Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed. RESULTS: In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod. CONCLUSIONS: Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.).

Cutoff of the reverse shock index multiplied by the Glasgow coma scale for predicting in-hospital mortality in adult patients with trauma: a retrospective cohort study.

BACKGROUND: Early identification of patients at risk of potential death and timely transfer to appropriate healthcare facilities are critical for reducing the number of preventable trauma deaths. This study aimed to establish a cutoff value to predict in-hospital mortality using the reverse shock index multiplied by the Glasgow Coma Scale (rSIG). METHODS: This multicenter retrospective cohort study used data from 23 emergency departments in South Korea between January 2011 and December 2020. The outcome variable was the in-hospital mortality. The relationship between rSIG and in-hospital mortality was plotted using the shape-restricted regression spline method. To set a cutoff for rSIG, we found the point on the curve where mortality started to increase and the point where the slope of the mortality curve changed the most. We also calculated the cutoff value for rSIG using Youden's index. RESULTS: A total of 318,506 adult patients with trauma were included. The shape-restricted regression spline curve showed that in-hospital mortality began to increase when the rSIG value was less than 18.86, and the slope of the graph increased the most at 12.57. The cutoff of 16.5, calculated using Youden's index, was closest to the target under-triage and over-triage rates, as suggested by the American College of Surgeons, when applied to patients with an rSIG of 20 or less. In addition, in patients with traumatic brain injury, when the rSIG value was over 25, in-hospital mortality tended to increase as the rSIG value increased. CONCLUSIONS: We propose an rSIG cutoff value of 16.5 as a predictor of in-hospital mortality in adult patients with trauma. However, in patients with traumatic brain injury, a high rSIG is also associated with in-hospital mortality. Appropriate cutoffs should be established for this group in the future.

Analgesic Effect of SH003 and Trichosanthes kirilowii Maximowicz in Paclitaxel-Induced Neuropathic Pain in Mice.

Pacliatxel is a taxol-based chemotherapeutic drug that is widely used to treat cancer. However, it can also induce peripheral neuropathy, which limits its use. Although several drugs are prescribed to attenuate neuropathies, no optimal treatment is available. Thus, in our study, we analyzed whether SH003 and its sub-components could alleviate paclitaxel-induced neuropathic pain. Multiple paclitaxel injections (cumulative dose 8 mg/kg, i.p.) induced cold and mechanical allodynia from day 10 to day 21 after the first injection in mice. Oral administration of SH003, an herbal mixture extract of Astragalus membranaceus, Angelica gigas, and Trichosantheskirilowii Maximowicz (Tk), dose-dependently attenuated both allodynia. However, when administered separately only Tk decreased both allodynia. The effect of Tk was shown to be mediated by the spinal noradrenergic system as intrathecal pretreatment with α1- and α2-adrenergic-receptor antagonists (prazosin and idazoxan), but not 5-HT1/2, and 5-HT3-receptor antagonists (methysergide and MDL-72222) blocked the effect of Tk. The spinal noradrenaline levels were also upregulated. Among the phytochemicals of Tk, cucurbitacin D was shown to play a major role, as 0.025 mg/kg (i.p.) of cucurbitacin D alleviated allodynia similar to 500 mg/kg of SH003. These results suggest that Tk should be considered when treating paclitaxel-induced neuropathic pain.

EFFICACY OF COMBINED SYSTEMIC CORTICOSTEROID AND EARLY IMMUNOMODULATORY THERAPY WITHIN THREE MONTHS OF ONSET IN VOGT-KOYANAGI-HARADA DISEASE.

PURPOSE: To evaluate the clinical outcomes of combined systemic corticosteroid and early immunomodulatory therapy (IMT) within 3 months of onset in Vogt-Koyanagi-Harada (VKH) disease compared with conventional therapy. METHODS: This retrospective observational case series included 73 eyes of 38 patients with VKH, categorized into the conventional (n = 41) and the early IMT (n = 32) groups. Clinical information was gathered from patients' medical records. Primary outcome measures were visual acuity, subfoveal choroidal thickness, and uveitis outcome including occurrence of sunset glow fundus. RESULTS: The logarithm of minimal angle of resolution visual acuity of both groups improved, with statistically significant difference at the last follow-up (P < 0.01, Mann-Whitney U test). Their mean subfoveal choroidal thickness decreased, with no statistically significant difference at the last follow-up (P = 0.21, T-test). In the conventional and early IMT groups, 27 (65.9%) and 15 (46.9%) eyes, respectively, had chronic or chronic recurrent VKH and sunset glow fundus was observed in 33 (80.5%) and 16 (50.0%) eyes, respectively. CONCLUSION: Combined systemic corticosteroid and early IMT within 3 months of onset was superior to conventional therapy in the final visual and uveitis outcome of patients with VKH disease. Therefore, IMT may be added early in cases of VKH disease, even when under control with high-dose corticosteroid.

Syringaresinol Alleviates Oxaliplatin-Induced Neuropathic Pain Symptoms by Inhibiting the Inflammatory Responses of Spinal Microglia.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a serious side effect that impairs the quality of life of patients treated with the chemotherapeutic agent, oxaliplatin. The underlying pathophysiology of OIPN remains unclear, and there are no effective therapeutics. This study aimed to investigate the causal relationship between spinal microglial activation and OIPN and explore the analgesic effects of syringaresinol, a phytochemical from the bark of Cinnamomum cassia, on OIPN symptoms. The causality between microglial activation and OIPN was investigated by assessing cold and mechanical allodynia in mice after intrathecal injection of the serum supernatant from a BV-2 microglial cell line treated with oxaliplatin. The microglial inflammatory response was measured based on inducible nitric oxide synthase (iNOS), phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated nuclear factor-kappa B (p-NF-κB) expression in the spinal dorsal horn. The effects of syringaresinol were tested using behavioral and immunohistochemical assays. We found that oxaliplatin treatment activated the microglia to increase inflammatory responses, leading to the induction of pain. Syringaresinol treatment significantly ameliorated oxaliplatin-induced pain and suppressed microglial expression of inflammatory signaling molecules. Thus, we concluded that the analgesic effects of syringaresinol on OIPN were achieved via the modulation of spinal microglial inflammatory responses.

Clinical characteristics of endogenous Klebsiella pneumoniae endophthalmitis: a 13-year experience.

PURPOSE: This study aimed to investigate the clinical features and risk factors for poor visual outcomes in patients with endogenous Klebsiella pneumoniae endophthalmitis (EKE). METHODS: This retrospective interventional case series reviewed the medical records of 17 patients (21 eyes) with EKE from January 2007 to December 2019. Clinical findings, treatments, visual outcomes, and potential prognostic factors were evaluated. RESULTS: The mean age of the patients was 55.9 years and 13 patients (76.5%) were males. Diabetes (23.5%) was the most commonly associated systemic disease and liver abscess (70.6%) was the major infection source. Poor initial visual acuity worse than counting fingers was significantly associated with poor final visual outcome (p = 0.003). In this study, adjunctive intravitreal dexamethasone injection and primary vitrectomy were not associated with final visual outcome. Secondary enucleation/evisceration was performed in 14.3%. CONCLUSIONS: EKE usually has a poor visual prognosis, and early diagnosis with fair initial visual acuity would be crucial in saving vision.

Adenosine A2B receptor down-regulates metabotropic glutamate receptor 5 in astrocytes during postnatal development.

Metabotropic glutamate receptor 5 (mGluR5) in astrocytes is a key molecule for controlling synapse remodeling. Although mGluR5 is abundant in neonatal astrocytes, its level is gradually down-regulated during development and is almost absent in the adult. However, in several pathological conditions, mGluR5 re-emerges in adult astrocytes and contributes to disease pathogenesis by forming uncontrolled synapses. Thus, controlling mGluR5 expression in astrocyte is critical for several diseases, but the mechanism that regulates mGluR5 expression remains unknown. Here, we show that adenosine triphosphate (ATP)/adenosine-mediated signals down-regulate mGluR5 in astrocytes. First, in situ Ca2+ imaging of astrocytes in acute cerebral slices from post-natal day (P)7-P28 mice showed that Ca2+ responses evoked by (S)-3,5-dihydroxyphenylglycine (DHPG), a mGluR5 agonist, decreased during development, whereas those evoked by ATP or its metabolite, adenosine, increased. Second, ATP and adenosine suppressed expression of the mGluR5 gene, Grm5, in cultured astrocytes. Third, the decrease in the DHPG-evoked Ca2+ responses was associated with down-regulation of Grm5. Interestingly, among several adenosine (P1) receptor and ATP (P2) receptor genes, only the adenosine A2B receptor gene, Adora2b, was up-regulated in the course of development. Indeed, we observed that down-regulation of Grm5 was suppressed in Adora2b knockout astrocytes at P14 and in situ Ca2+ imaging from Adora2b knockout mice indicated that the A2B receptor inhibits mGluR5 expression in astrocytes. Furthermore, deletion of A2B receptor increased the number of excitatory synapse in developmental stage. Taken together, the A2B receptor is critical for down-regulation of mGluR5 in astrocytes, which would contribute to terminate excess synaptogenesis during development.

Identification of gallic acid as a active ingredient of Syzygium aromaticum against tacrolimus-induced damage in renal epithelial LLC-PK1 cells and rat kidney.

Tacrolimus (FK506), a calcineurin inhibitor, is an effective immunosuppressive agent mainly used to lower the risk of organ rejection after allogeneic organ transplant. However, FK506-associated adverse effects, such as nephrotoxicity, may limit its therapeutic use. In this study, we confirmed that epigallocatechin-3-gallate (EGCG), sanguiin H-6, and gallic acid increased cell survival following FK506-induced cytotoxicity in renal epithelial LLC-PK1. Among these compounds, gallic acid exerted the strongest protective effect, further confirmed in the FK506-induced nephrotoxicity rat model. Additionally, we identified supporting evidence for the nephroprotective function of gallic acid using molecular docking and bioavailability investigations.

Aromatic and Aliphatic Apiuronides from the Bark of Cinnamomum cassia.

Cinnamomum cassia Presl (Cinnamon) has been widely cultivated in the tropical or subtropical areas, such as Yunnan, Fujian, Guandong, and Hainan in China, as well as India, Vietnam, Thailand, and Malaysia. Four new glycosides bearing apiuronic acid (1, 4, 6, and 7) and their sodium or potassium salts (2, 3, and 5), together with 31 known compounds, were isolated from a hot water extract of the bark of C. cassia via repeated chromatography. The structures of the new compounds (1-7) were determined by NMR, IR, MS, and ICP-AES data and by acid hydrolysis and sugar analysis. This is the first report of the presence of apiuronic acid glycosides. Some of the isolates were evaluated for their analgesic effects on a neuropathic pain animal model induced by paclitaxel. Cinnzeylanol (8), cinnacaside (9), kelampayoside A (10), and syringaresinol (11) showed analgesic effects against paclitaxel-induced cold allodynia.

CLINICAL SIGNIFICANCE OF RETINAL VASCULAR OCCLUSION IN MOYAMOYA DISEASE: Case Series and Systematic Review.

PURPOSE: Although moyamoya disease primarily affects the carotid artery in the ophthalmic artery bifurcation area, retinal vascular abnormalities in moyamoya disease have rarely been reported. The purpose of this report is to describe clinical findings of patients with retinal vascular occlusion in patients with moyamoya disease and present its clinical significance. METHODS: We reviewed and analyzed patients with moyamoya disease with retinal vascular occlusions. For this, a retrospective medical chart review was performed in a tertiary medical center and a literature search was performed using PubMed and EMBASE until September 2020. RESULTS: Patients with retinal artery occlusion (RAO) were significantly younger than patients with retinal vein occlusion (25.0 vs. 40.1 years, P = 0.023). Of 14 patients, retinal vascular occlusion was the presenting sign of moyamoya disease in 8 (57.1%) patients. The occlusion site at the carotid artery was proximal to the ophthalmic artery bifurcation area in 8 (57.1%) patients. Legal blindness occurred in 8 (57.1%) patients at final visits. CONCLUSION: Retinal vascular occlusion is a rare but sight-threatening ocular complication in patients with moyamoya disease. Overall, younger age may be a risk factor for RAO, whereas older age for retinal vein occlusion. Retinal vascular occlusion can be an important indicator of moyamoya disease screening, especially in relatively younger and healthy patients.

Characteristics of fall-related head injury versus non-head injury in the older adults.

BACKGROUND: This study aimed to examine the characteristics of older adults patients who suffered a head injury after a ground-level fall in comparison to non-head injury patients as well as the factors associated with severity in those with head injury only. METHODS: Patients were classified into two groups, the head injury group and the non-head injury group. The characteristics were compared and factors associated with head injury were evaluated. Factors relating to severe injury in the head injury group were also investigated. RESULTS: The head injury group comprised 42 % of a study subjects. Male sex; fall time of 18:00-23:59; fall location of medical facility, transportation area, and public or commercial facility; fall in an outdoor area; fall during daily activity; alcohol ingestion; fall from stairs; non-slippery floor conditions; concrete flooring; sloped flooring; and presence of obstacles on the floor were risk factors for head injury in the older adults after a ground-level fall. Male sex and age over 70 years; fall time of 00:00-05:59; fall in a residential facility; fall in an indoor area; fall during daily activity; fall from stairs; non-slippery floor conditions; and presence of obstacles on the floor were factors associated with severe injury in the head injury group. CONCLUSIONS: Male sex with advanced age, indoor fall, and the presence of obstacles on the floor were risk factors for severe injury in the head injury group in older adults individuals who suffered a ground-level fall. It is necessary to develop appropriate ground-level fall prevention programs by evaluating the individual and environmental characteristics of older adults patients.

JI017 Attenuates Oxaliplatin-Induced Cold Allodynia via Spinal TRPV1 and Astrocytes Inhibition in Mice.

Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of Aconitum carmichaelii, Angelica gigas, and Zingiber officinale. Its anti-tumor effect has been reported; however, the efficacy of JI017 against oxaliplatin-induced allodynia has never been explored. Single oxaliplatin injection [6 mg/kg, intraperitoneal, (i.p.)] induced both cold and mechanical allodynia, and oral administration of JI017 (500 mg/kg) alleviated cold but not mechanical allodynia in mice. Real-time polymerase chain reaction (PCR) analysis demonstrated that the upregulation of mRNA of spinal transient receptor potential vanilloid 1 (TRPV1) and astrocytes following oxaliplatin injection was downregulated after JI017 treatment. Moreover, TRPV1 expression and the activation of astrocytes were intensely increased in the superficial area of the spinal dorsal horn after oxaliplatin treatment, whereas JI017 suppressed both. The administration of TRPV1 antagonist [capsazepine, intrathecal (i.t.), 10 µg] attenuated the activation of astrocytes in the dorsal horn, demonstrating that the functions of spinal TRPV1 and astrocytes are closely related in oxaliplatin-induced neuropathic pain. Altogether, these results suggest that JI017 may be a potent candidate for the management of oxaliplatin-induced neuropathy as it decreases pain, spinal TRPV1, and astrocyte activation.

Zingiber officinale Roscoe Rhizomes Attenuate Oxaliplatin-Induced Neuropathic Pain in Mice.

Oxaliplatin is a platinum derivative chemotherapeutic drug widely used against cancers, but even a single treatment can induce a severe allodynia that requires treatment interruption and dose diminution. The rhizome of Zingiber officinale roscoe (Z. officinale, ginger), has been widely used in traditional medicine to treat various diseases causing pain; however, its effect against oxaliplatin-induced neuropathic pain has never been assessed. In mice, a single oxaliplatin (6 mg/kg, i.p.) treatment induced significant cold and mechanical allodynia. Cold and mechanical allodynia were assessed by acetone drop and von Frey filament tests, respectively. Water extracts of Z. officinale (100, 300, and 500 mg/kg, p.o.) significantly attenuated both cold and mechanical allodynia induced by oxaliplatin. Intrathecal pre-treatment with the antagonist 5-HT1A (NAN-190, i.t., 1 µg), but not with the antagonist 5-HT2A (ketanserin, i.t., 1 µg), significantly blocked the analgesic effect of Z. officinale against both cold and mechanical allodynia. However, 5-HT3 antagonist (MDL-72222, i.t., 15 µg) administration only blocked the anti-allodynic effect of Z. officinale against cold allodynia. Real-time PCR analysis demonstrated that Z. officinale significantly increased the mRNA expression of the spinal 5-HT1A receptor that was downregulated after oxaliplatin injection. These results suggest that Z. officinale may be a viable treatment option for oxaliplatin-induced neuropathic pain.

EFFICACY OF DOUBLE DOSE PHOTODYNAMIC THERAPY FOR CIRCUMSCRIBED CHOROIDAL HEMANGIOMA.

PURPOSE: To evaluate the efficacy of photodynamic therapy using a double dose of verteporfin for patients with circumscribed choroidal hemangioma. METHODS: This retrospective comparative case series evaluated data from 10 patients who were treated using double dose photodynamic therapy (12 mg/m) and seven patients who were treated using the standard dose (6 mg/m). A laser was applied with a radiant exposure of 50 J/cm. The ophthalmologic examinations were performed at baseline and 1 year after the treatment and included best-corrected visual acuity, slit-lamp biomicroscopy, fundus examination, spectral domain optical coherence tomography, and B-scan ultrasonography. RESULTS: The mean age in the double dose group was 51.60 years, compared with 50.57 years in the standard-dose group. The only significant difference between the two groups' baseline characteristics was observed in their initial tumor heights. Foveal center thickness, subretinal fluid, and subfoveal choroidal thickness decreased significantly at 1 year after treatment in both groups. Tumor height and the greatest linear dimension of the tumor's base only decreased significantly in the double dose group (P = 0.031). Both groups did not experience significant visual improvements. CONCLUSION: Double dose photodynamic therapy was effective and safe for treating circumscribed choroidal hemangioma and provided better tumor regression with similar resorption of subretinal fluid, compared with standard-dose photodynamic therapy.

COMPARISON OF SHORT-TERM EFFICACY BETWEEN ORAL SPIRONOLACTONE TREATMENT AND PHOTODYNAMIC THERAPY FOR THE TREATMENT OF NONRESOLVING CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To compare the short-term therapeutic efficacy of oral spironolactone treatment with that of half-dose photodynamic therapy (PDT) in patients with nonresolving central serous chorioretinopathy. METHODS: This retrospective, interventional, comparative study included 41 patients with nonresolving central serous chorioretinopathy who exhibited subretinal fluid accumulation for more than 3 months. Of the 41 patients, 18 (18 eyes) received oral spironolactone treatment and 23 (23 eyes) received half-dose PDT. Treatment outcomes, including the central macular thickness, subretinal fluid height, subfoveal choroidal thickness, and best-corrected visual acuity, were measured at baseline and 1 and 3 months after treatment. RESULTS: There were no differences in baseline characteristics between the two groups. The central macular thickness and the subretinal fluid height significantly decreased at 1 and 3 months after treatment. The central macular thickness at 1 month was lesser in the PDT group than in the spironolactone group. The subfoveal choroidal thickness decreased at 1 and 3 months only in the PDT group, whereas best-corrected visual acuity showed a significant improvement at 3 months in both groups. CONCLUSION: Our results suggest that the short-term efficacy of oral spironolactone treatment for the management of nonresolving central serous chorioretinopathy is comparable with that of half-dose PDT, with an excellent safety profile.

EFFICACY OF ADJUVANT TOPICAL DORZOLAMIDE-TIMOLOL IN PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION REFRACTORY TO ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY.

PURPOSE: To evaluate the efficacy of adjuvant topical dorzolamide-timolol in patients with neovascular age-related macular degeneration unresponsive to anti-vascular endothelial growth factor therapy. METHODS: This retrospective, interventional study included 15 patients with neovascular age-related macular degeneration refractory to anti-vascular endothelial growth factor. Patients used topical dorzolamide-timolol twice daily in the neovascular age-related macular degeneration eye and received anti-vascular endothelial growth factor therapy at each visit, with the same fixed interval and agent as before the addition of dorzolamide-timolol. Central macular thickness, maximal subretinal fluid height, and maximal pigment epithelial detachment height were measured at baseline and every visit. RESULTS: The mean follow-up period was 17.2 ± 5.5 weeks. The mean central macular thickness decreased from 383.5 µm at baseline to 298.3 µm at the final visit (P = 0.041). The mean maximal subretinal fluid height decreased from 105.0 µm at baseline to 58.3 µm at the final visit (P = 0.021). Complete resolution of subretinal fluid was observed in 3 of 11 subretinal fluid-type eyes. There was no significant change in the maximal pigment epithelial detachment height. The mean logarithm of the minimum angle of resolution visual acuity decreased from 0.61 (20/81 Snellen) at baseline to 0.66 (20/91 Snellen) at final visit, which was not significant (P = 0.314). The mean intraocular pressure decreased significantly from 14.9 mmHg at baseline to 12.3 mmHg at the final visit (P = 0.005). CONCLUSION: The use of adjuvant topical dorzolamide-timolol was effective in decreasing central macular thickness and subretinal fluid in patients with neovascular age-related macular degeneration refractory to continual fixed-interval intravitreal anti-vascular endothelial growth factor therapy, but did not result in functional improvement in this short-term study.

The Analgesic Effect of Venlafaxine and Its Mechanism on Oxaliplatin-Induced Neuropathic Pain in Mice.

The analgesic effect of venlafaxine (VLX), which is a selective serotonin and noradrenaline reuptake inhibitor (SNRI), has been observed on oxaliplatin-induced neuropathic pain in mice. Significant allodynia was shown after oxaliplatin treatment (6 mg/kg, i.p.); acetone and von Frey hair tests were used to assess cold and mechanical allodynia, respectively. Intraperitoneal administration of VLX at 40 and 60 mg/kg, but not 10 mg/kg, significantly alleviated these allodynia. Noradrenaline depletion by pretreatment of N-(2-Chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg, i.p.) blocked the relieving effect of VLX (40 mg/kg, i.p.) on cold and mechanical allodynia. However, serotonin depletion by three consecutive pretreatments of para-chlorophenylalanine (PCPA, 150 mg/kg/day, i.p.) only blocked the effect of VLX on mechanical allodynia. In cold allodynia, the α2-adrenergic antagonist idazoxan (10 µg, i.t.), but not the α1-adrenergic antagonist prazosin (10 µg, i.t.), abolished VLX-induced analgesia. Furthermore, idazoxan and 5-HT3 receptor antagonist bemesetron (MDL-72222, 15 µg, i.t.), but not prazosin or mixed 5-HT1, 2 receptor antagonist methysergide (10 µg, i.t.), abolished VLX-induced analgesia in mechanical allodynia. In conclusion, 40 mg/kg of VLX treatment has a potent relieving effect against oxaliplatin-induced neuropathic pain, and α2-adrenergic receptor, and both α2-adrenergic and 5-HT3 receptors are involved in this effect of VLX on cold and mechanical allodynia, respectively.

Neuroprotective Effects of Tetrahydrocurcumin against Glutamate-Induced Oxidative Stress in Hippocampal HT22 Cells.

In the central nervous system, glutamate is a major excitable neurotransmitter responsible for many cellular functions. However, excessive levels of glutamate induce neuronal cell death via oxidative stress during acute brain injuries as well as chronic neurodegenerative diseases. The present study was conducted to examine the effect of tetrahydrocurcumin (THC), a major secondary metabolite of curcumin, and its possible mechanism against glutamate-induced cell death. We prepared THC using curcumin isolated from Curcuma longa (turmeric) and demonstrated the protective effect of THC against glutamate-induced oxidative stress in HT22 cells. THC abrogated glutamate-induced HT22 cell death and showed a strong antioxidant effect. THC also significantly reduced intracellular calcium ion increased by glutamate. Additionally, THC significantly reduced the accumulation of intracellular oxidative stress induced by glutamate. Furthermore, THC significantly diminished apoptotic cell death indicated by annexin V-positive in HT22 cells. Western blot analysis indicated that the phosphorylation of mitogen-activated protein kinases including c-Jun N-terminal kinase, extracellular signal-related kinases 1/2, and p38 by glutamate was significantly diminished by treatment with THC. In conclusion, THC is a potent neuroprotectant against glutamate-induced neuronal cell death by inhibiting the accumulation of oxidative stress and phosphorylation of mitogen-activated protein kinases.

Effects of corn particle size on nutrient utilization in pigs evaluated under optimal and heat stress conditions.

The effects of corn particle size on nutrient digestibility and energy utilization in pigs were determined under optimal (experiment 1, 25 ± 1 °C) or heat stress (experiment 2, 37 ± 1 °C) conditions. In Exp. 1 and 2, five experimental diets were tested using a 5 × 5 Latin square design involving five barrows (Landrace × Yorkshire × Duroc, average initial body weight of 30 ± 1 kg and 45.0 ± 1.8 kg, respectively, in individual metabolic cages). Dietary treatments were as follows: 200-, 300-, 400-, 600-, 800-µm corn particle sizes obtained by mesh screens. Under optimal thermal conditions, digestibility of dry matter (DM) and crude fiber (CF) from 200-µm diet was higher (P < 0.05) compared to that from the 300-µm and 400-µm diets. The digestibility of crude protein (CP) and ether extract (EE) was the highest (P < 0.05) at the 200-µm particle size. The apparent total tract digestibility of energy was significantly higher (P < 0.05) on the 200-µm diet. Under heat stress, digestibility of CF when corn was ground to 600 µm was higher (P < 0.05) compared to 300 and 400 µm. Digestibility of NDF and ADF was the highest (P < 0.05) at 600-µm corn particle size. In conclusion, grinding corn to 200-µm corn particles had a positive effect on DM, CP, EE, and CF under optimal thermal condition, while the 600-µm corn particle size had positive effects on digestibility of CF, NDF, and ADF than 200-µm corn particle size under heat stress.

Itraconazole Attenuates Peritoneal Fibrosis Through Its Effect on the Sonic Hedgehog Signaling Pathway in Mice.

BACKGROUND: Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests that the sonic hedgehog (SHH) signaling pathway is involved in tissue fibrogenesis. Drugs that inhibit this pathway are emerging in the field of anti-fibrosis therapy. Itraconazole, an anti-fungal agent, was also recently recognized as an inhibitor of the SHH signaling pathway. In this study, we used a mouse model to investigate whether the SHH signaling pathway is involved in the development of peritoneal fibrosis and the effects of itraconazole on peritoneal fibrosis. METHODS: Peritoneal fibrosis was induced by intraperitoneal (IP) injection of 0.1% chlorhexidine gluconate (CG) solution every other day for 4 weeks, with or without itraconazole treatment (20 mg/kg, IP injection on a daily basis). Male C57BL/6 mice were divided into 4 groups: saline group, saline plus itraconazole group, CG group, and CG plus itraconazole group. Isotonic saline was administered intraperitoneally to the control group. The peritoneal tissues were evaluated for histological changes, expression of fibrosis markers, and the main components of the SHH signaling pathway. RESULTS: Peritoneal thickening was evident in the CG group and was significantly decreased by itraconazole administration (80.4 ± 7.7 vs. 28.2 ± 3.8 µm, p < 0.001). The expression of the following SHH signaling pathway components was upregulated in the CG group and suppressed by itraconazole treatment: SHH, patched, smoothened, and glioma-associated oncogene transcription factor 1. The IP injection of CG solution increased the expression of fibrosis markers such as α-smooth muscle actin and transforming growth factor-ß1 in the peritoneal tissues. Itraconazole treatment significantly decreased the expression of these markers. CONCLUSION: Our study provides the first evidence that the SHH signaling pathway may be implicated in peritoneal fibrosis. It also demonstrates that itraconazole treatment has protective effects on peritoneal fibrosis through the regulation of the SHH signaling pathway. These findings suggest that blockage of the SHH signaling pathway is a potential therapeutic strategy for peritoneal fibrosis.