cyano moiety M20.7 (rat and dog). After intravenous dosing, urinary excretion of radioactivity (47.6-72.4%) was the major route of elimination for rats and dogs as 18.9 to 21.3% of the dose was excreted into urine as unchanged parent drug. The recovery was good in both species (81-100% of the dose). Vildagliptin was mainly metabolized before excretion in both species. Similar to plasma, the most predominant metabolite in excreta was M20.7 in rats and dogs, and another major metabolite in dogs was M15.3.

Absorption, metabolism, and excretion of [14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans.

The absorption, metabolism, and excretion of (1-[[3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine (vildagliptin), an orally active and highly selective dipeptidyl peptidase 4 inhibitor developed for the treatment of type 2 diabetes, were evaluated in four healthy male subjects after a single p.o. 100-mg dose of [(14)C]vildagliptin. Serial blood and complete urine and feces were collected for 168 h postdose. Vildagliptin was rapidly absorbed, and peak plasma concentrations were attained at 1.1 h postdose. The fraction of drug absorbed was calculated to be at least 85.4%. Unchanged drug and a carboxylic acid metabolite (M20.7) were the major circulating components in plasma, accounting for 25.7% (vildagliptin) and 55% (M20.7) of total plasma radioactivity area under the curve. The terminal half-life of vildagliptin was 2.8 h. Complete recovery of the dose was achieved within 7 days, with 85.4% recovered in urine (22.6% unchanged drug) and the remainder in feces (4.54% unchanged drug). Vildagliptin was extensively metabolized via at least four pathways before excretion, with the major metabolite M20.7 resulting from cyano group hydrolysis, which is not mediated by cytochrome P450 (P450) enzymes. Minor metabolites resulted from amide bond hydrolysis (M15.3), glucuronidation (M20.2), or oxidation on the pyrrolidine moiety of vildagliptin (M20.9 and M21.6). The diverse metabolic pathways combined with a lack of significant P450 metabolism (1.6% of the dose) make vildagliptin less susceptible to potential pharmacokinetic interactions with comedications of P450 inhibitors/inducers. Furthermore, as vildagliptin is not a P450 inhibitor, it is unlikely that vildagliptin would affect the metabolic clearance of comedications metabolized by P450 enzymes.

Kainate-induced mitochondrial oxidative stress contributes to hippocampal degeneration in senescence-accelerated mice.

We have demonstrated that kainate (KA) induces a reduction in mitochondrial Mn-superoxide dismutase (Mn-SOD) expression in the rat hippocampus and that KA-induced oxidative damage is more prominent in senile-prone (SAM-P8) than senile-resistant (SAM-R1) mice. To extend this, we examined whether KA seizure sensitivity contributed to mitochondrial degeneration in these mouse strains. KA-induced seizure susceptibility in SAM-P8 mice paralleled prominent increases in lipid peroxidation and protein oxidation and was accompanied by significant impairment in glutathione homeostasis in the hippocampus. These findings were more pronounced in the mitochondrial fraction than in the hippocampal homogenate. Consistently, KA-induced decreases in Mn-SOD protein expression, mitochondrial transmembrane potential, and uncoupling protein (UCP)-2 expression were more prominent in SAM-P8 than SAM-R1 mice. Marked release of cytochrome c from mitochondria into the cytosol and a higher level of caspase-3 cleavage were observed in KA-treated SAM-P8 mice. Additionally, electron microscopic evaluation indicated that KA-induced increases in mitochondrial damage and lipofuscin-like substances were more pronounced in SAM-P8 than SAM-R1 animals. These results suggest that KA-mediated mitochondrial oxidative stress contributed to hippocampal degeneration in the senile-prone mouse.

Protective effects of extract of Cleistocalyx operculatus flower buds and its isolated major constituent against LPS-induced endotoxic shock by activating the Nrf2/HO-1 pathway.

The flower buds of Cleistocalyx operculatus are used as an important ingredient in herbal tea and herbal products in several tropical countries. However, their protective effects and underlying mechanisms on lipopolysaccharide (LPS)-induced endotoxic shock remain unclear. The aim of this study was to investigate the anti-inflammatory effects of ethanol extract of C. operculatus flower buds (ECO) and its major constituent 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) in macrophages and in an experimental LPS-induced sepsis mouse model. ECO inhibited the LPS-induced production and expression of pro-inflammatory mediators in macrophages. In an endotoxic shock mouse model, the oral administration of ECO rescued LPS-induced mortality, and attenuated LPS-induced increases in the serum levels of pro-inflammatory mediators, and damage of the lung and liver tissues. ECO increased the nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2), as well as the expression of Nrf2 target genes, including heme oxygenase-1 (HO-1), in macrophages. Similar to the effects of ECO, DMC also inhibited the LPS-induced inflammatory response in macrophages and endotoxic shock in mice, and activated the Nrf2/HO-1 pathway. In conclusion, our findings suggested that ECO and its major constituent, DMC, attenuated LPS-induced endotoxic shock by activating the Nrf2/HO-1 pathway.

Anti-inflammatory constituents from Psychotria prainii H. Lév.

One new and three known compounds were isolated from the ethanol extract of Psychotria prainii aerial parts. By means of spectroscopic methods, their structures were elucidated to be deacetylasperulosidic acid 6-ethyl ether (1), asperulosidic acid (2), asperuloside (3) and obtucarbamates C (4). The isolated compounds were evaluated for their inhibitory effect on NO production in LPS-stimulated RAW264.7 cells. Among them, compounds 2 and 4 exhibited strong effect with the IC50 values of 5.75 ± 0.85 and 6.92 ± 0.43 µM, respectively. This is the first report for the chemical composition and biological activity of P. prainii.