Effectiveness of opioid switching for dyspnea and its predictors in cancer patients: a single-center retrospective observational study.

BACKGROUND: Morphine is the most used opioid for dyspnea, but other opioids such as oxycodone and fentanyl are increasingly used, and opioid switching to these is sometimes undertaken. No studies have verified the effectiveness of opioid switching for relief of dyspnea. We retrospectively investigated the effectiveness of opioid switching for dyspnea and its predictors. METHODS: All patients with opioid switching for dyspnea during hospitalization at Komaki City Hospital from January 2019 to August 2022 were included. Opioid switching was defined as a change to another opioid, and the assessment period for evaluating the effectiveness and adverse events of opioid switching was set as 1 week. Patients with Numeric Rating Scale or Japanese version of the Support Team Assessment Schedule reduction for dyspnea of at least 1, or with clear improvement based on medical records, were considered valid. Mitigating factors for dyspnea were identified using logistic regression analysis. RESULTS: Of the 976 patients with opioid switching, 57 patients had opioid switching for relief of dyspnea. Of these, opioid switching was effective in 21 patients (36.8%). In a multivariate analysis, older patients (odds ratio: 5.52, 95% CI: 1.50-20.20, P < 0.01), short prognosis for post-opioid switching (odds ratio: 0.20, 95% CI: 0.04-0.87, P = 0.03) and cachexia (odds ratio: 0.12, 95% CI: 0.02-0.64, P < 0.01) were significantly associated with opioid switching effects for dyspnea. There were no serious adverse events after opioid switching. CONCLUSION: This study indicates that opioid switching for dyspnea may have some effect. Furthermore, opioid switching for dyspnea may be more effective in older patients and less effective in terminally ill patients or in those with cachexia.

α-Tocotrienol in rice bran enhances steroidogenesis in mouse Leydig cell via increased gene expression of steroidogenic acute regulatory protein and induction of its mitochondrial translocation.

Rice is a staple food in the Asian region and one of the world's major energy sources. Testosterone is a steroid hormone that maintains physical, sexual, and cognitive ability, and its decline causes health problems like late-onset hypogonadism. Evaluation of various grain extracts showed rice bran to stimulate testosterone secretion from Leydig model cells. α-Tocotrienol was found as a bioactive compound in rice bran, and mechanistic analysis showed the stimulation of steroid hormone synthesis through enhanced gene expression of steroidogenic acute regulatory protein as well as inducing mitochondrial localization of the protein. Preliminary study showed an increasing trend in serum testosterone levels in mice by oral intake of α-tocotrienol. These results suggest that α-tocotrienol intake may be effective in preventing symptoms caused by low testosterone levels.

Murine fecal microRNAs alter the composition of cultured gut microbiota.

Fecal microRNAs (miRNAs) derived from intestinal epithelial cells have been suggested to influence gut microbiota homeostasis. The present study examined whether fecal miRNAs alter the structure of cultured gut microbiota. Fecal bacteria isolated from murine cecal contents were cultured for 24 h under anaerobic conditions. Supplementation with fecal small RNAs isolated from cecal contents altered the structure of cultured fecal microbiota as assessed by 16S rRNA gene sequence analysis. In particular, fecal small RNAs increased Enterococcus spp. Fractionation of fecal small RNAs by ultrafiltration showed that small RNAs smaller than 10 kDa significantly increased enterococci compared to those larger than 10 kDa, as assessed by quantitative PCR, suggesting that the increase in enterococci by fecal small RNAs can mainly be attributed to miRNAs. Negative control miRNA that has low homology to miRNA sequences of human, mouse, and rat, failed to increase enterococci. Therefore, the findings from the present study employing cultured fecal bacteria suggest that fecal small RNAs, most likely host-derived miRNAs, alter gut microbiota structure by expanding enterococci in a sequence-dependent manner.

Taste 2 Receptor Is Involved in Differentiation of 3T3-L1 Preadipocytes.

Expression of taste 2 receptor (T2R) genes, also known as bitter taste receptor genes, has been reported in a variety of tissues. The white adipose tissue of mice has been shown to express Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, but the function of T2Rs in adipocytes remains unclear. Here, we show that fasting and stimulation by bitter compounds both increased Tas2r expression in mouse white adipose tissue, and serum starvation and stimulation by bitter compounds both increased the expression of Tas2r genes in 3T3-L1 adipocytes, suggesting that T2Rs have functional roles in adipocytes. RNA sequencing analysis of 3T3-L1 adipocytes stimulated by epicatechin, the ligand of Tas2r126, suggested that this receptor may play a role in the differentiation of adipocytes. Overexpression of Tas2r126 in 3T3-L1 preadipocytes decreases fat accumulation after induction of differentiation and reduces the expression of adipogenic genes. Together, these results indicate that Tas2r126 may be involved in adipocyte differentiation.

Proteinous pancreatic lipase inhibitor is responsible for the antiobesity effect of young barley (Hordeum vulgare L.) leaf extract.

Young barley leaves (Hordeum vulgare L.) have various health effects and are employed as an ingredient in the production of health-promoting foods. Promoting antiobesity is one such health effect; however, the mechanism and bioactive compounds are unclear. In this research, young barley leaf extract (YB) was demonstrated to possess pancreatic lipase inhibitory activity. The addition of YB to a high-fat diet in mice increased fecal lipid content, indicating reduced absorption of lipids as the mechanism underlying antiobesity effect. The investigation of bioactive compounds in YB resulted in the identification of fructose-bisphosphate aldolase as a proteinous lipase inhibitor. Maximum inhibition of the protein was 45%, but inhibition was displayed at a concentration as low as 16 ng/mL, which is a characteristic inhibition compared with other reported proteinous lipase inhibitors.

Bioactive compounds in plant materials for the prevention of diabetesand obesity.

Plant materials have been widely studied for their preventive and therapeutic effects for type 2 diabetes mellitus (T2DM) and obesity. The effect of a plant material arises from its constituents, and the study of these bioactive compounds is important to achieve a deeper understanding of its effect at the molecular level. In particular, the study of the effects of such bioactive compounds on various biological processes, from digestion to cellular responses, is required to fully understand the overall effects of plant materials in these health contexts. In this review, I summarize the bioactive compounds we have recently studied in our research group that target digestive enzymes, dipeptidyl peptidase-4, myocyte glucose uptake, and lipid accumulation in adipocytes. Abbreviations: AC: adenylyl cyclase; AMPK: AMP-activated protein kinase; ßAR: ß-adrenergic receptor; CA: catecholamine; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; DPP-4: dipeptidyl peptidase-4; ERK: extracellular signal-regulated kinase; GC: guanylyl cyclase; GH: growth hormone; GLP-1: glucagon-like peptide-1; GLUT: glucose transporter; HSL: hormone-sensitive lipase; IR: insulin receptor; IRS: insulin receptor substrate; MAPK: mitogen-activated protein kinase; MEK: MAPK/ERK kinase; MG: maltase-glucoamylase; NP: natriuretic peptide; NPR: natriuretic peptide receptor; mTORC2: mechanistic target of rapamycin complex-2; PC: proanthocyanidin; PI3K: phosphoinositide 3-kinase; PKA: cAMP-dependent protein kinase; PKB (AKT): protein kinase B; PKG: cGMP-dependent protein kinase; PPARγ: peroxisome proliferator-activated receptor-γ; SGLT1: sodium-dependent glucose transporter 1; SI: sucrase-isomaltase; T2DM: type 2 diabetes mellitus; TNFα: tumor necrosis factor-α.

Macrocarpal C isolated from Eucalyptus globulus inhibits dipeptidyl peptidase 4 in an aggregated form.

Dipeptidyl peptidase 4 (DPP-4) inhibitors are used for the treatment of type-2 diabetes mellitus. Various synthetic inhibitors have been developed to date, and plants containing natural DPP-4 inhibitors have also been identified. Here, 13 plant samples were tested for their DPP-4 inhibitory activity. Macrocarpals A-C were isolated from Eucalyptus globulus through activity-guided fractionation and shown to be DPP-4 inhibitors. Of these, macrocarpal C showed the highest inhibitory activity, demonstrating an inhibition curve characterised by a pronounced increase in activity within a narrow concentration range. Evaluation of macrocarpal C solution by turbidity, nuclear magnetic resonance spectroscopy and mass spectrometry indicated its aggregation, which may explain the characteristics of the inhibition curve. These findings will be valuable for further study of potential small molecule DPP-4 inhibitors.

[PROBLEMS ASSOCIATED WITH THE DIAGNOSIS OF PROLONGED/CHRONIC COUGH IN CLINICAL SETTINGS].

BACKGROUND: Many patients visit primary care clinics or local hospitals with a complaint of prolonged/chronic cough. Among the different types of chronic cough, cough variant asthma (CVA) and postinfectious cough may be the most common types, and their differential diagnosis is difficult. Some physicians tend to prescribe inhaled corticosteroids before establishing a definitive diagnosis. METHODS: We retrospectively investigated useful findings for diagnosis in 77 patients with a complaint of prolonged/ chronic cough to detect meaningful findings for differential diagnosis and to identify problems associated with diagnosis in clinical practice. RESULTS: CVA was diagnosed in 39 patients, and postinfectious cough was diagnosed in 19. Compared with postinfectious cough, CVA was associated with significant characteristics such as "diurnal variation of symptoms," "response to inhalation of short acting ß2 agonist (SABA)," and "recurrent episodes of symptoms." CVA was associated with high FeNO levels as well, and high FeNO levels were specific to CVA. However, these useful characteristics were not significant in the patients who had been prescribed ICS before visiting our hospital. CONCLUSIONS: Medical examination and determination of FeNO levels are useful for the differential diagnosis of prolonged/chronic cough, before treatment with ICS.

Ability of higenamine and related compounds to enhance glucose uptake in L6 cells.

ß2-Adrenergic receptor (ß2AR) agonists are employed as bronchodilators to treat pulmonary disorders, but are attracting attention for their modulation of glucose handling and energy expenditure. Higenamine is a tetrahydroisoquinoline present in several plant species and has ß2AR agonist activity, but the involvement of each functional groups in ß2AR agonist activity and its effectiveness compared with endogenous catecholamines (dopamine, epinephrine, and norepinephrine) has rarely been studied. Glucose uptake of muscle cells are known to be induced through ß2AR activation. Here, the ability to enhance glucose uptake of higenamine was compared with that of several methylated derivatives of higenamine or endogenous catecholamines. We found that: (i) the functional groups of higenamine except for the 4'-hydroxy group are required to enhance glucose uptake; (ii) higenamine shows a comparable ability to enhance glucose uptake with that of epinephrine and norepinephrine; (iii) the S-isomer shows a greater ability to enhance glucose uptake compared with that of the R-isomer.

Isolation and lipolytic activity of eurycomanone and its epoxy derivative from Eurycoma longifolia.

Eurycomanone (1) and 13ß,21-epoxyeurycomanone (2) were isolated from Eurycoma longifolia for studies of lipolytic activity. Compound 1 enhanced lipolysis in adipocytes with an EC50 of 14.6µM, while its epoxy derivate, compound 2, had a stronger activity with an EC50 of 8.6µM. Based on molecular mechanistic study using several specific inhibitors to lipolytic signaling pathways, it was found that PKA inhibitor totally diminished the lipolytic activity of 1 and 2. Further immunoblotting analysis confirmed the activation of phosphorylated PKA by both 1 and 2. With the growing need to develop new anti-obesity agents, eurycomanone and its epoxy derivate can be used as promising lead compounds to target lipid catabolism.

Astilbe thunbergii reduces postprandial hyperglycemia in a type 2 diabetes rat model via pancreatic alpha-amylase inhibition by highly condensed procyanidins.

Type 2 diabetes mellitus (T2DM) is a common global health problem. Prevention of this disease is an important task, and functional food supplements are considered an effective method. We found potent pancreatic α-amylase inhibition in Astilbe thunbergii root extract (AT) and confirmed that AT treatment in a T2DM rat model reduces post-starch administration blood glucose levels. Activity-guided isolation revealed procyanidin (AT-P) as the α-amylase inhibitory component with IC50 = 1.7 µg/mL against porcine pancreatic α-amylase. Structure analysis of AT-P revealed it is a B-type procyanidin comprised of four types of flavan-3-ols, some with a galloyl group, and catechin attached as the terminal unit. The abundant AT-P content and its comparable α-amylase inhibition to acarbose, the anti-diabetic medicine, suggest that AT is a promising food supplement for diabetes prevention.

Synthesis and Detailed Examination of Spectral Properties of (S) and (R)-Higenamine 4'-O-ß-d-Glucoside and HPLC Analytical Conditions to Distinguish the Diastereomers.

Higenamine is a tetrahydroisoquinoline present in several plants that has ß-adrenergic receptor agonist activity. Study of the biosynthesis of higenamine has shown the participation of norcoclaurine synthase, which controls the stereochemistry to construct the (S)-isomer. However, when isolated from nature, higenamine is found as the racemate, or even the (R)-isomer. We recently reported the isolation of higenamine 4'-O-ß-d-glucoside. Herein, its (R)- and (S)-isomers were synthesized and compared to precisely determine the stereochemistry of the isolate. Owing to their similar spectral properties, determination of the stereochemistry based on NMR data was considered inappropriate. Therefore, a high-performance liquid chromatography method was established to separate the isomers, and natural higenamine 4'-O-ß-d-glucoside was determined to be a mixture of isomers.

Isolation of rugosin A, B and related compounds as dipeptidyl peptidase-IV inhibitors from rose bud extract powder.

Dipeptidyl peptidase-IV (DPP-IV) is a protease responsible for the degradation of the incretin hormone. A number of DPP-IV inhibitors have been approved for use in the treatment of type 2 diabetes. While these inhibitors are effective for this treatment, methods for the prevention of this disease are also required as diabetes patient numbers are currently increasing rapidly worldwide. We screened the DPP-IV inhibitory activities of edible plant extracts with the intention of using these extracts in a functional food supplement for the prevention of diabetes. Rose (Rosa gallica) bud extract powder was a promising material with high inhibitory activity. In this study, seven ellagitannins were isolated as active compounds through activity-guided fractionations, and their DPP-IV inhibitory activities were measured. Among them, rugosin A and B showed the highest inhibitory activities and rugosin B was shown as the major contributing compound in rose bud extract powder.

Overexpression of microRNA-155 suppresses chemokine expression induced by Interleukin-13 in BEAS-2B human bronchial epithelial cells.

BACKGROUND: MicroRNAs are non-coding small RNAs that regulate expression of target genes by binding to 3' untranslated regions. In this study, we used bronchial epithelial cells to investigate in vitro the role of the microRNA miR-155 in the expression of chemokines associated with airway inflammation. miR-155 has previously been reported to regulate allergic inflammation. METHODS: BEAS-2B bronchial epithelial cells were cultured and transfected with mimic or inhibitor oligonucleotides to overexpress or downregulate miR-155, as confirmed by real-time PCR. Cells were then stimulated with tumor necrosis factor-alpha, interleukin-13 (IL-13), and a double stranded RNA that binds Toll-like receptor 3. Expression and secretion of the chemokines CCL5, CCL11, CCL26, CXCL8, and CXCL10 were then quantified by real-time PCR and ELISA, respectively. Phosphorylation of signal transducer and activator of transcription 6 (STAT6), a target of the IL-13 receptor, was analyzed by ELISA. RESULTS: miR-155 overexpression significantly suppressed IL-13-induced secretion of CCL11 and CCL26. These effects were specific, and were not observed for other chemokines, nor in cells with downregulated miR-155. miR-155 overexpression also suppressed CCL11 and CCL26 mRNA, but did not affect expression of the IL-13 receptor or phosphorylation of STAT6. CONCLUSIONS: miR-155 specifically inhibits IL-13-induced expression of eosinophilic chemokines CCL11 and CCL26 in bronchial epithelial cells, even though the 3'-untranslated region of these genes do not contain a consensus binding site for miR-155.

Higenamine 4'-O-ß-d-glucoside in the lotus plumule induces glucose uptake of L6 cells through ß2-adrenergic receptor.

Hypoglycemic effect is an efficient means to modulate elevated blood glucose levels in patients with diabetes. We found that the extract of lotus plumule (the germ of Nelumbo nucifera Gaertn. seed) showed potent glucose uptake enhancement activity against L6 myotubes, which results in a hypoglycemic effect. This activity was further investigated, and an active constituent was identified as a single bioactive compound, higenamine 4'-O-ß-d-glucoside. Mechanistic studies employing phosphatidylinositol 3-kinase (PI3K) inhibitor, AMP-activated protein kinase (AMPK) inhibitor, or adrenergic receptor antagonist showed that the compound induced its activity through ß2-adrenergic receptor. Patients with type II diabetes mellitus frequently develop insulin resistance. Owing to the differences between the mechanism of action of insulin and of the isolated compound, the compound or lotus plumule itself may have the possibility of modulating blood glucose levels in insulin-resistant patients effectively.

Hydroxylamine enhances glucose uptake in C2C12 skeletal muscle cells through the activation of insulin receptor substrate 1.

Diabetes mellitus is a global disease, and the number of patients with it is increasing. Of various agents for treatment, those that directly act on muscle are currently attracting attention because muscle is one of the main tissues in the human body, and its metabolism is decreased in type II diabetes. In this study, we found that hydroxylamine (HA) enhances glucose uptake in C2C12 myotubes. Analysis of HA's mechanism revealed the involvement of IRS1, PI3K and Akt that is related to the insulin signaling pathway. Further investigation about the activation mechanism of insulin receptor or IRS1 by HA may provide a way to develop a novel anti-diabetic agent alternating to insulin.

Clinical features and outcomes of aspiration pneumonia compared with non-aspiration pneumonia: a retrospective cohort study.

Pneumonia is a leading cause of death among elderly patients. Although aspiration pneumonia (AP) commonly occurs with aging, its clinical features and outcomes are still uncertain. The aims of this study were to describe the clinical features and outcomes of AP and to assess whether presence of AP affects clinical outcomes in patients with community-acquired pneumonia (CAP) and healthcare-associated pneumonia (HCAP). We retrospectively analyzed patients with CAP and HCAP hospitalized in our institution in Japan from October 2010 to March 2012. We compared clinical features and outcomes between AP and non-AP, and investigated risk factors for recurrence of pneumonia and death. Of 214 consecutive patients, 100 (46.7%) were diagnosed as having aspiration pneumonia. These patients were older and had lower body mass index, more comorbidities, and poorer Eastern Cooperative Oncology Group performance status (ECOG PS) than the patients with non-AP. Patients with AP had more severe disease, required longer hospital stays, and had a frequent recurrence rate of pneumonia and higher mortality. In multivariate analyses, AP, age, and ECOG PS were related to recurrence of pneumonia, and the prognostic factors were CURB-65 score and ECOG PS. AP was not a significant indicator for prognosis but was the strongest risk factor for recurrence of pneumonia. Clinical background and outcomes including recurrence and mortality of AP were obviously different from those of non-AP; therefore AP should be considered as a distinct subtype of pneumonia, and it is important to prevent the recurrence of pneumonia in the patients with AP.

Flavan-3-ols, flavonoids, anthocyanidins and triterpenoids induces TIE2 phosphorylation -a candidate target for the vascular protective effects.

Vascular system is essential for the body to maintain health. Dysregulated vascular system leads to cardiovascular diseases and are observed in ischaemic stroke, Alzheimer's disease, amyotrophic lateral sclerosis, and diabetes. TIE2 is a tyrosine kinase receptor expressed on vascular endothelial cells and contributes to the maintenance of a vascular system. In this paper, we screened for natural products with an activity to induce phosphorylation of TIE2, which will be beneficial for protection of a vascular system. Employing HeLa cells expressing TIE2, flavan-3-ols, flavonoids, anthocyanidins and triterpenoids were identified as active compounds that induce TIE2 phosphorylation. Several of the identified compounds are previously reported to protect endothelial cells from inflammation. Thus, the result provided TIE2 as the candidate receptor protein of those compounds for the protective effect of endothelial cells and the identified compounds will be a good candidate for maintenance of a vascular system.

Substrate-like water soluble lipase inhibitors from Filipendula kamtschatica.

Filipendula kamtschatica is a plant utilized as a traditional medicine by Ainu people in Japan, but its chemical constituents are not much studied. Pancreatic lipase inhibitors are a promising tool for the treatment of obesity. We searched for natural lipase inhibitors from F. kamtschatica and two new compounds were isolated along with the known flavonoid glycoside. The structure elucidation of new compounds revealed these two to be 2-O-caffeoyl-4-O-galloyl-L-threonic acid and 3-O-caffeoyl-4-O-galloyl-L-threonic acid, which can be recognized as a pancreatic lipase's substrate-like structure. The isolated compounds all showed an inhibitory activity against porcine pancreatic lipase and one of the isomer, 3-O-caffeoyl-4-O-galloyl-L-threonic acid, possessed the most potent activity with IC(50) value showing an order lower value compared to others. The substrate-like structure of the new compounds seemed to be important for their activity.

Synthesis and the intestinal glucosidase inhibitory activity of 2-aminoresorcinol derivatives toward an investigation of its binding site.

2-Aminoresorcinol is a potent and selective intestinal glucosidase inhibitor. Unlike the majority of glucosidase inhibitors, it shows an uncompetitive mode of inhibition. In this study, we tested the intestinal glucosidase inhibitory activity of various 2-aminoresorcinol derivatives. We found that structural changes, in amino and two phenolic hydroxyl groups had a negative impact on inhibitory activity, but methylation of the phenolic hydroxyl group was found to maintain its activity and replacement of the aromatic ring with an acyl or alkoxy carbonyl group at the 4th position also retained its activity. This enable us to design a molecular probe for further study of the inhibition mechanism of 2-aminoresorcinol.