Tropisetron Protects Against Acetaminophen-Induced Liver Injury via Suppressing Hepatic Oxidative Stress and Modulating the Activation of JNK/ERK MAPK Pathways

Objectives. To investigate the protective effects of tropisetron on acetaminophen- (APAP-) induced liver injury in a mice model.Methods. C57BL/6 male mice were given tropisetron (0.3 to 10 mg/kg) 30 minutes before a hepatotoxic dose of acetaminophen (300 mg/kg) intraperitoneally. Twenty hours after APAP intoxication, sera alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, hepatic myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) activities, and liver histopathological changes were examined. The MAP kinases were also detected by western blotting.Results. Our results showed that tropisetron pretreatment significantly attenuated the acute elevations of the liver enzyme ALT level, hepatic MPO activity, and hepatocytes necrosis in a dose-dependent manner (0.3–10 mg/kg) in APAP-induced hepatotoxicity mice. Tropisetron (1 and 3 mg/kg) suppressed APAP-induced hepatic lipid peroxidation expression and alleviated GSH and SOD depletion. Administration of tropisetron also attenuated the phosphorylation of c-Jun-NH2-terminal protein kinase (JNK) and extracellular signal-regulated kinase (ERK) caused by APAP.Conclusion. Our data demonstrated that tropisetron’s hepatoprotective effect was in part correlated with the antioxidant, which were mediated via JNK and ERK pathways on acetaminophen-induced liver injury in mice.

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Hepatoprotective effects of Sapium sebiferum in paracetamol-induced liver injury

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v10i2.22576 ◽

2015 ◽

Vol 10 (2) ◽

pp. 393 ◽

Cited By ~ 3

Author(s):

Liaqat Hussain ◽

Muhammad Sajid Hamid Akash ◽

Madeha Tahir ◽

Kanwal Rehman

Keyword(s):

Liver Injury ◽

Serum Levels ◽

Therapeutic Effects ◽

Sapium Sebiferum ◽

Dependent Manner ◽

Protective Effects ◽

Drug Induced ◽

Standard Drug ◽

Hepatoprotective Effects ◽

Dose Dependent

Sapium sebiferum leaves were used to determine its hepatoprotective effects against paracetamol-induced hepatotoxicity in mice. A dose dependent study was conducted using two different doses (200 mg/kg and 400 mg/kg) of the extract of S. sebiferum against toxic effects of paracetamol (500 mg/kg) in experimental animal model. Silymarin (50 mg/kg) was used as standard drug to compare therapeutic effects of S. sebiferum with control and paracetamol-treated groups. Paracetamol significantly increased the serum levels of liver enzyme markers like alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, and direct bilirubin. The extract showed protective effects by normalizing the liver enzymes markers in a dose dependent manner. Histopathological results confirmed the hepatoprotective effects of leaves of S. sebiferum. We conclude that leaves of S. sebiferum have strong hepatoprotective effects against paracetamol-induced liver injury and can be used in liver injuries caused by drug-induced toxicity.

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Involvement of the extracellular signal-regulated kinase 1/2 signaling pathway in amylin's eating inhibitory effect

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00380.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. R340-R351 ◽

Cited By ~ 32

Author(s):

Catarina Soares Potes ◽

Christina Neuner Boyle ◽

Peter John Wookey ◽

Thomas Riediger ◽

Thomas Alexander Lutz

Keyword(s):

Area Postrema ◽

Inhibitory Effect ◽

Dependent Manner ◽

Neuronal Responses ◽

Extracellular Signal Regulated Kinase ◽

Erk Phosphorylation ◽

Extracellular Signal ◽

Anorectic Effect ◽

Feeding Trials ◽

Dose Dependent

Peripheral amylin inhibits eating via the area postrema (AP). Because amylin activates the extracellular-signal regulated kinase 1/2 (ERK) pathway in some tissues, and because ERK1/2 phosphorylation (pERK) leads to acute neuronal responses, we postulated that it may be involved in amylin's eating inhibitory effect. Amylin-induced ERK phosphorylation (pERK) was investigated by immunohistochemistry in brain sections containing the AP. pERK-positive AP neurons were double-stained for the calcitonin 1a/b receptor, which is part of the functional amylin-receptor. AP sections were also phenotyped using dopamine-β-hydroxylase (DBH) as a marker of noradrenergic neurons. The effect of fourth ventricular administration of the ERK cascade blocker U0126 on amylin's eating inhibitory action was tested in feeding trials. The number of pERK-positive neurons in the AP was highest ∼10–15 min after amylin treatment; the effect appeared to be dose-dependent (5–20 μg/kg amylin). A portion of pERK-positive neurons in the AP carried the amylin-receptor and 22% of the pERK-positive neurons were noradrenergic. Pretreatment of rats with U0126 decreased the number of pERK-positive neurons in the AP after amylin injection. U0126 also attenuated the ability of amylin to reduce eating, at least when the animals had been fasted 24 h prior to the feeding trial. Overall, our results suggest that amylin directly stimulates pERK in AP neurons in a time- and dose-dependent manner. Part of the AP neurons displaying pERK were noradrenergic. At least under fasting conditions, pERK was shown to be a necessary part in the signaling cascade mediating amylin's anorectic effect.

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Almost nontoxic tetrodotoxin analog, 5,6,11-trideoxytetrodotoxin, as an olfactory chemoattractant for the grass puffer

10.1101/2021.09.12.459881 ◽

2021 ◽

Author(s):

Yasuhisa Noguchi ◽

Takehisa Suzuki ◽

Keigo Matsutani ◽

Ryota Nakahigashi ◽

Yoshiki Satake ◽

...

Keyword(s):

Sensory Neurons ◽

Olfactory Sensory Neurons ◽

Dependent Manner ◽

Behavioral Experiments ◽

Extracellular Signal Regulated Kinase ◽

Behavioral Studies ◽

Defense Substance ◽

Extracellular Signal ◽

Dose Dependent ◽

Fluorescent Dextran

Toxic puffers contain the potent neurotoxin, tetrodotoxin (TTX). Although TTX is considered to serve as a defense substance, previous behavioral studies have demonstrated that TTX (extracted from the ovary) acts as an attractive pheromone for some toxic puffers. To determine the putative pheromonal action of TTX, we examined whether grass puffers (Takifugu alboplumbeus) can detect TTX using electrophysiological, morphological, and behavioral experiments. Electroolfactogram results suggest that the olfactory epithelium of grass puffers responded in a dose-dependent manner to a type of TTX analog (5,6,11-trideoxyTTX), although it did not respond to TTX. We also examined the attractive action of 5,6,11-trideoxyTTX on grass puffers by recording their swimming behavior under dark conditions. Grass puffers preferred to stay on the side of the aquarium where 5,6,11-trideoxyTTX was administered, and their swimming speed decreased. Additionally, odorant-induced labeling of olfactory sensory neurons using a fluorescent dextran conjugate or immunohistochemistry against phosphorylated extracellular signal regulated kinase (pERK) revealed that labeled olfactory sensory neurons were localized in the region surrounding "islets" where there was abundant cilia on the olfactory lamella. 5,6,11-trideoxyTTX has been known to accumulate in grass puffers, but its toxicity is much lower (almost nontoxic) than TTX. Our results suggest that grass puffers can detect 5,6,11-trideoxyTTX using their nose and may positively use this functionally unknown TTX analog as an olfactory chemoattractant.

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Curcumin Induces Cross-Regulation Between Autophagy and Apoptosis in Uterine Leiomyosarcoma Cells

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e31828c9581 ◽

2013 ◽

Vol 23 (5) ◽

pp. 803-808 ◽

Cited By ~ 27

Author(s):

Bin Li ◽

Takashi Takeda ◽

Kenji Tsuiji ◽

Tze Fang Wong ◽

Mari Tadakawa ◽

...

Keyword(s):

Cell Proliferation ◽

Western Blotting ◽

Uterine Leiomyosarcoma ◽

Dependent Manner ◽

Inhibitory Effects ◽

Extracellular Signal Regulated Kinase ◽

Sequestosome 1 ◽

Extracellular Signal ◽

Experimental Findings ◽

Dose Dependent

ObjectiveUterine leiomyosarcoma (LMS) has an unfavorable response to standard chemotherapy. A natural occurring compound, curcumin, has been shown to have inhibitory effects on cancers. We previously demonstrated that curcumin reduced uterine LMS cell proliferation by targeting the AKT-mTOR pathway and activating apoptosis. To further explore the anticancer effect of curcumin, we investigated the efficacy of curcumin on autophagy in LMS cells.MethodsCell proliferation in human uterine LMS cell lines, SKN and SK-UT-1, was assessed after exposure to rapamycin or curcumin. Autophagy was detected by Western blotting for light chain 3 and sequestosome 1 (SQSTM1/p62) expression. Apoptosis was confirmed by Western blotting for cleaved poly (ADP-ribose) polymerase (PARP).ResultsBoth rapamycin and curcumin potently inhibited SKN and SK-UT-1 cell proliferation in a dose-dependent manner. Curcumin induced autophagy and apoptosis in SKN and SK-UT-1 cells, whereas rapamycin, a specific mTOR inhibitor, did not. Curcumin increased extracellular signal-regulated kinase 1/2 activity in both SKN and SK-UT-1 cells, whereas PD98059, an MEK1 inhibitor, inhibited both the extracellular signal-regulated kinase 1/2 pathway and curcumin-induced autophagy.ConclusionsThese experimental findings suggest that curcumin is a potent inhibitor of cell proliferation in uterine LMS and provide new insights about ongoing signaling events leading to the possible development of a new therapeutic agent.

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Anti-Melanogenic Effect of Chestnut Spike Extract through Downregulation of Tyrosinase-Related Proteins and Activation of ERK 1/2

Natural Product Communications ◽

10.1177/1934578x1801300825 ◽

2018 ◽

Vol 13 (8) ◽

pp. 1934578X1801300

Author(s):

Jung-Hee Byeon ◽

Md Badrul Alam ◽

Ki-Chan Kim ◽

Sangsun Heo ◽

Ji-young Lim ◽

...

Keyword(s):

Specific Inhibitor ◽

Phenotypic Trait ◽

Dependent Manner ◽

Melanin Content ◽

Extracellular Signal Regulated Kinase ◽

Extracellular Signal ◽

Key Factor ◽

Related Proteins ◽

Dose Dependent ◽

Mitf Expression

Melanin has been reported to be the key factor for skin homeostasis. Besides defining an important human phenotypic trait, melanin overproduction may cause various disorders such as vitiligo, Addison's disease, Cushing's syndrome, and melasma. In this study, we aimed to investigate the anti-melanogenic potential of dried spike extract of chestnut. The extract inhibited tyrosinase (TYR) activity in a dose-dependent manner. Cellular melanin content decreased markedly after treatment with the extract. The spike extract inhibited microphthalmia-associated transcription factor (MITF) expression and downregulated TYR, TYRP-1, and TYRP-2 protein expression by increasing the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 signalling pathway in melan-a cells. In addition, treatment with U0126, a specific inhibitor of ERK, restored melanin content. Collectively, these results suggest that the chestnut spike extract attenuated melanogenesis by inhibiting MITF expression and downregulating TYR, TYRP-1, and TYRP-2 protein expressions via activation of ERK1/2 pathway.

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ERK Signaling Pathway Plays a Key Role in Baicalin Protection Against Acetaminophen-Induced Liver Injury

The American Journal of Chinese Medicine ◽

10.1142/s0192415x17500082 ◽

2017 ◽

Vol 45 (01) ◽

pp. 105-121 ◽

Cited By ~ 19

Author(s):

Chia-Chih Liao ◽

Yuan-Ji Day ◽

Hung-Chen Lee ◽

Jiin-Tarng Liou ◽

An-Hsun Chou ◽

...

Keyword(s):

Liver Injury ◽

Signaling Pathway ◽

Inflammatory Responses ◽

Erk Signaling ◽

Dependent Manner ◽

Protective Effects ◽

Beneficial Effects ◽

Apap Overdose ◽

Scutellariae Radix ◽

Extracellular Signal

Acetaminophen (APAP) overdose causes hepatocytes necrosis and acute liver failure. Baicalin (BA), a major flavonoid of Scutellariae radix, has potent hepatoprotective properties in traditional medicine. In the present study, we investigated the protective effects of BA on a APAP-induced liver injury in a mouse model. The mice received an intraperitoneal hepatotoxic dose of APAP (300[Formula: see text]mg/kg) and after 30[Formula: see text]min, were treated with BA at concentrations of 0, 15, 30, or 60[Formula: see text]mg/kg. After 16[Formula: see text]h of treatment, the mice were sacrificed for further analysis. APAP administration significantly elevated the serum alanine transferase (ALT) enzyme levels and hepatic myeloperoxidase (MPO) activity when compared with control animals. Baicalin treatment significantly attenuated the elevation of liver ALT levels, as well as hepatic MPO activity in a dose- dependent manner (15–60[Formula: see text]mg/kg) in APAP-treated mice. The strongest beneficial effects of BA were seen at a dose of 30[Formula: see text]mg/kg. BA treatment at 30[Formula: see text]mg/kg after APAP overdose reduced elevated hepatic cytokine (TNF-[Formula: see text] and IL-6) levels, and macrophage recruitment around the area of hepatotoxicity in immunohistochemical staining. Significantly, BA treatment can also decrease hepatic phosphorylated extracellular signal-regulated kinase (ERK) expression, which is induced by APAP overdose. Our data suggests that baicalin treatment can effectively attenuate APAP-induced liver injury by down-regulating the ERK signaling pathway and its downstream effectors of inflammatory responses. These results support that baicalin is a potential hepatoprotective agent.

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Necroptosis protects against exacerbation of acute pancreatitis

Cell Death and Disease ◽

10.1038/s41419-021-03847-w ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Michittra Boonchan ◽

Hideki Arimochi ◽

Kunihiro Otsuka ◽

Tomoko Kobayashi ◽

Hisanori Uehara ◽

...

Keyword(s):

Acute Pancreatitis ◽

Necrotizing Pancreatitis ◽

Neutrophil Infiltration ◽

Dependent Manner ◽

Protective Effects ◽

Interacting Protein ◽

Inflammatory Conditions ◽

Edematous Pancreatitis ◽

Genetic Deletion ◽

Dose Dependent

AbstractThe sensing of various extrinsic stimuli triggers the receptor-interacting protein kinase-3 (RIPK3)-mediated signaling pathway, which leads to mixed-lineage kinase-like (MLKL) phosphorylation followed by necroptosis. Although necroptosis is a form of cell death and is involved in inflammatory conditions, the roles of necroptosis in acute pancreatitis (AP) remain unclear. In the current study, we administered caerulein to Ripk3- or Mlkl-deficient mice (Ripk3−/− or Mlkl−/− mice, respectively) and assessed the roles of necroptosis in AP. We found that Ripk3−/− mice had significantly more severe pancreatic edema and inflammation associated with macrophage and neutrophil infiltration than control mice. Consistently, Mlkl−/− mice were more susceptible to caerulein-induced AP, which occurred in a time- and dose-dependent manner, than control mice. Mlkl−/− mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment.

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VEGF Mediates Retinal Müller Cell Viability and Neuroprotection through BDNF in Diabetes

Biomolecules ◽

10.3390/biom11050712 ◽

2021 ◽

Vol 11 (5) ◽

pp. 712

Author(s):

Yun-Zheng Le ◽

Bei Xu ◽

Ana J. Chucair-Elliott ◽

Huiru Zhang ◽

Meili Zhu

Keyword(s):

Specific Protein ◽

Müller Cell ◽

Dependent Manner ◽

Vascular Abnormalities ◽

Extracellular Signal ◽

Muller Cell ◽

Protein Kinase Akt ◽

Sirna Knockdown ◽

Endothelial Growth Factor ◽

Dose Dependent

To investigate the mechanism of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in Müller cell (MC) viability and neuroprotection in diabetic retinopathy (DR), we examined the role of VEGF in MC viability and BDNF production, and the effect of BDNF on MC viability under diabetic conditions. Mouse primary MCs and cells of a rat MC line, rMC1, were used in investigating MC viability and BDNF production under diabetic conditions. VEGF-stimulated BDNF production was confirmed in mice. The mechanism of BDNF-mediated MC viability was examined using siRNA knockdown. Under diabetic conditions, recombinant VEGF (rVEGF) stimulated MC viability and BDNF production in a dose-dependent manner. rBDNF also supported MC viability in a dose-dependent manner. Targeting BDNF receptor tropomyosin receptor kinase B (TRK-B) with siRNA knockdown substantially downregulated the activated (phosphorylated) form of serine/threonine-specific protein kinase (AKT) and extracellular signal-regulated kinase (ERK), classical survival and proliferation mediators. Finally, the loss of MC viability in TrkB siRNA transfected cells under diabetic conditions was rescued by rBDNF. Our results provide direct evidence that VEGF is a positive regulator for BDNF production in diabetes for the first time. This information is essential for developing BDNF-mediated neuroprotection in DR and hypoxic retinal diseases, and for improving anti-VEGF treatment for these blood–retina barrier disorders, in which VEGF is a major therapeutic target for vascular abnormalities.

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Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

International Journal of Molecular Sciences ◽

10.3390/ijms22094717 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4717

Author(s):

Jin-Young Lee ◽

Da-Ae Kim ◽

Eun-Young Kim ◽

Eun-Ju Chang ◽

So-Jeong Park ◽

...

Keyword(s):

Bone Resorption ◽

Bone Formation ◽

Map Kinases ◽

Osteoclast Differentiation ◽

Dependent Manner ◽

Dual Action ◽

Dose Dependent ◽

Resorptive Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.

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Effects of Propentofylline on Hypoxia—Hypoglycemia-Induced Calcium Accumulation in Gerbil Hippocampal Slices

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1992.41 ◽

1992 ◽

Vol 12 (2) ◽

pp. 301-305 ◽

Cited By ~ 12

Author(s):

Fumito Kadoya ◽

Akira Mitani ◽

Tatsuru Arai ◽

Kiyoshi Kataoka

Keyword(s):

Cerebral Ischemia ◽

Intracellular Calcium ◽

Neuronal Damage ◽

Hippocampal Slices ◽

Dependent Manner ◽

Protective Effects ◽

Calcium Accumulation ◽

Xanthine Derivative ◽

Acute Increase ◽

Dose Dependent

The xanthine derivative propentofylline (HWA 285) has been reported to show protective effects against neuronal damage induced by cerebral ischemia. In the present study, microfluorometry was used to investigate the effect of propentofylline on the hypoxia–hypoglycemia-induced intracellular calcium accumulation in gerbil hippocampal slices. When slices were superfused with hypoxic–hypoglycemic medium that did not contain propentofylline, an acute increase in calcium accumulation was detected 75–200 s (mean latency of 123 s) after the beginning of hypoxia–hypoglycemia. When slices were superfused with hypoxic–hypoglycemic mediums that contained 10 μ M, 100 μ M, and 1 m M propentofylline, the latency of the acute increase in calcium accumulation was prolonged in all subregions of the hippocampus in a dose-dependent manner: mean latencies in field CA1 were 146, 168, and 197 s after hypoxia–hypoglycemia, respectively. This retardation in calcium accumulation may be involved in the mechanisms by which propentofylline diminishes ischemic injury.

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