Acertannin Prevented Dextran Sulfate Sodium-induced Colitis by Inhibiting the Colonic Expression of IL-23 and TNF-α in C57BL/6J Mice.

The present study investigates the effects of acertannin on colitis induced by dextran sulfate sodium (DSS) and changes in the colonic levels of the cytokines interleukin (IL)-1ß, IL-6, IL-10, IL-23, tumor necrosis factor (TNF)-α, the chemokine monocyte chemoattractant protein (MCP)-1, and vascular endothelial growth factor (VEGF).We examine the following: inflammatory colitis was induced in mice by 2% DSS drinking water given ad libitum for 7 days. Red blood cell, platelets, and leukocyte counts and hematocrit (Ht), hemoglobin (Hb), and colonic cytokine and chemokine levels were measured. The disease activity index (DAI) was lower in DSS-treated mice orally administered acertannin (30 and 100 mg/kg) than in DSS-treated mice. Acertannin (100 mg/kg) inhibited reductions in the red blood cell count and Hb and Ht levels in DSS-treated mice. Acertannin prevented DDS-induced mucosal membrane ulceration of the colon and significantly inhibited the increased colonic levels of IL-23 and TNF-α. Our findings suggest that acertannin has potential as a treatment for inflammatory bowel disease (IBD).

Long-Term Oral Administration of Piceatannol (3,5,3',4'-Tetrahydroxystilbene) Attenuates Colon Tumor Growth Induced by Azoxymethane Plus Dextran Sulfate Sodium in C57BL/6J Mice.

AIM: The effects of 3,5,3',4'-tetrahydroxystilbene (piceatannol) on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colon cancer growth and changes in IL-1ß, IL-6, tumor necrosis factor-α (cytokines), MCP-1, vascular endothelial growth factor, and PD-1 colon levels were investigated herein. METHODS: AOM (10 mg/kg, i.p.) on day 0 induced colorectal carcinogenesis. On day 3, mice were provided with water containing 1.5% (w/v) DSS ad libitum for 3 day, and this 3-day drinking protocol was repeated twice. Piceatannol (5 and 12.5 mg/kg, twice daily) was orally administered to mice for 7-, 7-, 7-, and 6-day and then discontinued for 14-, 15-, and 16-day. Cytokines, chemokine, and PD-1 colon levels were measured by the respective ELISA kits. RESULTS: In mice administered piceatannol (12.5 mg/kg), the tumor number, tumor area, and Ki-67-positive cell numbers decreased by 30.1%, 57.2%, and 89.1%, respectively, colon MCP-1 and PD-1 levels showed reductions of 43.8% and 70.9%, respectively, and COX-2-positive cell numbers declined by 60.2%. CONCLUSIONS: The inhibitory effects of piceatannol on AOM/DSS-induced colon tumor growth appear to be associated with reductions in colon MCP-1 and PD-1 levels through the downregulated expression of COX-2 in the tumor microenvironment.

Resveratrol Prevents Tumor Growth and Metastasis by Inhibiting Lymphangiogenesis and M2 Macrophage Activation and Differentiation in Tumor-associated Macrophages.

Antitumor and antimetastatic effects of resveratrol on tumor-induced lymphangiogenesis through the regulation of M2 macrophages in tumor-associated macrophages currently remain unknown. Therefore, we herein examined the effects of resveratrol on M2 macrophage activation and differentiation, and those of resveratrol-treated condition medium (CM) in M2 macrophages on vascular endothelial cell growth factor (VEGF)-C-induced migration, invasion, and tube formation by human lymphatic endothelial cells (HLECs). Resveratrol (50 µM or 5-50 µM) inhibited the production of interleukin-10 and monocyte chemoattractant protein-1 in M2 macrophages, whereas it promoted that of transforming growth factor-ß1. Resveratrol (25 and 50 µM) inhibited the phosphorylation of signal transducer and activator of transcript 3 without affecting its expression in the differentiation process of M2 macrophages. Furthermore, resveratrol-treated CM of M2 macrophages inhibited VEGF-C-induced HLEC migration, invasion, and lymphangiogenesis. Resveratrol (25 mg/kg, twice daily) inhibited tumor growth and metastasis to the lung and also reduced the area of lymphatic endothelial cells in tumors (in vivo). These results suggest that the antitumor and antimetastatic effects of resveratrol were partly due to antilymphangiogenesis through the regulation of M2 macrophage activation and differentiation.

Effects of a High-Fat or High-Sucrose Diet on Ultraviolet B Irradiation-Induced Carcinogenesis and Tumor Growth in Melanin-Possessing Hairless Mice.

We herein compared the effects of the chronic feeding of high-fat (HF), high-sucrose (HS), and low-fat/low-sucrose (control) diets on carcinogenesis following chronic ultraviolet B (UVB) irradiation in hairless mice. UVB irradiation-induced carcinogenesis was more prominent in HF diet-fed group than in control diet- and HS diet-fed groups. The HS diet group, as well as the HF diet one, showed tumor development and growth, increased skin matrix metalloproteinase (MMP) and blood plasminogen activator inhibitor-1 (PAI-1) levels, and decreased blood leptin and adiponectin levels after long-term UVB irradiation. These changes were smaller in the HS diet group than in the HF diet group. In addition, no difference was noted in the above changes between the control and HS diet groups. The increase induced in adipose tissue weight by the HF diet was markedly reduced by UVB irradiation. This result suggests that the abundant availability of lipids in hypertrophic adipose tissue may be related to tumor incidence and growth through increases in blood PAI-1 and skin MMP-9 expression levels and decreases in blood adiponectin levels by UVB irradiation. In conclusion, HF diet-induced hypertrophic adipose tissue is an important cancer risk factor that promotes UV irradiation-induced carcinogenesis and tumor growth.

Whey peptides prevent chronic ultraviolet B radiation-induced skin aging in melanin-possessing male hairless mice.

Whey proteins or peptides exhibit various actions, including an antioxidant action, an anticancer action, and a protective action against childhood asthma and atopic syndrome. The effects of orally administered whey peptides (WPs) on chronic ultraviolet B (UVB) radiation-induced cutaneous changes, including changes in cutaneous thickness, elasticity, wrinkle formation, etc., have not been examined. In this study, we studied the preventive effects of WPs on cutaneous aging induced by chronic UVB irradiation in melanin-possessing male hairless mice (HRM). UVB (36-180 mJ/cm(2)) was irradiated to the dorsal area for 17 wk in HRM, and the measurements of cutaneous thickness and elasticity in UVB irradiated mice were performed every week. WPs (200 and 400 mg/kg, twice daily) were administered orally for 17 wk. WPs inhibited the increase in cutaneous thickness, wrinkle formation, and melanin granules and the reduction in cutaneous elasticity associated with photoaging. Furthermore, it has been reported that UVB irradiation-induced skin aging is closely associated with the increase in expression of matrix metalloproteinase (MMP), vascular endothelial growth factor (VEGF), Ki-67-, and 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells. WPs also prevented increases in the expression of MMP-2 and pro-MMP-9, VEGF, and Ki-67- and 8-OHdG-positive cells induced by chronic UVB irradiation. It was found that WPs prevent type IV collagen degradation, angiogenesis, proliferation, and DNA damage caused by UVB irradiation. Overall, these results demonstrate the considerable benefit of WPs for protection against solar UV-irradiated skin aging as a supplemental nutrient.

Effects of morroniside isolated from Cornus officinalis fruits on functional gastrointestinal disorders and gastric ulcer in mice.

The dried fruits of Cornus officinalis (Cornaceae) are used in Kampo medicine (e.g. Hachimigan and Goshajinkigan) to treat senile osteoporosis, diabetes, gastric atony, frequent urination, and diarrhea/constipation associated with aging. The present study investigated the effects of a C. officinalis fruit extract and morroniside, an iridoid compound from isolated these fruits, on the reduction in gastric emptying small intestinal motility caused by 5-hydroxytryptamine (5-HT) and 1-(3-chlorophenyl) biguanide (5-HT3 receptor agonist), and gastric ulcers induced by 150 or 75 mM HCl/90 % EtOH (HCl-EtOH) and/or 5-HT in mice. C. officinalis extract (500 mg/kg) and morroniside (20 and 50 mg/kg) suppressed the reduction in gastric emptying induced by 5-HT- and 5-HT3 agonist. C. officinalis extract, morroniside and 5-HT3 receptor antagonist (ramosetron) attenuated 5-HT-induced diarrhea. Furthermore, morroniside (20 and 50 mg/kg) prevented EtOH/HCl-induced gastric ulcers and those caused by 5-HT. Morroniside (20 and 50 mg/kg) attenuated elevations in the plasma levels of corticosterone, corticotropin-releasing factor (CRF), and adrenocorticotropic hormone (ACTH) in 75 mM HCl/90 % EtOH- and 5-HT-treated mice. The results obtained herein suggest the potential of morroniside as an effective treatment for irritable bowel syndrome, such as diarrhea and functional dyspepsia (reductions in gastric emptying and small intestinal motility), caused by 5-HT. The present study suggests a role for morroniside in the regulation of elevations in CRF, ACTH, and corticosterone levels through hypothalamic-pituitary-adrenal axis activity induced by stress loading, such as a 5-HT treatment and/or HCl/EtOH stimulation.

Hop (Humulus lupulus L.) extract inhibits obesity in mice fed a high-fat diet over the long term.

Hops (Humulus lupulus L.) are traditionally used to add bitterness and flavour to beer. Although the isomerised hop extracts produced by the brewing process have been thought to ameliorate lipid and glucose metabolism, the influence of untreated hop extracts on high-fat (HF) diet-induced obesity is unclear. The present study examined the anti-obesity effects of a hop extract in male C57BL/6J mice fed a HF diet, or HF diet plus 2 or 5 % hop extract for 20 weeks. The oral glucose tolerance test was performed at week 19. Furthermore, water excretion was evaluated in water-loaded Balb/c male mice. The effects of the extract on lipid accumulation and PPARγ expression in 3T3-L1 adipocytes were examined. The hop extract inhibited the increase in body and adipose tissue weight, adipose cell diameter and liver lipids induced by the HF diet. Furthermore, it improved glucose intolerance. The extract enhanced water excretion in water-loaded mice. Various fractions of the hop extract inhibited lipid accumulation and PPARγ expression in 3T3-L1 adipocytes. Hop extracts might be useful for preventing obesity and glucose intolerance caused by a HF diet.

Acertannin prevents azoxymethane/dextran sulfate sodium-induced colon cancer growth by inhibiting the colonic expression of interleukin-1ß, monocyte chemoattractant protein-1, cyclooxygenase-2, and thymocyte selection-associated high mobility group box proteins (TOX)/TOX2 in C57BL/6J mice.

Colon cancer was the second leading cause of cancer-related death in 2019. We herein investigated the effects of acertannin containing Acer species on azoxymethane (AOM)/dextran sulfate sodium (DDS)-induced colon cancer growth and changes in the colonic levels of interleukin (IL)-1ß, monocyte chemoattractant protein (MCP)-1, IL-10, and programmed cell death-1 (PD-1). Colorectal carcinogenesis was induced by an intraperitoneal injection of AOM (10 mg/kg) on days 0 and 27. Mice were given 1% (w/v) DSS drinking water ad libitum on days 7-14, 32-33, and 35-38. Acertannin (30 and 100 mg/kg) was orally administered on days 1-16, discontinued for 11 days (days 16-26), and then administered again on days 27-41. The colonic levels of cytokines, a chemokine, and PD-1 were measured using the respective ELISA kits. The number and area of tumors in mice treated with acertannin (100 mg/kg) decreased by 53.9 and 63.1%, respectively. Furthermore, the colonic levels of IL-1ß, MCP-1, IL-10, and PD-1 showed reductions of 57.3, 62.9, 62.8, and 100%, respectively, while the numbers of cyclooxygenase-2 (COX-2)-, thymocyte selection-associated high mobility group box proteins (TOX)/TOX2-, PD-1-, and signal transducer and activator of transcription 3 (STAT3) phosphorylation-positive numbers decreased by 79.6, 77.9, 93.8, and 100%, respectively. In conclusion, the inhibitory effects of acertannin on AOM/DSS-induced colon tumor growth appear to be associated with reductions in the colonic levels of IL-1ß, MCP-1, IL-10, and PD-1 through the down-regulated expression of COX-2 and TOX/TOX2 in the tumor microenvironment.

Geniposide prevents tumor growth by inhibiting colonic interleukin-1ß and monocyte chemoattractant protein-1 via down-regulated expression of cyclooxygenase-2 and thymocyte selection-associated high mobility box proteins TOX/TOX2 in azoxymethane/dextran sulfate sodium-treated mice.

Colon cancer was the second leading cause of cancer-related deaths in Japan in 2019. The effects of geniposide isolated from Gardenia jasminoides fructus (Rubiaceae) on the azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced growth of colon tumors and changes in interleukin (IL)-1 ß, monocyte chemoattractant protein (MCP)-1, IL-10, and programmed cell death-1 (PD-1) levels in the colon were investigated. The intraperitoneal administration of AOM (10 mg/kg) on days 0 and 27 induced colorectal carcinogenesis. Free access to 1% (w/v) DSS drinking water was given to mice on days 7-15, 32-33, and 35-38. Geniposide (30 and 100 mg/kg) was orally administered on days 1-16, discontinued for 11 days (days 16 to 26), and then administered again on days 27-41. Colonic levels of cytokines, chemokine, and PD-1 were measured using by enzyme-linked immunosorbent assay (ELISA). Increases in colorectal tumor numbers and areas were significantly inhibited by geniposide. In addition, geniposide (100 mg/kg) reduced colonic levels of IL-1 ß, MCP-1, PD-1 and IL-10 by 67.4, 57.2, 100%, and 100% respectively. Cyclooxygenase (COX)-2- and thymocyte selection high mobility group box proteins (TOX/TOX2)-positive cell numbers were significantly reduced by geniposide. Geniposide (30 and 100 mg/kg) decreased the phosphorylation of signal transducer and activator of transcription 3 (STAT3) expressions in immunohistochemical analysis by 64.2 and 98.2%, respectively. Thus, the inhibitory effects of geniposide on colon tumor growth may be associated with reductions in the colonic levels of IL-1 ß, MCP-1, IL-10, and PD-1 via the down-regulated expression of COX-2 and TOX/TOX2 through the inhibition of Phospho-STAT3 expression (in vivo and in vitro).

Effects of ginsenoside Rb1 on skin changes.

Ginseng roots (Panax ginseng CA Meyer) have been used traditionally for the treatment, especially prevention, of various diseases in China, Korea, and Japan. Both experimental and clinical studies suggest ginseng roots to have pharmacological effects in patients with life-style-related diseases such as non-insulin-dependent diabetic mellitus, atherosclerosis, hyperlipidemia, and hypertension. The topical use of ginseng roots to treat skin complaints including atopic suppurative dermatitis, wounds, and inflammation is also described in ancient Chinese texts; however, there have been relatively few studies in this area. In the present paper, we describe introduce the biological and pharmacological effects of ginsenoside Rb1 isolated from Red ginseng roots on skin damage caused by burn-wounds using male Balb/c mice (in vivo) and by ultraviolet B irradiation using male C57BL/6J and albino hairless (HR-1) mice (in vivo). Furthermore, to clarify the mechanisms behind these pharmacological actions, human primary keratinocytes and the human keratinocyte cell line HaCaT were used in experiments in vitro.

Recovery of psychomotor function after total intravenous anesthesia with remifentanil-propofol or fentanyl-propofol.

PURPOSE: Total intravenous anesthesia (TIVA) with propofol combined with remifentanil or fentanyl has commonly been used to achieve general anesthesia. The purpose of this study was to examine recovery of psychomotor function, by use of the Trieger dot test, after TIVA with remifentanil-propofol or with fentanyl-propofol. METHODS: Forty patients were randomly divided into two groups of 20, to receive TIVA with either remifentanil-propofol (group R) or fentanyl-propofol (group F). Anesthesia was induced by intravenous injection of propofol. In group R, remifentanil at 0.3 µg/kg/min was infused continuously during surgery. In group F, 3 µg/kg fentanyl was injected as an initial dose and 1 µg/kg fentanyl was administered intravenously every 30 min during surgery. Psychomotor function, as measured by the Trieger dot test, was evaluated before anesthesia and 30, 60, 90, 120, and 150 min after the end of TIVA. RESULTS: From assessment of the Trieger dot test, the number of dots missed in group R from 30 to 120 min after the end of TIVA was significantly lower than in group F. The maximum distance of dots missed in group R from 30 to 120 min after the end of TIVA was significantly shorter than in group F. The average distance of dots missed in group R from 30 to 120 min after the end of TIVA was significantly shorter than in group F. CONCLUSION: Recovery of psychomotor function in TIVA with remifentanil-propofol is faster than that in TIVA with fentanyl-propofol.

Two hydroxyflavanones isolated from Scutellaria baicalensis roots prevent colitis-associated colon cancer in C57BL/6 J mice by inhibiting programmed cell death-1, interleukin 10, and thymocyte selection-associated high mobility group box proteins TOX/TOX2.

BACKGROUND: Colorectal cancer was the second leading cause of mortality in 2019 and the number of new colorectal cancer cases was the highest in 2018 and 2019 in Japan. PURPOSE: The present study investigated the inhibitory effects of 2(S)-2',5,6',7-tetrahydroxyflavanone and 2 (R), 3(R)-2',3,5,6'-7-pentahydroxyflavanone on the incidence and growth of tumors in azoxymethane (AOM) plus dextran sulfate sodium (DSS)-treated mice. METHODS: The intraperitoneal administration of AOM (10 mg/kg) on day 0 induced colorectal carcinogenesis. Mice were given free and unlimited access to drinking water containing 1.5% (w/v) DSS on days 5 - 8, 30 - 33, and 56 - 57. They were orally administered tetra- and penta-hydroxyflavanones (10 and 30 mg/kg) for 10, 11, and 14 days followed by discontinuation intervals of 20 and 15 days. Cytokine, chemokine, programmed cell death-1 (PD-1), cyclooxygenase (COX)-2, and thymocyte selection-associated high mobility group box protein (TOX)/TOX2 expression levels were measured using their respective ELISA kits and an immunohistochemical analysis. RESULTS: The number and area of tumors decreased by 60.6 and 72.9% in mice administered 10 mg/kg tetra- and pentahydroxyflavanones, respectively, with reductions of 95.0 and 87.0% in Ki-67-positive cells, 91.7 and 92.7% in COX-2-postive cells, and 83.1 and 93.8% in TOX/TOX2-positive cells, respectively, in the colon. On the other hand, two tera- and pentahydroxyflavanone had no effect on p53 (a tumor suppressor by cell cycle arrest and apoptosis)-positive cells. The administration of 10 mg/kg tetra- and pentahydroxyflavanones to AOM/DSS-treated mice also resulted in decreases of 59.5 and 42.5% in IL-10 levels and 58.1 and 93.9% in PD-1 levels, respectively, in the colon. CONCLUSION: The inhibitory effects of tetra- and pentahydroxyflavanones on the growth of colon tumors in AOM/DSS-treated mice appear to be associated with decreases in the colon levels of IL-10 and PD-1 through the down-regulated expression of COX-2 and CD8+ T-cell exhaustion by TOX/TOX2 in the tumor microenvironment.

Evidence of late root formation of molars in Anderson's red-backed vole, Eothenomysandersoni (Thomas, 1905) (Cricetidae, Rodentia), and arguments for its generic allocation.

We evaluated the molars in Anderson's red-backed vole (n = 114) from the Kii Peninsula of Honshu, Japan. Two of the specimens are considered extremely old aged based on their dimensions and on the loss of alveolar capsules of M2, and a third one is also old based on its strongly worn left M3 and M1. Of the former two individuals, one showed an incipient closure of re-entrant angles at its basal end, as estimated from the difference between the occlusal patterns of the occlusal and basal surfaces of the left M2. The latter individual also showed a complete closure of the basal end in the left M3. These patterns differ from incipient roots observed in other vole taxa but were similar to a previous example of incipient roots in Anderson's red-backed vole. Therefore, we suggest that molar roots in this species form at an extremely late age or by strong wear. Root formation in molars is considered an important diagnostic character, as Eothenomys molars lack roots, while Craseomys molars develop roots at a late age. However, this dental character may be particularly difficult to assess in voles under natural conditions. Considering previous phylogenetic findings based on molecular analyses, Craseomys is the most appropriate genus for Anderson's and other Asiatic red-backed voles.

QT dispersion and rate-corrected QT dispersion during electroconvulsive therapy in elderly patients.

BACKGROUND: Electroconvulsive therapy (ECT) induces increase of QT dispersion (QTD) and the rate-corrected QTD (QTcD), which are associated with increased risk of ventricular arrhythmias and cardiovascular mortality. The effects of electrical stimulus during ECT on QTD and QTcD in elderly patients are of considerable interest. OBJECTIVE: The purpose of this study was to clarify the differential effects of electrical stimulus caused by ECT on interbeat interval, QT interval, the rate-corrected QT (QTc) interval, QTD, and the QTcD under propofol anesthesia between younger and elderly patients with major depression. METHODS: Twenty younger psychiatric patients (aged 30-40 years) and 20 elderly patients (aged 65-75 years) scheduled for ECT were studied under propofol anesthesia. A 12-lead electrocardiogram was monitored to measure parameters. Muscle paralysis was achieved by administering 1-mg/kg succinylcholine intravenously, and the efficacy of ECT was determined by the tourniquet technique. RESULTS: The mean arterial pressure in the elderly was significantly higher than that of the younger patients from immediately to 2 minutes after electrical stimulus. The interbeat interval in the elderly was significantly lower than that of the younger patients from immediately to 1 minute after electrical stimulus. There was no statistically significant difference in the QT interval between the groups. The baseline value of QTc interval was higher than the normal limits, and the QTc interval in the elderly was significantly lower than that of the younger patients from immediately to 1 minute after electrical stimulus. The baseline value of QTD was higher than the normal limits, and the QTD in the elderly was significantly higher than that of the younger patients from immediately to 7 minutes after electrical stimulus. The baseline value of QTcD was higher than the normal limits, and the QTcD in the elderly was significantly higher than that of the younger patients from immediately to 7 minutes after electrical stimulus. CONCLUSIONS: The QTc interval, QTD, and QTcD may be higher than the normal limits before anesthesia in patients with major depression. The QTD and QTcD in the elderly, which are associated with increased risks of ventricular arrhythmias, are higher than those of the younger patients after electrical stimulus during ECT. Electrical stimulus may induce further increased risks of cardiac events in elderly patients.

Assessment of the ECG T-Wave in Patients With Subarachnoid Hemorrhage.

BACKGROUND: Prolongation of the interval from the peak to the end of the T wave (Tp-Te) on a 12-lead electrocardiogram (ECG) is associated with ventricular arrhythmias. The aim of this study was to clarify associations between Tp-Te, Tp-Te/QT, and Tp-Te/rate-corrected QT (QTc) with clinical severity of subarachnoid hemorrhage (SAH) and clinical outcomes. METHODS: This retrospective study included 222 patients with acute SAH (group S) and 306 patients with unruptured cerebral aneurysms (group U). Tp-Te, Tp-Te/QT, and Tp-Te/QTc were manually measured in standard 12-lead ECG recordings on admission and comparisons made between patients in groups S and U. The relationships of these ECG parameters with Hunt and Hess grade and Glasgow outcome scale were analyzed using multiple logistic regression analysis after adjustment for confounding factors. RESULTS: Tp-Te, Tp-Te/QT, and Tp-Te/QTc were significantly greater in group S than in group U (group S: 109±30, 0.26±0.07, and 0.24±0.06 ms; group U: 84±12, 0.22±0.03, and 0.21±0.03 ms, respectively; P < 0.0001). In addition, in the multiple logistic regression analyses these variables were positively correlated with the Hunt and Hess grade (Tp-Te odds ratio [95% confidence interval], 2.414 [1.375-4.238], P=0.002; Tp-Te/QT, 1.886 [1.085-3.277], P = 0.024; Tp-Te/QTc, 1.873 [1.07-3.278], P=0.028, and negatively correlated with Glasgow outcome scale Tp-Te odds ratio [95% confidence interval], 4.168 [2.409-7.209], P<0.001; Tp-Te/QT, 2.434 [1.413-4.192], P=0.001; Tp-Te/QTc 2.953 [1.703-5.123], P<0.001). CONCLUSIONS: Tp-Te, Tp-Te/QT, and Tp-Te/QTc are associated with disease severity and clinical outcome in patients with SAH.

Switching From Pregabalin to Mirogabalin in Patients with Peripheral Neuropathic Pain: A Multi-Center, Prospective, Single-Arm, Open-Label Study (MIROP Study).

INTRODUCTION: Mirogabalin, which is a selective ligand of the α2δ subunit of voltage-gated Ca2+ channels, was recently approved in Japan for peripheral neuropathic pain. The α2δ ligands, including mirogabalin and pregabalin, are associated with significant risk of adverse events (AEs) such as somnolence or dizziness, leading to poor compliance and subsequent inefficacy. Safety and efficacy data for switching patients from pregabalin to mirogabalin are scarce. METHODS: This prospective, single-arm, open-label study involving ten participating centers in Japan recruited patients aged ≥ 20 years with peripheral neuropathic pain [visual analog scale (VAS) score ≥ 40 mm]. Where necessary, patients underwent a 1-week tapering period to reduce their pregabalin dose, after which pregabalin was stopped and mirogabalin dose was increased using a step-wise dose titration. Patients underwent dose increases after the first and second weeks if there were no tolerability issues, followed by the effective doses until the end of the study (4 weeks). The primary endpoint was the incidence of somnolence, dizziness, and peripheral edema; secondary endpoints included changes in VAS score. AEs were monitored for safety. RESULTS: Of 157 patients who provided informed consent, 152 patients were enrolled; 136 (89.5%) patients completed the study. The overall incidences of somnolence, dizziness, and peripheral edema were 41.4, 15.8, and 2.6%, respectively. Most patients (> 70%) experienced mild AEs, and one patient experienced a severe AE (dizziness). Most patients (> 70%) were able to achieve dose titration to an effective dose. Overall mean VAS score significantly decreased (Δ15.7 mm, p < 0.0001) by the end of the study. CONCLUSIONS: Mirogabalin switching from pregabalin is well tolerated and effective in pain management for peripheral neuropathic pain using a step-wise titration. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031190113).

Chronic intake of a high-cholesterol diet resulted in hepatic steatosis, focal nodular hyperplasia and fibrosis in non-obese mice.

We investigated the effects of a high-cholesterol (HC) diet administered long term (25 or 55 weeks) on metabolic disorders including hepatic damage in mice. The mice were fed the HC diet (15 % milk fat, 1.5 % cholesterol and 0.1 % cholic acid, w/w) for 25 or 55 weeks. Body and adipose tissue weights were similar to those of mice fed a control diet. Consumption of the HC diet long term resulted in hypercholesterolaemia, hepatic steatosis and gallstones. In addition, focal nodular hyperplasia (FNH) and mild fibrosis of the liver developed in all mice fed the HC diet for 55 weeks. Plasma levels of monocyte chemoattractant protein (MCP)-1 were elevated, and the level of hepatic platelet-derived growth factor (PDGF)-B protein was increased in mice fed the HC diet compared with those fed the control diet. Thus, it seems likely that the liver fibrosis and FNH caused by the long-term consumption of a HC diet may be partly due to an elevation of plasma MCP-1 and hepatic PDGF expression.

Effects of olive leaf extract and its main component oleuroepin on acute ultraviolet B irradiation-induced skin changes in C57BL/6J mice.

Olive (Olea europaea L.) leaves have long been used in folk medicine and herbal tea in Europe and the Mediterranean area. The Mediterranean climate is characterized by high temperatures, and by strong ultraviolet B (UVB) radiation causing the skin to age, increasing wrinkling, pigmentation and skin thickness. The aim of this study was to examine the effects of an olive leaf extract and its component oleuropein on skin damage caused by acute UVB irradiation in C57BL/6J mice. The extract (300 or 1000 mg/kg) and oleuropein (25 or 85 mg/kg) were administered orally twice daily for 14 days. UVB was administered daily at a dose of 120 mJ/cm(2) for the first 5 days and then every other day for 9 days. Both treatments inhibited the increases in skin thickness induced by radiation. They also inhibited increases in the Ki-67- and 8-hydroxy-2'-deoxyguanosine-positive cell numbers, melanin granule area and matrix metalloproteinase-13 (MMP-13) expression. These preventive effects on UVB-induced skin damage might be caused in part by inhibiting the degradation of extracellular matrixes in the corium, and by the proliferation of epidermal cells through the inhibition of increases in MMP-13 levels and reactive oxygen species induced by irradiation.

Dihydroxystilbenes prevent azoxymethane/dextran sulfate sodium-induced colon cancer by inhibiting colon cytokines, a chemokine, and programmed cell death-1 in C57BL/6J mice.

The incidence of colon cancer increased worldwide in 2019 and its treatment is urgent from a quality of life perspective. A relationship has been reported between elevated numbers of tumor-associated macrophages (TAMs) in the tumor microenvironment and a poor prognosis in cancer patients, and M2 TAMs have been shown to promote tumor growth by immunosuppression through the stimulation of programmed death-1 (PD-1, an immune check point receptor), interleukin (IL)-1ß, and monocyte chemoattractant protein (MCP)-1. We herein examined the effects of three synthetic dihydroxystilbenes (2,3-, 3,4-, and 4,4'-dihydroxystilbenes) on colon carcinogenesis, colon tumor growth, and colon cytokines (IL-1ß, IL-6, and tumor necrosis factor (TNF)-α), a chemokine (MCP-1), vascular endothelial growth factor (VEGF), and PD-1 levels in azoxymethane (AOM) plus dextran sulfate sodium (DSS)-treated C57BL/6J mice. The three dihydroxystilbenes inhibited colon carcinogenesis and tumor growth as well as increases in colon IL-1ß, IL-6, MCP-1, and PD-1 levels in AOM/DDS-treated mice (in vivo). The three dihydroxystilbenes also suppressed COX-2 expression in colon tumors (in vivo). The results obtained also revealed that the three dihydroxystilbenes inhibited PD-1 elevations in M2-THP-1 macrophages (in vitro). Therefore, the inhibition of AOM/DSS-induced colon carcinogenesis and colon tumor growth by 2,3-, 3,4-, and 4,4'-dihydroxystilbenes appears to be due to the suppression of M2 TAM differentiation and activation and PD-1 expression (immunosuppression) via reductions in COX-2 expression levels in the colon tumor microenvironment.

Olive leaf extract and its main component oleuropein prevent chronic ultraviolet B radiation-induced skin damage and carcinogenesis in hairless mice.

Chronic exposure to solar UV radiation damages skin, increasing its thickness and reducing its elasticity, and causes skin cancer. Our aim in this study was to examine the effects of an olive leaf extract and its component oleuropein on skin damage and the incidence of skin tumors caused by long-term UVB irradiation in hairless mice. Male hairless mice (5 wk old) were divided into 6 groups, including a non-UVB group, a vehicle-treated UVB group (control), 2 olive leaf extract-treated UVB groups, and 2 oleuropein-treated UVB groups. Five groups were UVB irradiated (36-180 mJ/cm(2)) 3 times each week for 30 wk and skin thickness and elasticity after UVB irradiation were measured every week. Olive leaf extract (300 and 1000 mg/kg) and oleuropein (10 and 25 mg/kg) were administered orally twice daily every day for 30 wk. The extract and oleuropein significantly inhibited increases in skin thickness and reductions in skin elasticity, and skin carcinogenesis and tumor growth. Furthermore, they prevented increases in the expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13 as well as in levels of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) in the skin. Based on histological evaluation, they prevented increases in the expression of Ki-67 and CD31-positive cells induced by the irradiation. These results suggest that the preventative effects of the olive leaf extract and oleuropein on chronic UVB-induced skin damage and carcinogenesis and tumor growth may be due to inhibition of the expression of VEGF, MMP-2, MMP-9, and MMP-13 through a reduction in COX-2 levels.