[6]-gingerol and [6]-shogaol, active ingredients of the traditional Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced pain via action on Na + channels

Hitomi, Suzuro; Ono, Kentaro; Terawaki, Kiyoshi; Matsumoto, Chinami; Mizuno, Keita; Yamaguchi, Kensei; Imai, Ryota; Omiya, Yuji; Hattori, Tomohisa; Kase, Yoshio; Inenaga, Kiyotoshi

doi:10.1016/j.phrs.2016.12.026

Cited by 59 publications

(26 citation statements)

References 65 publications

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“…The rhizome of Zingiber officinale (ginger) is also used as traditional medicine with health benefits to treat muscular aches and pains worldwide. Its main ingredients 6-gingerol and 6-shogaol are reported to relief 5-fluorouracil-induced oral ulcerative mucositis and pain by regulating Na + channels, playing an essential role in ginger-associated analgesia of pain (Hitomi et al, 2017 ). Tocotrienols are natural compounds existed in vegetable oil, which are a promising analogs of vitamin E for cancer therapeutics by sensitizing cancer cells to chemotherapeutic agents (Sailo et al, 2018 ).…”

Section: Prevention Of Oral Mucositis Partly By Reducing Oxidative Stmentioning

confidence: 99%

Natural Product Interventions for Chemotherapy and Radiotherapy-Induced Side Effects

et al. 2018

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Cancer is the second leading cause of death in the world. Chemotherapy and radiotherapy are the common cancer treatments. However, the development of adverse effects resulting from chemotherapy and radiotherapy hinders the clinical use, and negatively reduces the quality of life in cancer patients. Natural products including crude extracts, bioactive components-enriched fractions and pure compounds prepared from herbs as well as herbal formulas have been proved to prevent and treat cancer. Of significant interest, some natural products can reduce chemotherapy and radiotherapy-induced oral mucositis, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, hematopoietic system injury, cardiotoxicity, and neurotoxicity. This review focuses in detail on the effectiveness of these natural products, and describes the possible mechanisms of the actions in reducing chemotherapy and radiotherapy-induced side effects. Recent advances in the efficacy of natural dietary supplements to counteract these side effects are highlighted. In addition, we draw particular attention to gut microbiotan in the context of prebiotic potential of natural products for the protection against cancer therapy-induced toxicities. We conclude that some natural products are potential therapeutic perspective for the prevention and treatment of chemotherapy and radiotherapy-induced side effects. Further studies are required to validate the efficacy of natural products in cancer patients, and elucidate potential underlying mechanisms.

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Section: Prevention Of Oral Mucositis Partly By Reducing Oxidative Stmentioning

confidence: 99%

Natural Product Interventions for Chemotherapy and Radiotherapy-Induced Side Effects

et al. 2018

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“…[6]-Gingerol ((S)-5-hydroxy-1-(4-hydroxy-3methoxyphenol)-3-decanone) is an aromatic polyphenol that is a major constituent of ginger. Previous studies on rodents reported antioxidant [ 3 ], analgesic [ 4 , 5 ], anti-inflammatory [ 6 ], and anti-tumor and pro-apoptotic [ 7 – 9 ] properties of [6]-Gingerol. Interestingly, a recent study reported that [6]-Gingerol also has potent insulin secreting, anti-hyperglycemic, lipid lowering, and anti-oxidant properties in a Lepr db/db type 2 diabetic mouse model [ 10 ], all of which are essential hallmarks of an effective anti-diabetic agent.…”

Section: Introductionmentioning

confidence: 99%

[6]-Gingerol, from Zingiber officinale, potentiates GLP-1 mediated glucose-stimulated insulin secretion pathway in pancreatic β-cells and increases RAB8/RAB10-regulated membrane presentation of GLUT4 transporters in skeletal muscle to improve hyperglycemia in Leprdb/db type 2 diabetic mice

Samad

Mohsin

Razu

et al. 2017

BMC Complement Altern Med

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Background[6]-Gingerol, a major component of Zingiber officinale, was previously reported to ameliorate hyperglycemia in type 2 diabetic mice. Endocrine signaling is involved in insulin secretion and is perturbed in db/db Type-2 diabetic mice. [6]-Gingerol was reported to restore the disrupted endocrine signaling in rodents. In this current study on Leprdb/db diabetic mice, we investigated the involvement of endocrine pathway in the insulin secretagogue activity of [6]-Gingerol and the mechanism(s) through which [6]-Gingerol ameliorates hyperglycemia.MethodsLeprdb/db type 2 diabetic mice were orally administered a daily dose of [6]-Gingerol (200 mg/kg) for 28 days. We measured the plasma levels of different endocrine hormones in fasting and fed conditions. GLP-1 levels were modulated using pharmacological approaches, and cAMP/PKA pathway for insulin secretion was assessed by qRT-PCR and ELISA in isolated pancreatic islets. Total skeletal muscle and its membrane fractions were used to measure glycogen synthase 1 level and Glut4 expression and protein levels.Results4-weeks treatment of [6]-Gingerol dramatically increased glucose-stimulated insulin secretion and improved glucose tolerance. Plasma GLP-1 was found to be significantly elevated in the treated mice. Pharmacological intervention of GLP-1 levels regulated the effect of [6]-Gingerol on insulin secretion. Mechanistically, [6]-Gingerol treatment upregulated and activated cAMP, PKA, and CREB in the pancreatic islets, which are critical components of GLP-1-mediated insulin secretion pathway. [6]-Gingerol upregulated both Rab27a GTPase and its effector protein Slp4-a expression in isolated islets, which regulates the exocytosis of insulin-containing dense-core granules. [6]-Gingerol treatment improved skeletal glycogen storage by increased glycogen synthase 1 activity. Additionally, GLUT4 transporters were highly abundant in the membrane of the skeletal myocytes, which could be explained by the increased expression of Rab8 and Rab10 GTPases that are responsible for GLUT4 vesicle fusion to the membrane.ConclusionsCollectively, our study reports that GLP-1 mediates the insulinotropic activity of [6]-Gingerol, and [6]-Gingerol treatment facilitates glucose disposal in skeletal muscles through increased activity of glycogen synthase 1 and enhanced cell surface presentation of GLUT4 transporters.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-017-1903-0) contains supplementary material, which is available to authorized users.

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“…With regard to anti-inflammatory effects, we have shown that various ingredients in HST decrease the interleukin 1β-induced prostaglandin E2 (PGE2) production www.nature.com/scientificreports www.nature.com/scientificreports/ in HOKs with multi-targeting effects, such as dual suppression of cyclooxygenase-2 expression and PGE2 metabolic activity 26 . For analgesic effects, the swab application of HST on an OUM rat model suppressed spontaneous and mechanical pain through Na + channel blockage, which was mediated by several ingredients in HST 27,28 . We now add a new pharmacological action by demonstrating that HST exhibits wound healing activity, with its pharmacological actions being regulated by different the constituent medicinal herbs (Supplementary Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…Several in vitro studies also reported that HST induced antibacterial and antioxidant effects, suggesting that these effects were involved in the mechanisms of HST with respect to the improvement of OUM [23][24][25] . Moreover, our previous studies in vitro and in vivo revealed additional mechanisms of HST in OUM, including both anti-inflammatory and analgesic effects [26][27][28] . Nevertheless, an important process during the restoration of ulcer sites is rapid repair of the ulcer site by migration and covering of the epithelium cells.…”

mentioning

confidence: 93%

The Japanese herbal medicine Hangeshashinto enhances oral keratinocyte migration to facilitate healing of chemotherapy-induced oral ulcerative mucositis

Miyano¹,

Eto

Hitomi

et al. 2020

Sci Rep

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chemotherapy often induces oral ulcerative mucositis (oUM) in patients with cancer, characterized by severe painful inflammation. Mouth-washing with the Japanese herbal medicine hangeshashinto (HST) ameliorates chemotherapy-induced OUM in patients with colorectal cancer. Previously, we demonstrated that HST decreased interleukin 1β-induced prostaglandin E2 production in human oral keratinocytes (HOKs) and OUM-induced mechanical or spontaneous pain in rats. However, HST effects on tissue repair functions in HOKs remain unclear. Here, we examined the effects of HST on scratchinduced wound healing in vitro and in vivo. In vitro, HSt enhanced wound healing mainly through scratch-induced HOK migration. Screening of the seven constituent medicinal herbs and their major components revealed that Scutellaria root, processed ginger, and Glycyrrhiza components mainly induced the scratch-induced HOK migration. Pharmacokinetic analyses indicated that the active ingredient concentrations in rat plasma following oral HST administration were below the effective doses for HOK migration, suggesting direct effects of HST in OUM. Mitogen-activated protein kinase and C-X-C chemokine receptor 4 inhibitors significantly suppressed HST-induced HOK migration. Moreover, HST enhanced tissue repair in our OUM rat model. Thus, HST likely enhanced OUM tissue repair through oral keratinocyte migration upon MAPK and CXCR4 activation and may be useful in patients with cancer-associated OUM. Patients with cancer receiving chemotherapy, radiotherapy, hematopoietic stem cell transplant, and terminal care often present with severe oral ulcerative mucositis (OUM), which evokes painful inflammation and limits fundamental life behaviours such as 'eating, drinking, and talking' 1-15. In addition, OUM increases the risk of systemic infection via opportunistic microorganisms, which may lead to the extension of hospitalization 5,15-19. OUM also often induces patients with cancer to discontinue/modify their therapy regimen, which adversely affects patient prognosis 13,15,16,20. Therefore, the effective management of OUM is indispensable for improving both the quality of life and prognosis for the patient 15 .

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[6]-gingerol and [6]-shogaol, active ingredients of the traditional Japanese medicine hangeshashinto, relief oral ulcerative mucositis-induced pain via action on Na + channels

Cited by 59 publications

References 65 publications

Natural Product Interventions for Chemotherapy and Radiotherapy-Induced Side Effects

Natural Product Interventions for Chemotherapy and Radiotherapy-Induced Side Effects

[6]-Gingerol, from Zingiber officinale, potentiates GLP-1 mediated glucose-stimulated insulin secretion pathway in pancreatic β-cells and increases RAB8/RAB10-regulated membrane presentation of GLUT4 transporters in skeletal muscle to improve hyperglycemia in Leprdb/db type 2 diabetic mice

The Japanese herbal medicine Hangeshashinto enhances oral keratinocyte migration to facilitate healing of chemotherapy-induced oral ulcerative mucositis

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