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.

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.

Neurometabolite Levels and Relevance to Central Sensitization in Chronic Orofacial Pain Patients: A Magnetic Resonance Spectroscopy Study.

Background: Refractory chronic pain in the orofacial region involves central sensitization (CS). However, not all chronic pain patients exhibit CS. An objective assessment of CS may be useful for pain management. Changes in the balance of excitatory and inhibitory neural activity or excessive activity of nerves and glial cells may cause CS and contribute to pain chronification. Patients and Methods: 1H-magnetic resonance spectra were acquired from the anterior cingulate cortex (ACC) and thalamus in 20 patients with chronic orofacial pain and suspected CS, and 21 healthy volunteers, using a single-voxel point-resolved spectroscopy sequence. The patients were assessed using the Central Sensitization Inventory. Results: Aspartate/total creatine (tCr) and glutathione in the ACC were significantly higher in the patient group. However, no significant difference was observed between groups in the neurometabolites measured in the thalamus. Patients also exhibited a tendency for increased gamma-aminobutyric acid (GABA)/tCr in the ACC. There were positive relationships between Central Sensitization Inventory scores and glutamate + glutamine (Glx) in the thalamus, a positive trend for Glx in the ACC and a negative relationship for GABA/tCr in the ACC. Conclusion: The high levels of aspartate/tCr and glutathione in the patient group suggest excitatory neuronal activity and hyperactivity of neurons and glial cells. The correlation analysis results suggest that excitatory and inhibitory neurometabolites are involved in the chronification of orofacial pain, including CS.

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.

Saponins are responsible for the anti-obesogenic activity of Acacia concinna.

Acacia concinna (Willd.) DC. is a medicinal plant sourced mainly from Southeast Asia. The pods of Acacia concinna (A. concinna) are a potential candidate to treat or prevent obesity; however, these medicinal attributes have not been examined in detail. In this study, the anti-obesogenic compounds in A. concinna pods were investigated. Chromatographic separation of the pod extract guided by pancreatic lipase inhibitory activity led to the isolation of saponins. Decomposition analysis of the saponins revealed their chemical composition to be acacic acid, monoterpenes, and five types of sugars (glucose, xylose, rhamnose, quinovose, arabinose). The predicted structures of the saponins from decomposition analysis were confirmed by LC-MS analysis, showing that these saponins are mixture of various derivatives of monoterpenes and sugar units. These saponins inhibited pancreatic lipase activity strongly with an IC50 of 7.9 µg/mL, and reduced lipid accumulation in 3T3-L1 adipocytes at 6.3 µg/mL. The saponins also enhanced lipolysis of 3T3-L1 adipocytes at 3.1 or 6.3 µg/mL by mediating the activity of protein kinase A and extracellular signal-regulated kinase pathways, suggesting that this mechanism is partly responsible for the observed reduction of lipid content in adipocytes. The results underline A. concinna as a potential source of the anti-obesogenic candidates for the future treatment and prevention of obesity.

Selection of Thai Medicinal Plants with Anti-Obesogenic Potential via In Vitro Methods.

The prevalence of obesity is increasing globally. Despite the availability of a variety of anti-obesogenic drugs, including therapies under clinical development, these treatments are often indicated for patients with severe obesity, making them unsuitable for patients with mild obesity or for preventative use. In Thailand, traditional remedies employing medicinal plants are widely used to maintain health and treat disease. These treatments are generally inexpensive and readily available at markets, making them good treatment options for preventing obesity. To evaluate the anti-obesogenic potential of Thai medicinal plants, we employed three in vitro methods: pancreatic lipase inhibition, lipolysis enhancement, and lipid accumulation reduction assays. Among 70 Thai medicinal plants, Eurycoma longifolia Jack, Tiliacora triandra Diels, and Acacia concinna (Willd.) DC. were selected as the most favorable candidates because they exhibited anti-obesogenic activity in all three assays. These medicinal plants are expected to have efficient anti-obesogenic effects, making them promising candidates for further study.

Silychristin derivatives conjugated with coniferylalcohols from silymarin and their pancreatic α-amylase inhibitory activity.

Silymarin is a mixture of flavonolignans extracted from the fruit of Silybum marianum (milk thistle). The latter is used as a medicinal plant to treat liver and gallbladder disorders. Recently, silymarin has been investigated for its effects against diabetes mellitus, and shown to reduce serum levels of glucose in model animals and in clinical trials. This effect can be explained mainly by the protective effect of silymarin against pancreatic beta-cells, but the involvement of other mechanisms is possible. We demonstrated the α-amylase inhibitory activity of silymarin and investigated the components responsible for this effect. Two major flavonolignans, silibinin and silychristin, did not show inhibition against α-amylase, but two novel silychristin derivatives conjugated with dehydrodiconiferyl alcohol were isolated as the mildly inhibiting components of silymarin. Further analyses indicated the presence of various silychristin derivatives in silymarin that may act synergistically to show α-amylase inhibitory activity.[Formula: see text].

Effect of osimertinib treatment on lung adenocarcinoma with squamous cell transformation harboring the T790M mutation: A case report and literature review.

We herein report a case of squamous cell transformation combined with the epidermal growth factor receptor (EGFR) mutation T790M associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in a 73-year-old male patient diagnosed with stage IVA lung adenocarcinoma. Gene alterations were analyzed by collecting and studying pleural effusion at the time of diagnosis. Examination revealed an exon 19 deletion in the EGFR gene. Following treatment with the second-generation EGFR-TKI afatinib, squamous cell carcinoma was identified by performing a re-biopsy of the recurrent site. Although the levels of cytokeratin 19 fragment, which is a tumor marker for the follow-up of squamous cell carcinoma, were increased at that point, the levels of carcinoembryonic antigen, a marker particularly associated with adenocarcinoma, remained within normal limits. The T790M mutation and the original exon 19 deletion were detected simultaneously. The patient received treatment with the third-generation EGFR-TKI osimertinib, achieving a good clinical response. These findings suggest that osimertinib is beneficial for lung adenocarcinoma patients with squamous cell transformation harboring the T790M mutation.

Quassinoids in Brucea javanica are potent stimulators of lipolysis in adipocytes.

Obesity is associated with a number of metabolic disorders. Lipolysis is the initial step in the metabolism of lipids stored in adipocytes and is therefore considered a therapeutic target for obesity. Quassinoids are unique terpenes found in plants of the Simaroubaceae family, which were recently reported to have lipolytic activity and to suppress weight gain. Brucea javanica is a plant employed in traditional medicines in Asia, which is known to contain various quassinoids. Here, we investigated the lipolytic activity of B. javanica extracts, and identified six quassinoids: brucein A, brucein B, brucein C, 3'-hydroxybrucein A, brusatol, and bruceantinol, which represent the bioactive principals. The quassinoids contained in B. javanica demonstrated lipolytic activity at nanomolar concentrations, which were an order of magnitude lower than those of the previously reported quassinoids, suggesting that they may be useful for the treatment of obesity.

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.

[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.

Incidence and predictive factors of lung cancer in patients with idiopathic pulmonary fibrosis.

The incidence and risk factors of lung cancer in patients with idiopathic pulmonary fibrosis (IPF) have been poorly investigated. We conducted a retrospective study of 632 patients with IPF to assess the incidence and risk factors of lung cancer development. Seventy patients developed lung cancer over a median follow-up period of 3.8 years. The incidence density of lung cancer development was 25.2 cases per 1000 person-years. The most frequent type was squamous cell carcinoma (30%), the majority developed lung cancer in the peripheral lung (82.9%) and adjacent to usual interstitial pneumonia (75.7%). In a multivariate Cox regression hazard model, pack-years of smoking ≥35 and coexisting emphysema were associated with lung cancer development. The 1-, 3- and 5-year all-cause mortality rates after lung cancer diagnosis were 53.5%, 78.6% and 92.9%, respectively. The incidence density of lung cancer is high in IPF patients and occurs more frequently in patients with smoking history of pack-years of smoking ≥35 and with coexisting emphysema. The majority of lung cancers develop adjacent to usual interstitial pneumonia. Knowledge of these factors may help direct efforts for early detection of lung cancer and disease management.

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.

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.

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 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.