Publications by authors named "Nipon Chattipakorn"

346 Publications

Necrostatin-1 reduces cardiac and mitochondrial dysfunction in prediabetic rats.

J Endocrinol 2021 Jul 1. Epub 2021 Jul 1.

N Chattipakorn, Cardiac Electrophysiology Research and Training Center, Chiang Mai university, Chiang Mai, 50200, Thailand.

High fat diet (HFD) consumption induces prediabetes and left ventricular dysfunction through many pathways including the cell death pathway, necroptosis. Although benefits of necroptosis inhibitor (necrostatin-1 or Nec-1) in the brain of prediabetic rats have been shown, the effects of Nec-1 on cardiac autonomic function, blood pressure, and cardiac function, and the mechanisms involved have not been investigated. Male Wistar rats were fed with either a normal diet (n=8) or HFD (n=24) for 12 weeks to induce prediabetes. Prediabetic rats were randomly assigned into 3 interventional groups (n=8/group): 1) vehicle, 2) Nec-1 (1.65 mg/kg, sc injection), and 3) metformin (300 mg/kg, oral gavage feeding). Treatments lasted for 8 weeks. Normal saline was given to the vehicle group and a non-interventional group. Metabolic parameters, cardiac function and biochemical parameters were assessed. Prediabetic rats exhibited peripheral metabolic impairment as indicated by increased body weight, hyperinsulinemia with euglycemia, and dyslipidemia. Prediabetic rats also exhibited cardiac autonomic imbalance, high blood pressure, cardiac dysfunction, cardiac mitochondrial dysfunction, mitochondrial dynamic imbalance, and increased necroptosis and apoptosis. Treatment with Nec-1 did not affect peripheral metabolic parameters, however it effectively reduced cardiac autonomic imbalance, blood pressure, and cardiac dysfunction via reduced cardiac inflammation, necroptosis, mitochondrial dysfunction, and increased mitochondrial fusion. Treatment with metformin reduced peripheral metabolic impairment and cardiac dysfunction via decreased cardiac mitochondrial dysfunction, mitochondrial dynamic imbalance, and apoptosis. In summary, Nec-1 directly suppressed necroptosis, cardiac mitochondrial dysfunction, and increased mitochondrial fusion independent to peripheral metabolic function, leading to an improvement in cardiac function in prediabetic rats.
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http://dx.doi.org/10.1530/JOE-21-0134DOI Listing
July 2021

The metabolic role of spermidine in obesity: Evidence from cells to community.

Obes Res Clin Pract 2021 Jul-Aug;15(4):315-326. Epub 2021 Jul 1.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand. Electronic address:

Spermidine is a natural polyamine existing in all living cells known to play an important role in cellular functions. Recently, several studies have reported the effect of alterations in the spermidine pool on metabolic pathways. It has been shown that activation of spermidine/spermine N-1-acetyl-transferase (SSAT), the rate-limiting enzyme in polyamine catabolism, improved glucose and lipid metabolism. In addition, spermidine supplementation has been shown to protect against diet-induced obesity in animal models. However, some clinical studies demonstrated that polyamine levels are increased in childhood obesity and metabolic syndrome patients with type 2 diabetes (T2DM), while polyamine-rich food is associated with a lower incidence of cardiovascular disease (CVD). Therefore, this review aims to summarize and discuss the evidence from in vitro, in vivo and clinical studies on the possible roles of spermidine on metabolic pathways under physiological and obese conditions. All consistent and inconsistent findings are discussed and further studies aiming to fill any gaps in the knowledge are proposed.
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http://dx.doi.org/10.1016/j.orcp.2021.06.009DOI Listing
July 2021

Blockage of Fc Gamma Receptors Alleviates Neuronal and Microglial Toxicity Induced by Palmitic Acid.

J Alzheimers Dis 2021 Jun 17. Epub 2021 Jun 17.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Background: Palmitic acid (PA) promotes brain pathologies including Alzheimer's disease (AD)-related proteins, neuroinflammation, and microglial activation. The activation of neurons and microglia via their Fc gamma receptors (FcγRs) results in producing inflammatory cytokines.

Objective: To investigate the expression of FcγRs, FcγR signaling proteins, AD-related proteins, proinflammatory cytokines, and cell viability of neurons and microglia in association with PA exposure as well as the effects of FcγR blockade on these parameters in response to PA.

Methods: 200 and 400μM PA-conjugated BSA were applied to SH-SY5Y and HMC3 cells for 24 h. For FcγR blockage experiment, both cells were exposed to FcγR blocker before receiving of 200 and 400μM of PA-conjugated BSA for 24 h.

Results: PA significantly increased AD-related proteins, including Aβ and BACE1, as well as increasing TNFα, IL-1β, and IL-6 in SH-SY5Y and HMC3 cells. However, the p-Tau/Tau ratio was only increased in SH-SY5Y cells. These results were associated with an increase in FcγRs activation and a decrease in cell viability in both cell types. FcγRs blockage diminished the activation of FcγR in SH-SY5Y and HMC3 cells. Interestingly, blocking FcγRs before PA exposure reduced the increment of AD-related proteins, proinflammatory cytokines caused by PA. FcγRs blocking also inhibits cell death for 23%of SH-SY5Y cells and 64%of HMC3 cells, respectively.

Conclusion: These findings suggest that PA is a risk factor for AD via the increased AD-related pathologies, inflammation, FcγRs activation, and brain cell death, while FcγR blockage can alleviate these effects.
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http://dx.doi.org/10.3233/JAD-210417DOI Listing
June 2021

The effects of dapagliflozin on hepatic and visceral fat in type 2 diabetes patients with non-alcoholic fatty liver disease.

J Gastroenterol Hepatol 2021 Jun 15. Epub 2021 Jun 15.

Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Background And Aim: Sodium-glucose cotransporter 2 inhibitors have shown excellent results in glucose control in type 2 diabetes mellitus (T2DM) patients, while also promoting weight loss. These mechanisms may be beneficial in the treatment of non-alcoholic fatty liver disease (NAFLD). Our study aims to investigate the effect of dapagliflozin on hepatic and visceral fat contents and related biochemical markers in T2DM with NAFLD patients.

Methods: This is a double-blinded placebo-controlled randomized, single-center study. Non-insulin-dependent T2DM patients with NAFLD were prospectively enrolled and randomly assigned to receive either dapagliflozin (10 mg/day) or placebo for 12 weeks. The primary end-point was the changes in intrahepatic lipid contents, evaluated by the liver attenuation index.

Results: Of 40 patients enrolled, 38 patients completed the study (dapagliflozin group, n = 18; placebo group, n = 20). Baseline demographic and laboratory findings were similar in both groups. After 12 weeks of treatment, dapagliflozin significantly decreased intrahepatic lipid contents demonstrated by an increase in liver attenuation index in comparison with the placebo treatment (5.8 ± 5.1 vs 0.5 ± 6.1 Hounsfield units, P = 0.006). Significant reduction in bodyweight, bodyfat, visceral fat/subcutaneous fat ratio, hemoglobin A1c, and alanine aminotransferase were also observed in the dapagliflozin-treated group as compared with the placebo group (all P < 0.05). There was no significant difference in adipokines including adiponectin, leptin, and tumor necrosis factor-α changes between the dapagliflozin-treated group and the placebo group (all P = nonsignificant).

Conclusion: Dapagliflozin treatment for 12 weeks is associated with improvement in hepatic fat content, a decrease in visceral fat and bodyweight, enhanced glycemic control, and improved liver biochemistry among T2DM patients with NAFLD.
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http://dx.doi.org/10.1111/jgh.15580DOI Listing
June 2021

Carvedilol improves left ventricular diastolic dysfunction in patients with transfusion-dependent thalassemia.

Ann Pediatr Cardiol 2021 Apr-Jun;14(2):152-158. Epub 2021 May 3.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Background: Iron overload cardiomyopathy is the most common cause of death in patients with transfusion-dependent thalassemia.

Aim: The aim of this study was to determine the efficacy of carvedilol treatment in patients with transfusion-dependent thalassemia who had left ventricular diastolic dysfunction.

Methods: Eighteen patients with transfusion-dependent thalassemia who had left ventricular diastolic dysfunction were enrolled. All patients had normal left ventricular systolic function and were given carvedilol with the target dose of 0.8 mg/kg/day. Ventricular function and the level of cardiac iron were assessed by echocardiography and magnetic resonance imaging at 0, 3, and 6 months.

Results: The median age of the patients was 19 years (range 13-25 years). Four patients had severe left ventricular Grade III diastolic dysfunction and fourteen patients had Grade II diastolic dysfunction. The grade of left ventricular diastolic dysfunction was improved at 3 months after the carvedilol treatment. The Doppler parameters, including pulmonary vein atrial reversal velocity, pulmonary vein atrial reversal duration, and the difference of pulmonary vein atrial reversal and the mitral valve atrial contraction wave duration at 3 months after the carvedilol treatment, were significantly lower than these parameters before the treatment.

Conclusions: Among patients with transfusion-dependent thalassemia who had left ventricular diastolic dysfunction without systolic dysfunction, treatment with carvedilol for 3 months was associated with improvement in Doppler parameters of left ventricular diastolic function. However, this finding and its clinical significance need to be confirmed in further double-blind controlled studies.
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http://dx.doi.org/10.4103/apc.APC_63_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174640PMC
May 2021

Inhibition of CDK9 attenuates atherosclerosis by inhibiting inflammation and phenotypic switching of vascular smooth muscle cells.

Aging (Albany NY) 2021 06 8;13(11):14892-14909. Epub 2021 Jun 8.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.

Background: Recent studies have demonstrated a key role of vascular smooth muscle cell (VSMC) dysfunction in atherosclerosis. Cyclin-dependent kinases 9 (CDK9), a potential biomarker of atherosclerosis, was significantly increased in coronary artery disease patient serum and played an important role in inflammatory diseases. This study was to explore the pharmacological role of CDK9 inhibition in attenuating atherosclerosis.

Methods: A small-molecule CDK9 inhibitor, LDC000067, was utilized to treat the high fat diet (HFD)-fed ApoE mice and human VSMCs.

Results: The results showed that inflammation and phenotypic switching of VSMCs were observed in HFD-induced atherosclerosis in ApoE mice, which were accompanied with increased CDK9 in the serum and atherosclerotic lesions where it colocalized with VSMCs. LDC000067 treatment significantly suppressed HFD-induced inflammation, proliferation and phenotypic switching of VSMCs, resulting in reduced atherosclerosis in the ApoE mice, while had no effect on plasma lipids. Further studies confirmed that LDC000067 and siRNA-mediated CDK9 knockdown reversed ox-LDL-induced inflammation and phenotypic switching of VSMCs from a contractile phenotype to a synthetic phenotype via inhibiting NF-κB signaling pathway in human VSMCs.

Conclusion: These results indicate that inhibition of CDK9 may be a novel therapeutic target for the prevention of atherosclerosis.
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http://dx.doi.org/10.18632/aging.202998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221363PMC
June 2021

The differences in mitochondrial function, mitochondrial dynamics, and cell death between odontogenic cysts/tumors and normal dental follicles.

Mitochondrion 2021 Jul 4;59:175-183. Epub 2021 Jun 4.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address:

We aimed to compare mitochondrial function, mitochondrial dynamics, apoptosis, and necroptosis between odontogenic cysts/tumors, including radicular cysts, dentigerous cysts, ameloblastoma, vs. dental follicles as control. We demonstrated that mitochondrial dysregulation and imbalanced mitochondrial dynamics were observed in ameloblastoma. Apoptosis was increased in dentigerous cysts, and ameloblastoma, while necroptosis was suppressed in ameloblastoma. Necroptosis in radicular cysts was higher than that of control, suggesting that the inflammation-associated cell death occurred in radicular cysts. Our findings suggest ameloblastoma exhibited mitochondrial dysfunction, decreased mitochondrial fusion, and potential apoptosis. Therefore, alleviating mitochondrial dysregulation and apoptosis may be novel-targeted therapy for odontogenic cysts and tumors.
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http://dx.doi.org/10.1016/j.mito.2021.06.004DOI Listing
July 2021

Staying fit and the obese aging heart condition.

Aging (Albany NY) 2021 05 13;13(10):13374-13375. Epub 2021 May 13.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

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http://dx.doi.org/10.18632/aging.203070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202890PMC
May 2021

An Indole-2-Carboxamide Derivative, LG4, Alleviates Diabetic Kidney Disease Through Inhibiting MAPK-Mediated Inflammatory Responses.

J Inflamm Res 2021 27;14:1633-1645. Epub 2021 Apr 27.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.

Aim: Elevated inflammatory signaling has been shown to play an important role in diabetic kidney disease (DKD). We previously developed a new anti-inflammatory compound LG4. In the present study, we have tested the hypothesis that LG4 could prevent DKD by suppressing inflammation and identified the underlying mechanism.

Methods: Streptozotocin-induced type 1 diabetic mice were used to develop DKD and evaluate the effects of LG4 against DKD. To identify the potential targets of LG4, biotin-linked LG4 was synthesized and subjected to proteome microarray screening. The cellular mechanism of LG4 was investigated in HG-challenged SV40MES13 cells.

Results: Although LG4 treatment had no effect on the body weight and blood glucose levels, it remarkably reversed the hyperglycemia-induced pathological changes and fibrosis in the kidneys of T1DM mice. Importantly, hyperglycemia-induced renal inflammation evidenced by NF-κB activation and TNFα and IL-6 overexpression was greatly ameliorated with LG4 treatment. Proteosome microarray screening revealed that JNK and ERK were the direct binding proteins of LG4. LG4 significantly reduced HG-induced JNK and ERK phosphorylation and subsequent NF-κB activation in vivo and in vitro. In addition, LG4 did not show further anti-inflammatory effect in HG-challenged mesangial cells with the presence of JNK or ERK inhibitor.

Conclusion: LG4 showed renoprotective activity through inhibiting ERK/JNK-mediated inflammation in diabetic mice, indicating that LG4 may be a therapeutic agent for DKD.
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http://dx.doi.org/10.2147/JIR.S308353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088301PMC
April 2021

Effectiveness of N-Acetylcysteine in the Treatment of Renal Deterioration Caused by Long-Term Exposure to Bisphenol A.

Biomolecules 2021 Apr 29;11(5). Epub 2021 Apr 29.

Renal Physiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Human health hazards caused by bisphenol A (BPA), a precursor for epoxy resins and polycarbonate-based plastics, are well documented and are closely associated with mitochondrial impairment and oxidative imbalance. This study aimed to assess the therapeutic efficacy of N-acetylcysteine (NAC) on renal deterioration caused by long-term BPA exposure and examine the signaling transduction pathway involved. Male Wistar rats were given vehicle or BPA orally for 12 weeks then the BPA-treated group was subdivided to receive vehicle or NAC concurrently with BPA for a further 4 weeks, while the vehicle-treated normal control group continued to receive vehicle through to the end of experiment. Proteinuria, azotemia, glomerular filtration reduction and histopathological abnormalities caused by chronic BPA exposure were significantly reduced following NAC therapy. NAC also diminished nitric oxide and lipid peroxidation but enhanced renal glutathione levels, and counteracted BPA-induced mitochondrial swelling, increased mitochondrial reactive oxygen species production, and the loss of mitochondrial membrane potential. The benefit of NAC was related to the modulation of signaling proteins in the AMPK-SIRT3-SOD2 axis. The present study shows the potential of NAC to restore mitochondrial integrity and oxidative balance after long-term BPA exposure, and suggests that NAC therapy is an effective approach to tackle renal deterioration in this condition.
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http://dx.doi.org/10.3390/biom11050655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145636PMC
April 2021

Platinum-based chemotherapy and bevacizumab instigate the destruction of human ovarian cancers via different signaling pathways.

Biochem Pharmacol 2021 Jun 29;188:114587. Epub 2021 Apr 29.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address:

The standard chemotherapy regimens of ovarian cancer are platinum-based chemotherapy (carboplatin and paclitaxel) and bevacizumab (BEV). However, the effects of BEV alone or combined with carboplatin and paclitaxel on mitochondrial dynamics, mitochondrial function, mitophagy, apoptosis, inflammation and vascular endothelial growth factor (VEGF) in human ovarian cancer mitochondria and cells have not yet been investigated. Therefore, we aimed to test the hypothesis that 1) platinum-based chemotherapy and BEV equally damage isolated mitochondria from human ovarian cancers, and ovarian cancer cells through inducing mitochondrial dynamics dysregulation, mitochondrial dysfunction, increased mitophagy and apoptosis, as well as altered inflammation and VEGF; and 2) combined therapies exert greater damage than monotherapy. Each isolated human ovarian cancer mitochondria (n = 16) or CaOV3 cells (n = 6) were treated with either platinum-based chemotherapy (carboplatin 10 μM and paclitaxel 5 μM), BEV (2 mg/mL) or combined platinum-based chemotherapy and BEV for 60 min or 24 h, respectively. Following the treatment, mitochondrial dynamics, mitochondrial function, mitophagy, apoptosis, cytotoxicity, inflammation and VEGF were determined. Platinum-based chemotherapy caused ovarian cancer mitochondria and cell damage through mitochondrial dysfunction, increased cell death with impairment of membrane integrity, and enhanced VEGF reduction, while BEV did not. BEV caused deterioration of ovarian cancer mitochondria and cells through mitochondrial-dependent apoptosis, but it had no effect on cell viability. Interestingly, combined platinum-based chemotherapy and BEV treatments had no addictive effects on all parameters except mitochondrial maximal respiration, when compared to monotherapy. Collectively, these findings suggest that platinum-based chemotherapy and BEV caused human ovarian cancer mitochondrial and cell damage through different mechanisms.
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http://dx.doi.org/10.1016/j.bcp.2021.114587DOI Listing
June 2021

Post-Ischemic Treatment of Recombinant Human Secretory Leukocyte Protease Inhibitor (rhSLPI) Reduced Myocardial Ischemia/Reperfusion Injury.

Biomedicines 2021 Apr 13;9(4). Epub 2021 Apr 13.

Graduate Programs in Biomedical Sciences, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok 65000, Thailand.

Myocardial ischemia/reperfusion (I/R) injury is a major cause of mortality and morbidity worldwide. Among factors contributing to I/R injury, proteolytic enzymes could also cause cellular injury, expand the injured area and induce inflammation, which then lead to cardiac dysfunction. Therefore, protease inhibition seems to provide therapeutic benefits. Previous studies showed the cardioprotective effect of secretory leukocyte protease inhibitor (SLPI) against myocardial I/R injury. However, the effect of a post-ischemic treatment with SLPI in an in vivo I/R model has never been investigated. In the present study, recombinant human (rh) SLPI (rhSLPI) was systemically injected during coronary artery occlusion or at the onset of reperfusion. The results show that post-ischemic treatment with rhSLPI could significantly reduce infarct size, Lactate Dehydrogenase (LDH) and Creatine kinase-MB (CK-MB) activity, inflammatory cytokines and protein carbonyl levels, as well as improving cardiac function. The cardioprotective effect of rhSLPI is associated with the attenuation of p38 MAPK phosphorylation, Bax, caspase-3 and -8 protein levels and enhancement of pro-survival kinase Akt and ERK1/2 phosphorylation. In summary, this is the first report showing the cardioprotective effects against myocardial I/R injury of post-ischemic treatments with rhSLPI in vivo. Thus, these results suggest that SLPI could be used as a novel therapeutic strategy to reduce myocardial I/R injury.
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http://dx.doi.org/10.3390/biomedicines9040422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070046PMC
April 2021

The mechanistic insights of the arrhythmogenic effect of trastuzumab.

Biomed Pharmacother 2021 Jul 23;139:111620. Epub 2021 Apr 23.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand; Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai 50200, Thailand; Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. Electronic address:

Cardiovascular diseases and cancers are the leading causes of deaths globally, and an increasing proportion of cancer patients is suffering from cardiac adverse effects of chemotherapeutic drugs. Trastuzumab, a monoclonal antibody that inhibits the activity of the human epidermal growth factor receptor 2 (HER2), is a potent targeted therapy for HER2-positive malignancies. Despite the impressive antineoplastic efficacy, the cardiotoxicity of trastuzumab frequently limits its use. Trastuzumab-induced cardiac contractile dysfunction has been extensively studied, yet the electrophysiological side effect of trastuzumab remains poorly characterized. Growing evidence from basic and clinical studies supports the link between trastuzumab treatment and arrhythmias. This review comprehensively summarizes relevant information from those reports, discusses their limitations, and suggests future research directions. We aim to encourage further investigations that will provide valuable insights to devise cardioprotective strategies against trastuzumab-induced cardiotoxicity.
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http://dx.doi.org/10.1016/j.biopha.2021.111620DOI Listing
July 2021

Hyperbaric oxygen therapy effectively alleviates D-galactose-induced-age-related cardiac dysfunction via attenuating mitochondrial dysfunction in pre-diabetic rats.

Aging (Albany NY) 2021 04 16;13(8):10955-10972. Epub 2021 Apr 16.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Currently, the prevalence of obesity in aging populations is fast growing worldwide. Aging induced by D-galactose (D-gal) is proven to cause the worsening of cardiac dysfunction in pre-diabetic rats via deteriorating cardiac mitochondrial function. Hyperbaric oxygen therapy (HBOT) has been shown to attenuate D-gal-induced cognitive deterioration through decreased inflammation and apoptosis. We tested the hypothesis that HBOT alleviates D-gal induced cardiac dysfunction via improving mitochondrial function in pre-diabetic rats. Wistar rats (n=56) were fed normal diet or high-fat diet for 12 weeks. For subsequent 8 weeks, they were subcutaneously injected either vehicle (0.9% normal saline) or D-gal (150mg/kg/day). Rats were randomly subdivided into 7 groups at week 21: sham-treated (normal diet fed rats with vehicle (NDV), high-fat diet fed rats with vehicle (HFV), normal diet fed rats with D-gal (NDDg), high-fat diet fed rats with D-gal (HFDg)) and HBOT-treated (HFV, NDDg, HFDg). Sham rats received ambient pressure of oxygen while HBOT-treated ones received 100% oxygen given once daily for 60 minutes at 2 atmosphere absolute. HBOT reduced metabolic impairments, mitochondrial dysfunction and increased autophagy, resulting in an improvement of cardiac function in aged pre-diabetic rats.
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http://dx.doi.org/10.18632/aging.202970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8109141PMC
April 2021

An association between fibroblast growth factor 21 and cognitive impairment in iron-overload thalassemia.

Sci Rep 2021 Apr 13;11(1):8057. Epub 2021 Apr 13.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training (CERT) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.

Although an increased fibroblast growth factor 21 (FGF21) level was related to mild cognitive impairment (MCI) in metabolic syndrome patients, any association regarding FGF21 and MCI in thalassemia patients as well as mechanistic insight are questionable. Therefore, the objectives of this study were: (1) to investigate the prevalence and associative risk factors of MCI in thalassemia patients, (2) to evaluate the association between levels of FGF21 and MCI in thalassemia patients, and (3) to investigate brain FGF21 signaling in iron-overload thalassemia. Thalassemia patients were enrolled onto the study (n = 131). Montreal cognitive assessment (MoCA) was used to determine cognitive performance. Plasma FGF21 level was determined in all patients. Iron-overload β-thalassemic (HT) mice were used to investigate brain FGF21 level and signaling, the expression of synaptic proteins, and Alzheimer's like pathology. We found that 70% of thalassemia patients developed MCI. FGF21 level was positively correlated with the MCI. Interestingly, brain FGF21 resistance, as indicated by increased brain FGF21 levels with impaired FGF21 signaling, was found in iron-overload HT mice. The reduced synaptic protein expression and increased Alzheimer's like pathology were also observed. These suggest that FGF21 may play a role in MCI in thalassemia patients.
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http://dx.doi.org/10.1038/s41598-021-87597-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044130PMC
April 2021

Melatonin as a therapy in cardiac ischemia-reperfusion injury: Potential mechanisms by which MT2 activation mediates cardioprotection.

J Adv Res 2021 03 28;29:33-44. Epub 2020 Sep 28.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.

Introduction: Previous studies reported the beneficial effects of pretreatment with melatonin on the heart during cardiac ischemia/reperfusion (I/R) injury. However, the effects of melatonin given after cardiac ischemia, as well as its comparative temporal effects are unknown. These include pretreatment, during ischemia, and at the onset of reperfusion. Also, the association between melatonin receptors and cardiac arrhythmias, mitochondrial function and dynamics, autophagy, and mitophagy during cardiac I/R have not been investigated.

Objectives: We tested two major hypotheses in this study. Firstly, the temporal effect of melatonin administration exerts different cardioprotective efficacy during cardiac I/R. Secondly, melatonin provides cardioprotective effects via MT2 activation, leading to improvement in cardiac mitochondrial function and dynamics, reduced excessive mitophagy and autophagy, and decreased cardiac arrhythmias, resulting in improved LV function.

Methods: Male rats were subjected to cardiac I/R, and divided into 4 intervention groups: vehicle, pretreatment with melatonin, melatonin given during ischemia, and melatonin given at the onset of reperfusion. In addition, either a non-specific melatonin receptor (MT) blocker or specific MT2 blocker was given to rats.

Results: Treatment with melatonin at all time points alleviated cardiac I/R injury to a similar extent, quantified by reduction in infarct size, arrhythmia score, LV dysfunction, cardiac mitochondrial dysfunction, imbalance of mitochondrial dynamics, excessive mitophagy, and a decreased Bax/Bcl2 ratio. In H9C2 cells, melatonin increased %cell viability by reducing mitochondrial dynamic imbalance and a decrease in Bax protein expression. The cardioprotective effects of melatonin were dependent on MT2 activation.

Conclusion: Melatonin given before or after ischemia exerted equal levels of cardioprotection on the heart with I/R injury, and its beneficial effects on cardiac arrhythmias, cardiac mitochondrial function and dynamics were dependent upon the activation of MT2.
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http://dx.doi.org/10.1016/j.jare.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020169PMC
March 2021

Targeting necroptosis as therapeutic potential in chronic myocardial infarction.

J Biomed Sci 2021 Apr 9;28(1):25. Epub 2021 Apr 9.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.

Cardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.
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http://dx.doi.org/10.1186/s12929-021-00722-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034148PMC
April 2021

Effects of Metformin on Hepatic Steatosis in Adults with Nonalcoholic Fatty Liver Disease and Diabetes: Insights from the Cellular to Patient Levels.

Gut Liver 2021 Apr 7. Epub 2021 Apr 7.

Cardiac Electrophysiology Research and Training Center, Chiang Mai, Thailand.

Nonalcoholic fatty liver disease (NAFLD) patients with diabetes constitute a subgroup of patients with a high rate of liver-related complications. Currently, there are no specific drug recommendations for these patients. Metformin, a conventional insulin sensitizer agent, has been widely prescribed in patients with diabetes. Metformin treatment has been shown to be effective at alleviating hepatic lipogenesis in animal models of NAFLD, with a variety of mechanisms being deemed responsible. To date, most studies have enrolled diabetic patients who are treated with metformin, with the drug being taken continuously throughout the study. Although evidence exists regarding the benefits of metformin for NAFLD in preclinical studies, reports on the efficacy of metformin in adult NAFLD patients have had some discrepancies regarding changes in liver biochemistry and hepatic fat content. Evidence has also suggested possible effects of metformin as regards the prevention of hepatocellular carcinoma tumorigenesis. This review was performed to comprehensively summarize the available and clinical studies regarding the effects of metformin on liver steatosis for the treatment of adult NAFLD patients with diabetes. Consistent reports as well as controversial findings are included in this review, and the mechanistic insights are also provided. In addition, this review focuses on the efficacy of metformin as a monotherapy and as a combined therapy with other antidiabetic medications.
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http://dx.doi.org/10.5009/gnl20367DOI Listing
April 2021

The alterations of microbiota and pathological conditions in the gut of patients with colorectal cancer undergoing chemotherapy.

Anaerobe 2021 Apr 26;68:102361. Epub 2021 Mar 26.

Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, 50200, Thailand; Cardiac Electrophysiology Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand. Electronic address:

Colorectal cancer (CRC) has become a serious threat to human life and health. Most patients are diagnosed at the late stage of advanced CRC, resulting in losing their best opportunity for surgical treatment. Chemotherapy plays a crucial role in the control and treatment of advanced CRC. However, the cytotoxicity of chemotherapeutic drugs can easily cause the imbalance of gut flora, damage the barrier of the gastrointestinal mucosa, and mediate mucosal inflammation of the digestive tract, which is called "gastrointestinal mucositis." This mucositis can affect the quality of life of the host and even threaten their lives. Several studies reported the association between chemotherapy-mediated gastrointestinal mucositis in CRC and gut dysbiosis. However, the underlying mechanisms of this association are still unclear. The alternative or complementary treatments to reshape gut microbiota and slow down the side effects of chemotherapy have shown the improvement of gastrointestinal mucositis following chemotherapy in the CRC condition. This review will summarize and discuss the evidence of the association between chemotherapy-mediated gastrointestinal mucositis in CRC and altered gut microbiota from in vivo and clinical studies. The possible mechanisms of gastrointestinal mucositis, including the destruction of the gastrointestinal mucosal barrier, the induction of gut dysbiosis, and histopathological changes in the gut of CRC with chemotherapy will be illustrated. In addition, the nonpharmacological interventions and phytochemical extracts by using the manipulation of the microbial population for therapeutic purposes for relieving side effects of chemotherapy as well as a cancer treatment would be summarized and discussed in this review.
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http://dx.doi.org/10.1016/j.anaerobe.2021.102361DOI Listing
April 2021

Modulating mitochondrial dynamics attenuates cardiac ischemia-reperfusion injury in prediabetic rats.

Acta Pharmacol Sin 2021 Mar 12. Epub 2021 Mar 12.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.

Mitochondria are extraordinarily dynamic organelles that have a variety of morphologies, the status of which are controlled by the opposing processes of fission and fusion. Our recent study shows that inhibition of excessive mitochondrial fission by Drp1 inhibitor (Mdivi-1) leads to a reduction in infarct size and left ventricular (LV) dysfunction following cardiac ischemia-reperfusion (I/R) injury in high fat-fed induced pre-diabetic rats. In the present study, we investigated the cardioprotective effects of a mitochondrial fusion promoter (M1) and a combined treatment (M1 and Mdivi-1) in pre-diabetic rats. Wistar rats were given a high-fat diet for 12 weeks to induce prediabetes. The rats then subjected to 30 min-coronary occlusions followed by reperfusion for 120 min. These rats were intravenously administered M1 (2 mg/kg) or M1 (2 mg/kg) combined with Mdivi-1 (1.2 mg/kg) prior to ischemia, during ischemia or at the onset of reperfusion. We showed that administration of M1 alone or in combination with Mdivi-1 prior to ischemia, during ischemia or at the onset of reperfusion all significantly attenuated cardiac mitochondrial ROS production, membrane depolarization, swelling and dynamic imbalance, leading to reduced arrhythmias and infarct size, resulting in improved LV function in pre-diabetic rats. In conclusion, the promotion of mitochondrial fusion at any time-points during cardiac I/R injury attenuated cardiac mitochondrial dysfunction and dynamic imbalance, leading to decreased infarct size and improved LV function in pre-diabetic rats.
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http://dx.doi.org/10.1038/s41401-021-00626-3DOI Listing
March 2021

Hyperbaric oxygen therapy restores cognitive function and hippocampal pathologies in both aging and aging-obese rats.

Mech Ageing Dev 2021 04 1;195:111465. Epub 2021 Mar 1.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Center of Excellence in Cardiac Electrophysiology, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand. Electronic address:

The population of obese-elderly has increased prominently around the world. Both aging and obesity are major factors of neurodegeneration. The present study hypothesizes that HBOT attenuates metabolic disturbance, cognitive decline, hippocampal pathologies in aging and aging-obese model. Sixty Wistar rats were separated into 2 groups to receive normal-diet (ND) or high-fat diet (HFD) for 22 weeks. At week 13, ND rats were divided into two subgroups to receive vehicle (0.9 % NSS, s.c) or d-gal (150 mg/kg/d, s.c) for total 10 weeks. HFD rats were injected only d-gal (150 mg/kg/d, s.c; HFDD) for total 10 weeks. At week 20, rats in each subgroup were given sham-treatment (1ATA, 80 L/min, 80 min/day), or HBOT (2ATA, pure O, 250 L/min, 80 min/day) for 14 days. Novel object location test, metabolic parameters, and hippocampal pathologies were determined after HBOT. d-gal induced insulin resistance, increased oxidative stress, autophagy impairment, microglial hyperactivation, apoptosis, synaptic dysplasticity which resulted in cognitive impairment. d-gal-treated HFD-fed rats had the highest levels of oxidative stress, apoptosis, dendritic spine loss. HBOT attenuated insulin resistance, cognitive impairment, hippocampal aging and pathologies in both models. These findings suggest that HBOT restored insulin sensitivity, hippocampal functions, cognition in aging and aging-obese models.
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http://dx.doi.org/10.1016/j.mad.2021.111465DOI Listing
April 2021

Cognitive impairment in myocardial infarction and heart failure.

Acta Physiol (Oxf) 2021 05 10;232(1):e13642. Epub 2021 Mar 10.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Myocardial infarction (MI) occurs when coronary blood flow is decreased due to an obstruction/occlusion of the vessels, leading to myocardial death and progression to heart failure (HF). Cognitive impairment, anxiety, depression and memory loss are the most frequent mental health problems among patients with HF. The most common cause of cognitive decline is cardiac systolic dysfunction, which leads to reduced cerebral perfusion. Several in vivo and clinical studies provide information regarding the underlying mechanisms of HF in brain pathology. Neurohormonal activation, oxidative stress, inflammation, glial activation, dendritic spine loss and brain programmed cell death are all proposed as contributors of cognitive impairment in HF. Furthermore, several investigations into the effects of various medications on brain pathology utilizing MI models have been reported. In this review, potential mechanisms involving HF-associated cognitive impairment, as well as neuroprotective interventions in HF models, are discussed and summarized. In addition, gaps in the surrounding knowledge, including the types of brain cell death and the effects of cell death inhibitors in HF, are presented and discussed. This review provides valuable information that will suggest the potential therapeutic strategies for cognitive impairment in patients with HF.
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http://dx.doi.org/10.1111/apha.13642DOI Listing
May 2021

The Role of Acupuncture on the Gut-Brain-Microbiota Axis in Irritable Bowel Syndrome.

Am J Chin Med 2021 20;49(2):285-314. Epub 2021 Feb 20.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai, Thailand.

Irritable bowel syndrome (IBS) is a chronic dysfunction of the gastrointestinal tract, commonly characterized by abdominal pain or abdominal discomfort. These symptoms can substantially reduce the quality of life and work productivity of the patients. The exact pathogenesis of IBS remains unclear, as it has become apparent that multiple pathways are activated in the condition, including inflammation, immunology, neurology and psychology. Recent evidence has shown that symptoms in IBS are related to the dysfunction of the nervous system, particularly the viscerosomatic pathway, through immune-to-brain communication. The potential link between brain-gut relationships is gut microbiota. The management of IBS mostly focuses on symptomatically treating the patients. There are a wide range of standard treatments, including pharmacological to psychological interventions which are effective in some patients. Therefore, a combination of therapies including both standard and complimentary treatments, including Traditional Chinese Medicine (TCM) such as acupuncture, have been used in treating IBS patients. Several and clinical studies have demonstrated the efficacy of acupuncture in treating IBS. Increasing attention has been paid to research regarding the action mechanisms of acupuncture for IBS. This paper summarizes and discusses the possible mechanisms associated with acupuncture on the pathophysiology of IBS, including gastrointestinal (GI) motility, visceral hypersensitivity, the immune system, neurotransmitters, and the brain-gut axis. The results from and clinical studies have been included. In addition, the effects of acupuncture on gut microbiota in IBS are included and any contradictory findings are deliberated.
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http://dx.doi.org/10.1142/S0192415X21500154DOI Listing
February 2021

Oxidative Stress and Inflammatory Markers of Cordocentesis Blood in Response to Fetal Anemia.

Curr Mol Med 2021 Feb 4. Epub 2021 Feb 4.

Maternal Fetal Medicine Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, . Thailand.

Background: Hypothetically, fetal anemic hypoxia causes cellular damage with an increase in oxidative stress levels. This study, using hemoglobin (Hb) Bart's disease as a study model, aims to compare the levels of oxidative stress and inflammatory markers as well as fetal hemodynamics in anemic fetuses with those of non-anemic fetuses.

Materials And Methods: Forty pregnancies at risk of fetal Hb Bart's disease scheduled for cordocentesis at 18 to 22 weeks were recruited into the study. Fetal blood was collected to measure the levels of 8-Isoprostane (8-Isop), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and hemoglobin as well as for hemoglobin typing.

Results: There was no significant difference in cord blood 8-Isop, TNF-α, and IL-10 levels between the Hb Bart's disease group and the unaffected group, whereas several hemodynamic parameters, such as cardiac output, cardiac size, cardiac performance, middle cerebral artery - peak systolic velocity, etc., were significantly changed in the fetal Hb Bart's group. In the subgroup analysis, the level of serum 8-Isop in the severe anemia group tended to increase, though not significantly, compared with the non-anemic group (275.3±141.8 vs 203.9±49.2 pg/mL; p=0.079).

Conclusions: In response to anemia, fetuses might have a high capacity of hemodynamic adaptation without significant cellular damage, though a trend of an increase in oxidative stress marker was found in severe fetal anemia. Theoretically, intrauterine blood transfusion for fetal anemia during adaptive compensation may result in no residual insults.
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http://dx.doi.org/10.2174/1573405617666210204211744DOI Listing
February 2021

Mitochondrial dysfunction in fatal ventricular arrhythmias.

Acta Physiol (Oxf) 2021 04 19;231(4):e13624. Epub 2021 Feb 19.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Ventricular fibrillation (VF) and sudden cardiac arrest (SCA) remain some of the most important public health concerns worldwide. For the past 50 years, the recommendation in the Advanced Cardiac Life Support (ACLS) guidelines has been that defibrillation is the only option for shockable cardiac arrest. There is growing evidence to demonstrate that mitochondria play a vital role in the outcome of postresuscitation cardiac function. Although targeting mitochondria to improve resuscitation outcome following cardiac arrest has been proposed for many years, understanding concerning the changes in mitochondria during cardiac arrest, especially in the case of VF, is still limited. In addition, despite new research initiatives and improved medical technology, the overall survival rates of patients with SCA still remain the same. Understanding cardiac mitochondrial alterations during fatal arrhythmias may help to enable the formulation of strategies to improve the outcomes of resuscitation. The attenuation of cardiac mitochondrial dysfunction during VF through pharmacological intervention as well as ischaemic postconditioning could also be a promising target for intervention and inform a new paradigm of treatments. In this review, the existing evidence available from in vitro, ex vivo and in vivo studies regarding the roles of mitochondrial dysfunction during VF is comprehensively summarized and discussed. In addition, the effects of interventions targeting cardiac mitochondria during fatal ventricular arrhythmias are presented. Since there are no clinical reports from studies targeting mitochondria to improve resuscitation outcome available, this review will provide important information to encourage further investigations in a clinical setting.
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http://dx.doi.org/10.1111/apha.13624DOI Listing
April 2021

Identification of Circulating Endocan-1 and Ether Phospholipids as Biomarkers for Complications in Thalassemia Patients.

Metabolites 2021 Jan 26;11(2). Epub 2021 Jan 26.

Department of Biology, York University, Toronto, ON M3J1P3, Canada.

Despite advances in our knowledge and attempts to improve therapies, β-thalassemia remains a prevalent disorder with increased risk for the development of cardiomyopathy. Using an untargeted discovery-based lipidomic workflow, we uncovered that transfusion-dependent thalassemia (TDT) patients had a unique circulating lipidomic signature consisting of 387 lipid features, allowing their significant discrimination from healthy controls (Q-value < 0.01). In particular, TDT patients had elevated triacylglycerols and long-chain acylcarnitines, albeit lower ether phospholipids or plasmalogens, sphingomyelins, and cholesterol esters, reminiscent of that previously characterized in cardiometabolic diseases resulting from mitochondrial and peroxisomal dysfunction. Discriminating lipid (sub)classes correlated differentially with clinical parameters, reflecting blood (ether phospholipids) and iron (cholesterol ester) status or heart function (triacylglycerols). We also tested 15 potential serum biomarkers related to cardiometabolic disease and found that both lipocalin-2 and, for the first time, endocan-1 levels were significantly elevated in TDT patients and showed a strong correlation with blood parameters and three ether diacylglycerophosphatidylcholine species. In conclusion, this study identifies new characteristics of TDT patients which may have relevance in developing biomarkers and therapeutics.
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http://dx.doi.org/10.3390/metabo11020070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912378PMC
January 2021

Impacts of gut microbiota on gestational diabetes mellitus: a comprehensive review.

Eur J Nutr 2021 Aug 29;60(5):2343-2360. Epub 2021 Jan 29.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.

Background: Gestational diabetes mellitus (GDM) is a condition that seriously threatens mother and child health. The incidence of GDM has increased worldwide in the past decades. In addition, the complications of GDM such as type 2 diabetes (T2DM) and neonatal malformations could negatively affect the living quality of mothers and their children.

Aim: It has been widely known that the imbalance of gut microbiota or called 'gut dysbiosis' plays a key role in the development of insulin resistance and chronic low-grade inflammation in T2DM patients. However, the impacts of gut microbiota on GDM remain controversial. Here, we aim to comprehensively review the alterations of gut microbiota in GDM mothers and their offspring.

Results: The alterations of Firmicutes/Bacteroidetes (F/B) ratio, short-chain fatty acid (SCFA)-producing bacteria, bacteria with probiotics properties and gram-negative lipopolysaccharide (LPS)-producing bacteria play a vital role in the development of GDM. The beneficial roles of gut microbiota modification (probiotics, synbiotics and lifestyle modification) as a treatment of GDM were found in some, but not all studies.

Conclusion: In the near future, gut microbiota modification may be considered as one of the standard treatments for GDM. Moreover, further studies regarding the specific gut microbiota that are associated with the early development of GDM are required. This may contribute to the novel diagnostic markers for early stages of GDM.
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http://dx.doi.org/10.1007/s00394-021-02483-6DOI Listing
August 2021

Association of Chronic Opisthorchis Infestation and Microbiota Alteration on Tumorigenesis in Cholangiocarcinoma.

Clin Transl Gastroenterol 2020 12 22;12(1):e00292. Epub 2020 Dec 22.

Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Cholangiocarcinoma (CCA) is a common hepatobiliary cancer in East and Southeast Asia. The data of microbiota contribution in CCA are still unclear. Current available reports have demonstrated that an Opisthorchis viverrini (OV) infection leads to dysbiosis in the bile duct. An increase in the commensal bacteria Helicobacter spp. in OV-infected CCA patients is associated with bile duct inflammation, severity of bile duct fibrosis, and cholangiocyte proliferation. In addition, secondary bile acids, major microbial metabolites, can mediate cholangiocyte inflammation and proliferation in the liver. A range of samples from CCA patients (stool, bile, and tumor) showed different degrees of dysbiosis. The evidence from these samples suggests that OV infection is associated with alterations in microbiota and could potentially have a role in CCA. In this comprehensive review, reports from in vitro, in vivo, and clinical studies that demonstrate possible links between OV infection, microbiota, and CCA pathogenesis are summarized and discussed. Understanding these associations may pave ways for novel potential adjunct intervention in gut microbiota in CCA patients.
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http://dx.doi.org/10.14309/ctg.0000000000000292DOI Listing
December 2020

Effects of melatonin in wound healing of dental pulp and periodontium: Evidence from in vitro, in vivo and clinical studies.

Arch Oral Biol 2021 Mar 6;123:105037. Epub 2021 Jan 6.

Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand; Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand. Electronic address:

Introduction: Database research has revealed that melatonin has beneficial effects in pulpal and periodontal regeneration. Several studies reported protective effects of melatonin against inflammation in several organs including the heart, brain, and teeth. In addition to inflammation reduction, melatonin has been involved in tissue regeneration and wound healing. The aim of this review is to summarize the evidence from in vitro, in vivo and clinical studies on the effects of melatonin in wound healing of dental pulp and periodontium. This review gives a thorough summary of the possible role of melatonin in wound healing of dental pulp and periodontium in connection with anti-inflammatory and antioxidant effects, cell proliferation, and cell differentiation. Any contradictory evidence is also assessed.

Methods: The PubMed database was searched for all research articles published before April 2020 with the search terms "melatonin" and "dental pulp". Articles with the search terms "melatonin", "periodontal disease" and "bone" published before October 2019 were also included. Non-English articles were excluded.

Results: Melatonin has been shown to reduce inflammation, inhibit cell proliferation and regulate differentiation of pulp cells. Melatonin increased odontoblast activities, resulting in the differentiation in the dental pulp. However, melatonin did not initiate differentiation in undifferentiated pulp cells but seemed to have beneficial effects in periodontitis by promoting periodontium's wound healing.

Conclusion: Those findings suggest that melatonin could have beneficial effects on pulpal and periodontal cells under inflammatory conditions. However, discrepancies remain between in vitro and in vivo findings regarding the effect of melatonin on dental pulp and periodontium.
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http://dx.doi.org/10.1016/j.archoralbio.2020.105037DOI Listing
March 2021

Activation of TRPC (Transient Receptor Potential Canonical) Channel Currents in Iron Overloaded Cardiac Myocytes.

Circ Arrhythm Electrophysiol 2021 02 8;14(2):e009291. Epub 2021 Jan 8.

Department of Cell Biology and Molecular Medicine, Rutgers University, New Jersey Medical School, Newark (N.S.-A., N.F., J.K.G., L.-H.X.).

Background: Arrhythmias and heart failure are common cardiac complications leading to substantial morbidity and mortality in patients with hemochromatosis, yet mechanistic insights remain incomplete. We investigated the effects of iron (Fe) on electrophysiological properties and intracellular Ca (Ca) handling in mouse left ventricular cardiomyocytes.

Methods: Cardiomyocytes were isolated from the left ventricle of mouse hearts and were superfused with Fe/8-hydroxyquinoline complex (5-100 μM). Membrane potential and ionic currents including TRPC (transient receptor potential canonical) were recorded using the patch-clamp technique. Ca was evaluated by using Fluo-4. Cell contraction was measured with a video-based edge detection system. The role of TRPCs in the genesis of arrhythmias was also investigated by using a mathematical model of a mouse ventricular myocyte with the incorporation of the TRPC component.

Results: We observed prolongation of the action potential duration and induction of early and delayed afterdepolarizations in myocytes superfused with 15 µmol/L Fe/8-hydroxyquinoline complex. Iron treatment decreased the peak amplitude of the L-type Ca current and total K current, altered Ca dynamics, and decreased cell contractility. During the final phase of Fe treatment, sustained Ca waves and repolarization failure occurred and ventricular cells became unexcitable. Gadolinium abolished Ca waves and restored the resting membrane potential to the normal range. The involvement of TRPC activation was confirmed by TRPC channel current recordings in the absence or presence of functional TRPC channel antibodies. Computer modeling captured the same action potential and Ca dynamics and provided additional mechanistic insights.

Conclusions: We conclude that iron overload induces cardiac dysfunction that is associated with TRPC channel activation and alterations in membrane potential and Ca dynamics.
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http://dx.doi.org/10.1161/CIRCEP.120.009291DOI Listing
February 2021
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