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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 63  |  Page : 369-377  

Effects of the herbal medicines on voltage-dependent K+ 2 channels


1 Division of Longevity and Biofunctional Medicine and Healthy Aging Korean Medical Research Center, School of Korean Medicine, Pusan National University, Wanju-gun, Korea
2 Research Group of Innovative Special Food, Korea Food Research Institute, Wanju-gun; Department of Food Biotechnology, Korea University of Science and Technology, Daejeon, Korea
3 Division of Pharmacology, School of Korean Medicine, Pusan National University, Yangsan, China

Date of Submission17-Dec-2018
Date of Decision19-Mar-2019
Date of Web Publication16-May-2019

Correspondence Address:
Byung Joo Kim
Department of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan 50612
Korea
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/pm.pm_636_18

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   Abstract 


Background: Identification of selective ion channel inhibitors is necessary for understanding the physiological role of these proteins. The voltage-dependent K+ (Kv) channels, Kv2.1 and Kv2.2, are expressed in pancreatic islets, and the development of selective Kv2.1 inhibitors that do not cross-inhibit Kv2.2 may be useful for the treatment of type 2 diabetes. Objective: The aim of this study was to evaluate whether herbal medicines, such as the fruit of Schisandra chinensis (SCF), Atractylodes macrocephala Koidzumi (AMK), Poria cocos Wolf (PCW), Citrus unshiu peel (CUP), Magnolia officinalis Bark (M. officinalis), Alisma canaliculatum (A. canaliculatum), Rehmanniae Radix (RR), and Corni fructus (C. fructus), modulate Kv2 channels and cause insulin secretion. Materials and Methods: We used the whole-cell patch-clamp technique to analyze the effect of these herbal medicines on Kv channels. In addition, human embryonic kidney 293 cells overexpressing Kv2.1 and Kv2.2 channels were used to confirm the role of Kv2 channels. Results: SCF, AMK, PCW, CUP, M. officinalis, A. canaliculatum, and RR inhibited Kv2.1 channel currents in a concentration-dependent manner (100–500 μg/mL). However, C. fructus had no effects on Kv2.1 channel currents. In addition, SCF, AMK, M. officinalis, and A. canaliculatum inhibited Kv2.2 channel currents in a concentration-dependent manner, but PCW, CUP, and RR had no effects on Kv2.2 channel currents. Furthermore, RR, CUP, and PCW increased insulin secretion. Conclusion: These findings suggested that the herbal medicines, RR, CUP, and PCW, are potential novel agents for the prevention and treatment of diabetes.

Keywords: Diabetes, herbal medicine, Kv2.1, Kv2.2, voltage-dependent K+ channels


How to cite this article:
Kim JN, Lim EY, Kim YT, Kim H, Kim BJ. Effects of the herbal medicines on voltage-dependent K+ 2 channels. Phcog Mag 2019;15:369-77

How to cite this URL:
Kim JN, Lim EY, Kim YT, Kim H, Kim BJ. Effects of the herbal medicines on voltage-dependent K+ 2 channels. Phcog Mag [serial online] 2019 [cited 2019 Aug 20];15:369-77. Available from: http://www.phcog.com/text.asp?2019/15/63/369/258402



Summary

  • Fruit of Schisandra chinensis, Atractylodes macrocephala Koidzumi, Poria cocos Wolf (PCW), Citrus unshiu peel (CUP), Magnolia officinalis Bark, Alisma canaliculatum, and Rehmanniae Radix (RR) inhibited voltage-dependent K+ (Kv2.1) channel currents in a concentration-dependent manner
  • Corni fructus (100–500 μg/mL) had no effects on Kv2.1 channel currents
  • Administration of RR, CUP, and PCW caused an increase in insulin secretion
  • PCW, CUP, and RR are potential novel agents for the prevention and treatment of diabetes.




Abbreviations used: SCF: Fruit of Schisandra chinensis; AMK: Atractylodes macrocephala Koidzumi; PCW: Poria cocos Wolf; CUP: Citrus unshiu peel; M. officinalis: Magnolia officinalis Bark; A. canaliculatum: Alisma canaliculatum; RR: Rehmanniae Radix; C. fructus: Corni fructus; Kv channel: Voltage-dependent K+ channel.


   Introduction Top


Diabetes is a metabolic disease characterized by high blood glucose levels and type 2 diabetes is associated with both insulin resistance and insulin deficiency.[1],[2] In pancreatic islet β-cells, multiple ion channels regulate the plasma membrane potential (Vm), intracellular-free Ca 2+ concentration, and insulin secretion.[3] The β-cell defect found in type 2 diabetes mellitus is most commonly treated with the sulfonylurea class of compounds.[4],[5] Sulfonylureas antagonize ATP-sensitive K + channels, depolarizing the membrane, opening voltage-dependent Ca 2+ channels, and stimulating insulin secretion.[6],[7] In addition, voltage-dependent outward K + currents have been detected in the β-cells and are believed to mediate action potential repolarization,[8],[9],[10] limiting Ca 2+ influx and insulin secretion. Indeed, previous studies show that the general voltage-dependent K + (Kv) and Ca 2+-sensitive voltage-dependent K + channel antagonist, tetraethylammonium, augments membrane depolarization,[11],[12] Ca 2+ influx,[13] and insulin secretion [12],[14] in a glucose-dependent manner.[7] Among K + channels, both members of the Kv2 channel family, Kv2.1 and Kv2.2, are expressed in the pancreatic islets across several species,[7],[15],[16],[17] and Kv2.1 is highly enriched in the islet β-cells.[7],[16],[18] Kv2.1 regulates insulin secretion in β-cells and Kv2.2 modulates somatostatin release in δ-cells. Therefore, the development of selective Kv2.1 inhibitors without cross-inhibition of Kv2.2 will provide new agents for the treatment of type 2 diabetes.[7],[18],[19],[20],[21],[22],[23]

Management of type 2 diabetes usually begins with changing diet and exercise,[24] but most patients ultimately require pharmacotherapy, such as with an oral antidiabetic drug.[25] A variety of medicinal herbal products in Chinese medicine have beneficial effects in diabetes,[26] and many of these herbs have been formulated into multi-herbal preparations for enhanced effects.[27],[28] In addition, Chinese medicine formulas also have a favorable effect on obesity.[29] Obesity is a major global health problem because it is associated with an increased risk of metabolic disorders, including type 2 diabetes mellitus, hypertension, atherosclerosis, cancer, and cardiovascular disease.[30],[31]

In this study, to examine whether herbal medicines (fruit of Schisandra chinensis [SCF], Atractylodes macrocephala Koidzumi [AMK], Poria cocos Wolf [PCW], Citrus unshiu peel [CUP], Magnolia officinalis Bark [M. officinalis], Alisma canaliculatum [A. canaliculatum], Rehmanniae Radix [RR], and Corni fructus [C. fructus]) have antidiabetic effects, we investigated their inhibitory effects on Kv2.1 channels, but not on Kv2.2 channels, and how insulin secretion was affected.


   Materials and Methods Top


Preparation of herbal medicines

Dried RR, CUP, and PCW were purchased from Kapdang Co. (Seoul, Korea). The samples were identified by Dr. Yun Tai Kim and voucher specimens (#NP-1090) were deposited with the research group of innovative special food, Korea Food Research Institute. Dried herbal medicines (600 g each) were extracted with 70% ethanol (6000 mL) for 2 h at 20°C. The process was repeated once and the extracts were combined and filtered through a membrane filter (0.45 μm; Millipore, Billerica, MA, USA). After removing the solvents via rotary evaporation, the remaining extracts were freeze-dried, yielding approximately 15.6%–21.5% of the dried herbal medicine weight (w/w).

Cell culture and transfection

Human embryonic kidney 293 cells (ATCC, Manassas, VA, USA) were maintained according to the supplier's recommendations. 293 cells were transiently transfected with cDNA encoding mKv2.1 or mKv2.2 subcloned in the pIRES-green fluorescent protein vector with the use of lipofectamine 2000 reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's specifications.

Electrophysiological recordings

Electrophysiological recordings were taken at room temperature (22°C–25°C) 24–48 h after transfection using the patch-clamp technique in the whole-cell configuration. Cells were collected and maintained in a 35 mm 2 Petri dish (BD Biosciences, Bedford, MA, USA) in DMEM supplemented with 10% FBS at 37°C and 20% O2/10% CO2. An aliquot of cells was allowed to settle in a recording chamber for 5 min before perfusion was initiated. Whole-cell patch-clamp recordings were obtained using an Axopatch 700B amplifier and pClamp v. 10.4 software, and signals were digitized at 5 kHz using Digidata 1422A (Molecular Devices, Sunnyvale, CA, USA). For whole-cell recordings, the external solution contained 135 mM NaCl, 4 mM KCl, 1 mM MgCl2, 10 mM HEPES, 1.8 mM CaCl2, and 10 mM glucose (pH was adjusted to 7.4 with NaOH). The pipette solution contained 110 mM KCl, 5 mM MgCl2, 5 mM K4 BAPTA, 5 mM K2 ATP, and 10 mM HEPES (pH adjusted to 7.2 with KOH). Pipette tips were fire-polished to a resistance of 2–3 MΩ to facilitate Gigaseal formation (Narishige, Tokyo, Japan). Data were saved on a desktop computer and analyzed using Clampfit v. 10.4 (Molecular Devices), Prism v. 6.0 (GraphPad, La Jolla, CA, USA), and Origin v. 8.0 (Microcal, Northampton, MA, USA) software.

Insulin secretion experiments

Insulin secretion experiments were performed in Krebs–Ringer bicarbonate buffer containing 115 mM NaCl, 5 mM KCl, 24 mM NaHCO3, 2.5 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, and 0.1% bovine serum albumin as described previously.[16] An insulin secretion experiment was performed using a mouse insulin ELISA kit from Abnova Inc. (KA3812; Taipei, Taiwan). NIT-1 cells (ATCC) from a mouse insulinoma cell line were maintained in DMEM (Life Technologies, Grand Island, NY, USA) supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin at 37°C in 5% CO2. NIT-1 cell insulin secretion experiments were performed and data were normalized to controls.

Statistical analysis

Results are expressed as mean ± standard error of the mean. N values refer to the number of separate cells examined. Multiple comparison testing was performed using one-way ANOVA with Bonferroni's post hoc comparison. P < 0.05 was considered statistically significant.


   Results Top


Effects of fruit of Schisandra chinensis, Atractylodes macrocephala Koidzumi, Poria cocos Wolf, Citrus unshiu peel, Magnolia officinalis Bark, Alisma canaliculatum, Rehmanniae Radix, and Corni fructus on the voltage-gated potassium channel, Kv2.1

Under control conditions, step depolarizations from the holding potential of −60 mV elicited Kv2.1 channel currents. A representative current trace for SCF is shown in [Figure 1]a. SCF inhibited Kv2.1 channel currents in a concentration-dependent manner (100–500 μg/mL), and the peak and quasi steady-state currents (measured at the end of the test pulses) showed a similar degree of suppression during the voltage step pulses. This SCF-dependent inhibition was rapidly reversible. [Figure 1]b presents the peak current–voltage (I–V) relationships of Kv2.1 channel currents in the presence and absence of various concentrations of SCF. [Figure 1]c summarizes the concentration dependence of the inhibition of Kv2.1 channel currents by SCF. The results shown in [Figure 1]c were obtained at the end of current values at +50 mV and were normalized to the current amplitude in the absence of SCF. A nonlinear least-square fit of the logistic function to the concentration–response data yielded an apparent IC50 value of 226.1 μg/mL. In addition, other herbal medicines, such as AMK, PCW, CUP, M. officinalis, A. canaliculatum, and RR, also inhibited Kv2.1 channel currents in a concentration-dependent manner (100–500 μg/mL). [Figure 2]Aa, [Figure 2]Ba, [Figure 2]Ca, [Figure 2]Da and [Figure 3]Aa, [Figure 3]Ba present the peak I–V relationships of Kv2.1 channel currents in the presence and absence of various concentrations of AMK, PCW, CUP, M. officinalis, A. canaliculatum, and RR. [Figure 2]Ab, [Figure 2]Bb, [Figure 2]Cb, [Figure 2]Db and [Figure 3]Ab, [Figure 3]Bb summarize the concentration dependence of the inhibition of Kv2.1 channel currents by AMK, PCW, CUP, M. officinalis, A. canaliculatum, and RR. The results shown in [Figure 2]Ab, [Figure 2]Bb, [Figure 2]Cb, [Figure 2]Db and [Figure 3]Ab, [Figure 3]Bb were obtained at the end of current values at +50 mV and were normalized to the current amplitude in the absence of AMK, PCW, CUP, M. officinalis, A. canaliculatum, and RR. A nonlinear least-square fit of the logistic function to the concentration–response data yielded an apparent IC50 value of 187.4 μg/mL for AMK, 221.6 μg/mL for PCW, 484.1 μg/mL for CUP, 110.0 μg/mL for M. officinalis, 190.1 μg/mL for A. canaliculatum, and 387.6 μg/mL for RR, respectively. However, C. fructus (100–500 μg/mL) had no effects on Kv2.1 channel currents [Figure 3]C. These results suggest that SCF, AMK, PCW, CUP, M. officinalis, A. canaliculatum, and RR inhibited Kv2.1 channel currents in a concentration-dependent manner.
Figure 1: Effects of the fruit of SCF on Kv2.1 currents. (a) The superimposed current traces were elicited by 250-ms depolarizing pulses between −60 and +50 mV from a holding potential of −60 mV. (b) Current–voltage relationships of the peak and quasi-steady-state Kv2.1 channel currents in the presence and absence of SCF. (c) The SCF-induced inhibition of Kv2.1 channel currents was measured at the end of a 250-ms depolarizing pulse of +50 mV and normalized using the control current amplitude. SCF: Schisandra chinensis; Kv: Voltage-dependent K+

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Figure 2: Effects of AMK, PCW, CUP, and M. officinalis on Kv2.1 currents. (Aa, Ba, Ca, and Da) Current–voltage relationships of Kv2.1 channel currents in the presence and absence of AMK, PCW, CUP and M. officinalis (Ab, Bb, Cb, and Db). The AMK, PCW, CUP and M. officinalis-induced inhibition of Kv2.1 channel currents were measured at the end of a 250-ms depolarizing pulse of +50 mV and normalized using the control current amplitude. AMK: Atractylodes macrocephala Koidzumi; PCW: Poria cocos Wolf; CUP: Citrus unshiu peel; M. officinalis: Magnolia officinalis Bark; Kv: Voltage-dependent K+

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Figure 3: Effects of A. canaliculatum, RR, and C. fructus on Kv2.1 currents. (Aa, Ba, and Ca) Current–voltage relationships of Kv2.1 channel currents in the presence and absence of A. canaliculatum, RR, and C. fructus (Ab, Bb, and Cb). Average concentration dependence of Kv2.1 channel current inhibition by A. canaliculatum and RR. However, C. fructus had no effect on Kv2.1 channel currents. A. canaliculatum: Alisma canaliculatum; RR: Rehmanniae Radix; C. fructus: Corni fructus; Kv channel: Voltage-dependent K+ channel

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Effects of fruit of Schisandra chinensis, Atractylodes macrocephala Koidzumi, Poria cocos Wolf, Citrus unshiu peel, Magnolia officinalis Bark, Alisma canaliculatum, Rehmanniae Radix, and Corni fructus on voltage-gated potassium channel, Kv2.2

Similar to Kv2.1 channels, we investigated the effect of these herbal medicines on Kv2.2 channels. Under control conditions, step depolarizations from the holding potential of-60 mV elicited Kv2.2 channel currents. A representative current trace of SCF is shown in [Figure 4]a. SCF inhibited Kv2.2 channel currents in a concentration-dependent manner (100–500 μg/mL) and the peak and quasi steady-state currents (measured at the end of the test pulses) showed a similar degree of suppression during the voltage step pulses. This SCF-dependent inhibition was rapidly reversible. [Figure 4]b presents the peak I–V relationships of Kv2.2 channel currents in the presence and absence of various concentrations of SCF. [Figure 4]c summarizes the concentration dependence of the inhibition of Kv2.2 channel currents by SCF. The results shown in [Figure 4]c are the end of current values at +50 mV and were normalized to the current amplitude in the absence of SCF. A nonlinear least-square fit of the logistic function to the concentration-response data yielded an apparent IC50 value of 103.1 μg/mL. In addition, other herbal medicines, such as AMK, M. officinalis, and A. canaliculatum, also inhibited Kv2.2 channel currents in a concentration-dependent manner (100–500 μg/mL). [Figure 5]Aa, [Figure 5]Da and [Figure 6]Aa present the peak I–V relationships of Kv2.2 channel currents in the presence and absence of various concentrations of AMK, M. officinalis, and A. canaliculatum. [Figure 5]Ab, [Figure 5]Db and [Figure 6]Ab summarize the concentration dependence of the inhibition of Kv2.1 channel currents by AMK, M. officinalis, and A. canaliculatum. The results shown in [Figure 5]Ab, [Figure 5]Db and [Figure 6]Ab are the end of current values at +50 mV and were normalized to the current amplitude in the absence of AMK, M. officinalis, and A. canaliculatum. A nonlinear least-square fit of the logistic function to the concentration–response data yielded apparent IC50 values of 42.1 μg/mL for AMK, 96.0 μg/mL for M. officinalis, and 161.3 μg/mL for A. canaliculatum. However, PCW, CUP, and RR (100–500 μg/mL) had no effect on Kv2.2 channel currents [Figure 5]B, [Figure 5]C and [Figure 6]B. These results suggested that PCW, CUP, and RR inhibited Kv2.1 channel currents in a concentration-dependent manner.
Figure 4: Effects of SCF on Kv2.2 currents. (a) The superimposed current traces were elicited by 250-ms depolarizing pulses between −60 and +50 mV from a holding potential of −60 mV in the absence and presence of SCF. (b) Current–voltage relationships of the peak and quasi-steady-state Kv2.2 channel currents in the presence and absence of SCF. (c) The SCF-induced inhibition of Kv2.2 channel currents was measured at the end of a 250-ms depolarizing pulse of +50 mV and normalized using the control current amplitude. SCF: Schisandra chinensis; Kv: Voltage-dependent K+

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Figure 5: Effects of AMK, PCW, CUP, and M. officinalis on Kv2.2 currents. (Aa, Ba, Ca, and Da) Current–voltage relationships of Kv2.2 channel currents in the presence and absence of AMK, PCW, CUP and M. officinalis (Ab, Bb, Cb, and Db). Average concentration dependence of Kv2.2 channel current inhibition by AMK and M. officinalis. However, PCW and CUP had no effect on Kv2.2 channel currents. AMK: Atractylodes macrocephala Koidzumi; PCW: Poria cocos Wolf; CUP: Citrus unshiu peel; M. officinalis: Magnolia officinalis Bark; Kv: Voltage-dependent K+

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Figure 6: Effects of A. canaliculatum and RR on Kv2.2 currents. (Aa, Ba and Ca) Current–voltage relationships of Kv2.2 channel currents in the presence and absence of A. canaliculatum and RR (Ab, Bb, and Cb). Average concentration dependence of Kv2.2 channel current inhibition by A. canaliculatum and RR. However, RR had no effect on Kv2.2 channel currents. A. canaliculatum: Alisma canaliculatum; RR: Rehmanniae Radix; Kv channel: Voltage-dependent K+ channel

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Effects of Rehmanniae Radix, Citrus unshiu peel, and Poria cocos Wolf on insulin secretion

Peripheral insulin resistance and defects in insulin secretion from pancreatic β-cells characterize type 2 diabetes mellitus.[1] Voltage-dependent outward K + currents have been detected in β-cells and are believed to mediate action potential repolarization, limiting Ca 2+ influx and insulin secretion.[5],[9],[10],[11] Therefore, we evaluated the effects of RR, CUP, and PCW on insulin secretion using the murine pancreatic β-cell line, NIT-1. RR (3.2 ± 0.3 value, P < 0.01), CUP (3.7 ± 0.2 value, P < 0.01), and PCW (1.2 ± 0.4 value) enhanced insulin secretion from NIT-1 cells [Figure 7]. These results suggested that administration of RR, CUP, and PCW caused an increase in insulin secretion.
Figure 7: RR, CUP, and PCW enhance insulin secretion in pancreatic β-cells. RR, CUP, and PCW enhanced insulin secretion from NIT-1 cells compared with controls (n = 6). **P < 0.01 compared with control. CUP: Citrus unshiu peel; RR: Rehmanniae Radix; PCW: Poria cocos Wolf

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   Discussion Top


Traditional Chinese medicine (TCM) has several thousands of years of empirical clinical practice in several different East Asian countries.[32] One of the major goals of TCM is to restore and maintain the energy and equilibrium of the human body in different systems that are closely connected. In recent years, several herbal products prescribed in TCM have demonstrated a therapeutic beneficial effect on various diseases, including metabolic syndromes, and as therapy for chronic conditions. TCM therapy for diabetes has been used in East Asian countries. Several clinical trials show that TCM can provide diabetic patients with additional benefits, such as decreasing blood glucose levels, ameliorating insulin resistance and pancreatic islets function, weight loss, and low incidence of adverse events.[33],[34],[35] Pharmacological studies demonstrated that TCM could rehabilitate and ameliorate islet beta-cell trauma, increase insulin secretion, and strengthen the utilization of glucose in peripheral tissues.[26]

In the present study, we used eight herbal medicines, depending on whether they regulated Kv2 channels and insulin secretion. Several studies demonstrated the diverse pharmacological activities of SCF, including antioxidant,[36] antitumor,[37] anti-obesity,[38] anti-inflammatory,[39] cardioprotective,[40] hepatoprotective,[41] and gastrointestinal motility activities.[42] In addition, SCF had beneficial effects on metabolic diseases, including diabetes and obesity.[43],[44] SCF inhibited preadipocyte differentiation and adipogenesis in 3T3-L1 cells, leading to decreased body weight and fat mass in high fat diet (HFD)-induced obese rats.[45] AMK is used to treat diabetes and obesity [46] and has been reported to reduce body weight and serum lipid levels in HFD-induced animal models of obesity.[47] In addition, Atractylodes macrocephala Koidzumi (Atractylodis Rhizoma Alba (ARA)) prevented diet-induced obesity and glucose intolerance in C5BL/6 mice.[48] PCW has been used in China for the treatment of many types of diseases with signs of a deficiency of Yin in the kidneys and it improved insulin resistance in diabetes mellitus, in part, by regulating the canonical PI3K/Akt signaling pathway in the liver.[49] Mice supplemented with CUP extract also displayed a significant decrease in body weight gain and body fat mass,[50] and hepatic steatosis and hypertriglyceridemia were ameliorated via the inhibition of gene expression and increased activation of lipogenic enzymes and Fatty acid (FA) oxidation in the liver.[50] Therefore, CUP had a beneficial effect on the metabolic syndrome.[51]M. officinalis has been widely used as a traditional herbal remedy for various disorders such as obesity, hyperglycemia, hyperlipidemia, and diabetic complications, including cardiovascular, hepatic, and renal complications.[52]A. canaliculatum, a member of the plant family Alismataceae, has hepatoprotective,[53] antitumor,[54] and antibacterial effects.[55] RR is a perennial herb that belongs to the Scrophulariaceae family and has been used as an important ingredient in a variety of oriental medicines.[56] Recently, many studies have evaluated its effects on antioxidants,[57],[58] the autonomic nervous system,[59] and the human body.[60],[61] In addition, RR is effective for treating patients with various inflammatory and metabolic diseases, such as high blood pressure and diabetes.[62]C. fructus is an important crude herb used in TCM, and it is one of the 25 plant-based drugs most frequently used in China, Japan, and Korea. It is known to exhibit several biological activities, including hypoglycemic activity, and to improve liver and kidney function.[63] In addition, C. fructus has beneficial effects on diabetes and diabetic complications.[64]

Kv channels open in response to membrane depolarization and are present in many cell types. In excitable cells, Kv channels serve as the primary mechanism of repolarization of action potentials, whereas in nonexcitable cells, Kv channels control the cell resting potential.[21] The Kv2 channel family consists of two members, Kv2.1 and Kv2.2. Kv2.1 is prominently expressed in the brain, notably in the pyramidal neurons of the hippocampus and cortex, where it regulates excitability.[65] Kv2.1 also regulates insulin secretion from the pancreatic β-cells.[20] Kv2.2 is expressed in the brain,[66] smooth muscle,[67] and somatostatin secreting δ-cells of the pancreatic islet.[16],[68] Development of selective Kv2.1 inhibitors without cross-inhibition of Kv2.2 might provide new avenues for the treatment of type 2 diabetes mellitus.[7],[18],[19],[20],[21],[22],[23]

In the present study, SCF, AMK, PCW, CUP, M. officinalis, A. canaliculatum, and RR inhibited Kv2.1 channel currents in a concentration-dependent manner (100–500 μg/mL) [Figure 2]Aa, [Figure 2]Ba, [Figure 2]Ca, [Figure 2]Da and [Figure 3]Aa, [Figure 3]Ba. However, C. fructus had no effect on Kv2.1 channel currents [Figure 3]C. In addition, among SCF, AMK, PCW, CUP, M. officinalis, A. canaliculatum, and RR, only PCW, CUP, and RR had no effect on Kv2.2 channel currents [Figure 5]B, [Figure 5]C and [Figure 6]B. Therefore, we concluded that only PCW, CUP, and RR played key roles in insulin secretion. In addition, we evaluated the enhancement of insulin secretion after administration of PCW, CUP, and RR [Figure 7]. However, we do not know the active components of herbal medicines. Therefore, in the future, we will determine the efficacious components to clarify the precise mechanisms of these herbal medicines in diabetes mellitus.


   Conclusion Top


The present study shows that SCF, AMK, PCW, CUP, M. officinalis, A. canaliculatum, and RR inhibit Kv2.1 channel currents in a concentration-dependent manner. Among these, only PCW, CUP, and RR have no effects on Kv2.2 channel currents. In addition, PCW, CUP, and RR cause an increase in insulin secretion. Based on these results, we conclude that PCW, CUP, and RR are potential novel agents for the prevention and treatment of diabetes.

Financial support and sponsorship

This study was supported by a Korean National Research Foundation grant funded by the Korean government (MSIP) (Grant no. 2017R1A2B2003764) and by a grant from the Korea Food Research Institute (E0164502-03).

Conflicts of interest

There are no conflicts of interest.



 
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