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PloS One 2022In folklore, Heritiera fomes (H. fomes) has been extensively used in treatment of various ailments such as diabetes, cardiac and hepatic disorders. The present study...
In folklore, Heritiera fomes (H. fomes) has been extensively used in treatment of various ailments such as diabetes, cardiac and hepatic disorders. The present study aimed to elucidate the antidiabetic actions of hot water extract of H. fomes (HWHF), including effects on insulin release from BRIN BD11 cells and isolated mouse islets as well as glucose homeostasis in high-fat-fed rats. Molecular mechanisms underlying anti-diabetic activity along with isolation of active compounds were also evaluated. Non-toxic concentrations of HWHF stimulated concentration-dependent insulin release from isolated mouse islets and clonal pancreatic β-cells. The stimulatory effect was potentiated by glucose and isobutyl methylxanthine (IBMX), persisted in presence of tolbutamide or a depolarizing concentration of KCl but was attenuated by established inhibitors of insulin release such as diazoxide, verapamil, and Ca2+ chelation. HWHF caused depolarization of the β-cell membrane and increased intracellular Ca2+. The extract also enhanced glucose uptake and insulin action in 3T3-L1 differentiated adipocytes cells and significantly inhibited in a dose-dependent manner starch digestion, protein glycation, DPP-IV enzyme activity, and glucose diffusion in vitro. Oral administration of HWHF (250 mg/5ml/kg b.w.) to high-fat fed rats significantly improved glucose tolerance and plasma insulin responses and it inhibited plasma DPP-IV activity. HWHF also decreased in vivo glucose absorption and intestinal disaccharidase activity while increasing gastrointestinal motility and unabsorbed sucrose transit. Compounds were isolated from HWHF with similar molecular weights to quercitrin (C21 H20 O11) ranging from 447.9 to 449.9 Da which stimulated the insulin release in vitro and improved both glucose tolerance and plasma insulin responses in mice. In conclusion, H. fomes and its water-soluble phytochemicals such as quercitrin may exert antidiabetic actions mediated through a variety of mechanisms which might be useful as dietary adjunct in the management of type 2 diabetes.
Topics: Animals; Mice; Rats; Blood Glucose; Calcium; Coriolaceae; Diabetes Mellitus, Type 2; Glucose; Hypoglycemic Agents; Insulin; Insulin Secretion; Insulin, Regular, Human; Islets of Langerhans; Malvaceae; Plant Bark; Water
PubMed: 35239729
DOI: 10.1371/journal.pone.0264632 -
The Pan African Medical Journal 2020Neonatal hypoglycemia (NH) is one of the most common abnormalities encountered in the newborn. Hypoglycemia continues to be an important cause of morbidity in neonates... (Review)
Review
Neonatal hypoglycemia (NH) is one of the most common abnormalities encountered in the newborn. Hypoglycemia continues to be an important cause of morbidity in neonates and children. Prompt diagnosis and management of the underlying hypoglycemia disorder is critical for preventing brain damage and improving outcomes. Congenital hyperinsulinism (CHI) is the most common and severe cause of persistent hypoglycemia in neonates and children, it represents a group of clinically, genetically and morphologically heterogeneous disorders characterised by dysregulation of insulin secretion from pancreatic β-cells. It is extremely important to recognize this condition early and institute appropriate management to prevent significant brain injury leading to complications like epilepsy, cerebral palsy and neurological impairment. Histologically, CHI is divided mainly into two types focal and diffuse disease. The diffuse form is inherited in an autosomal recessive (or dominant) manner whereas the focal form is sporadic in inheritance and is localized to a small region of the pancreas. Recent discoveries of the genetic causes of CHI have improved our understanding of the pathophysiology, but its management is complex and requires the integration of clinical, biochemical, molecular, and imaging findings to establish the appropriate treatment according to the subtype. Here we present a case of sever congenital hyperinsulinism in a girl admitted for lethargy, irritability and general seizures accompanied with profound hypoglycemia, in spite of aggressive medical treatment, she died because of sever congenital hyperinsulinism diazoxide unresponsive.
Topics: Congenital Hyperinsulinism; Diazoxide; Fatal Outcome; Female; Humans; Infant, Newborn; Seizures; Severity of Illness Index
PubMed: 32537058
DOI: 10.11604/pamj.2020.35.53.16604 -
Cell & Bioscience 2020Openers of mitochondrial adenosine triphosphate-dependent potassium (mKATP) channels like diazoxide increase reactive oxygen species (ROS) production in cardiac cells...
BACKGROUND
Openers of mitochondrial adenosine triphosphate-dependent potassium (mKATP) channels like diazoxide increase reactive oxygen species (ROS) production in cardiac cells and reduce Ca elevations produced by ischemia-reperfusion, protecting the heart from damage. In this study we tested the hypothesis that opening mKATP channels regulates expression of the major components of store-operated Ca entry (SOCE) STIM1 and Orai1.
RESULTS
Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot experiments showed that diazoxide increased expression of STIM1 and Orai1 at the mRNA and protein levels, respectively, in adult rat cardiomyocytes. Immunofluorescence analyses revealed that diazoxide also disrupted the striated distribution pattern of STIM1. These effects were prevented by the ROS scavenger -acetyl cysteine (NAC), the mKATP channel antagonist 5-hydroxydecanoate (5-HD), or the protein synthesis inhibitor cycloheximide (CHX). Confocal microscopy revealed that diazoxide also led to nuclear translocation of the transcription factors c-Fos and NFκB, which was also blocked by NAC or 5-HD. Finally, the MAPK pathway inhibitor UO126 attenuated diazoxide-induced upregulation of STIM1 and Orai1 expression.
CONCLUSIONS
Our results suggest that opening mitochondrial potassium ATP channels with diazoxide upregulates the expression of STIM1 and Orai1 by de novo synthesis by a mechanism that involves NFkB, c-Fos, and ROS via MAPK/ERK signaling.
PubMed: 32817784
DOI: 10.1186/s13578-020-00460-w -
Frontiers in Endocrinology 2022Congenital hyperinsulinism is characterised by the inappropriate release of insulin during hypoglycaemia. This potentially life-threatening disorder can occur in... (Review)
Review
Congenital hyperinsulinism is characterised by the inappropriate release of insulin during hypoglycaemia. This potentially life-threatening disorder can occur in isolation, or present as a feature of syndromic disease. Establishing the underlying aetiology of the hyperinsulinism is critical for guiding medical management of this condition especially in children with diazoxide-unresponsive hyperinsulinism where the underlying genetics determines whether focal or diffuse pancreatic disease is present. Disease-causing single nucleotide variants affecting over 30 genes are known to cause persistent hyperinsulinism with mutations in the KATP channel genes ( and ) most commonly identified in children with severe persistent disease. Defects in methylation, changes in chromosome number, and large deletions and duplications disrupting multiple genes are also well described in congenital hyperinsulinism, further highlighting the genetic heterogeneity of this condition. Next-generation sequencing has revolutionised the approach to genetic testing for congenital hyperinsulinism with targeted gene panels, exome, and genome sequencing being highly sensitive methods for the analysis of multiple disease genes in a single reaction. It should though be recognised that limitations remain with next-generation sequencing with no single application able to detect all reported forms of genetic variation. This is an important consideration for hyperinsulinism genetic testing as comprehensive screening may require multiple investigations.
Topics: Child; Congenital Hyperinsulinism; Diazoxide; Humans; Insulin; KATP Channels; Mutation
PubMed: 35872984
DOI: 10.3389/fendo.2022.873254 -
ChemMedChem Apr 2021Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII...
Mitochondrial respiratory complex II (CII), also known as succinate dehydrogenase, plays a critical role in mitochondrial metabolism. Known but low potency CII inhibitors are selectively cytotoxic to cancer cells including the benzothiadiazine-based anti-hypoglycemic diazoxide. Herein, we study the structure-activity relationship of benzothiadiazine derivatives for CII inhibition and their effect on cancer cells for the first time. A 15-fold increase in CII inhibition was achieved over diazoxide, albeit with micromolar IC values. Cytotoxicity evaluation of the novel derivatives resulted in the identification of compounds with much greater antineoplastic effect than diazoxide, the most potent of which possesses an IC of 2.93±0.07 μM in a cellular model of triple-negative breast cancer, with high selectivity over nonmalignant cells and more than double the potency of the clinical agent 5-fluorouracil. No correlation between cytotoxicity and CII inhibition was found, thus indicating an as-yet-undefined mechanism of action of this scaffold. The derivatives described herein represent valuable hit compounds for therapeutic discovery in triple-negative breast cancer.
Topics: Antineoplastic Agents; Benzothiadiazines; Cell Proliferation; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Halogenation; Humans; Molecular Structure; Structure-Activity Relationship
PubMed: 33331124
DOI: 10.1002/cmdc.202000729 -
Juntendo Iji Zasshi = Juntendo Medical... 2023The role of autophagy in pancreatic β cells has been reported, but the relationship between autophagy and insulin metabolism is complex and is not fully understood yet.
OBJECTIVES
The role of autophagy in pancreatic β cells has been reported, but the relationship between autophagy and insulin metabolism is complex and is not fully understood yet.
DESIGN
We here analyze the relationship between autophagy and insulin metabolism from a morphological aspect.
METHODS
We observe the morphological changes of β cell-specific Atg7-deficient mice and Atg5-deficient MIN6 cells with electron microscopy.
RESULTS
We find that Atg7-deficient β cells exhibit a marked expansion of the endoplasmic reticulum (ER). We also find that the inhibitory state of insulin secretion causes morphological changes in the Golgi, including ministacking and swelling. The same morphological alterations are observed when insulin secretion is suppressed in Atg5-deficient MIN6 cells.
CONCLUSIONS
The defect of autophagy induces ER expansion, and inhibition of insulin secretion induces Golgi swelling, probably via ER stress and Golgi stress, respectively.
PubMed: 38854847
DOI: 10.14789/jmj.JMJ22-0040-OA -
Journal of Traditional Chinese Medicine... Dec 2022To evaluate the protective effects of serum containing Dangua Fang on vascular endothelium damaged by oxidative stress.
OBJECTIVE
To evaluate the protective effects of serum containing Dangua Fang on vascular endothelium damaged by oxidative stress.
METHODS
Five experiments were completed in this paper. In the first experiment, we found the most suitable serum containing Dangua Fang by comparing groups with different serum containing Dangua Fang. In the second experiments we analyzed Dangua Fang influencing endothelial cell viability and apoptosis and cell cycle. The third experiment on Dangua Fang intervention of mitochondrial respiratory chain. The fourth experiment on Dangua Fang intervention of mitochondrial membrane potential. And finally, on the fifth experiment we researched the mechanism of Dangua Fang improving mitochondrial function by comparing the Na-k-ATPase and peroxisome proliferator-activated receptor- gamma coactivator-1alpha (PGC-1α) in the Dangua group with the diazoxide group and Co Q+Vit C group.
RESULTS
We compared the control group in the first experiments and the OD values in DZ1 group was the most significant in all intervening groups. The recipe of DZ1 (5% serum containing Dangua Fang) was used in the following experiments. Compared with the control group, cell viability, cell cycle (G2 + S), cytochrome c oxidase (COX), R3 red/green, R2 red/green, R1 red/ green decreased and apoptosis, succinate dehy-drogenase (SDH), green (R2 + R3), Na-k-ATPase, PGC-1α increased in the model group. Compared with the model group, cell viability, G2+S, COX, R3 red/green, R2 red/green, R1 red/green raised and apoptosis, green (R2 + R3), Na-K-ATPase decreased in the Dangua group; G2 + S, R3 red/green, R2 red/green, R1 red/green raised and green (R2 + R3) decreased in the Co Q + Vit C group. Na-K-ATPase increased in the combined group ( 0.05 or < 0.01).
CONCLUSIONS
Dangua Fang protects oxidative stress-induced endothelial cells damaged by promotion of mitochondrial biogenesis, reduction of Na-K-ATPase activity and regulation of mitochondrial respiratory chain function restoring mitochondrial membrane potential.
Topics: Humans; Endothelial Cells; Transcription Factors; Oxidative Stress; Mitochondria; Adenosine Triphosphatases
PubMed: 36378047
DOI: 10.19852/j.cnki.jtcm.20220815.001 -
Endocrinology, Diabetes & Metabolism... Feb 2019Beckwith-Wiedemann syndrome (BWS) can be associated with embryonal tumours and congenital hyperinsulinism (CHI). We present an infant with BWS who developed congenital...
Beckwith-Wiedemann syndrome (BWS) can be associated with embryonal tumours and congenital hyperinsulinism (CHI). We present an infant with BWS who developed congenital hepatoblastoma and Wilms' tumour during infancy. The infant presented with recurrent hypoglycaemia requiring high intravenous glucose infusion and was biochemically confirmed to have CHI. He was resistant to diazoxide but responded well to octreotide and was switched to Lanreotide at 1 year of age. Genetic analysis for mutations of ABCC8 and KCNJ11 were negative. He had clinical features suggestive of BWS. Methylation-sensitive multiplex ligation-dependent probe amplification revealed hypomethylation at KCNQ1OT1:TSS-DMR and hypermethylation at H19 /IGF2:IG-DMR consistent with mosaic UPD(11p15). Hepatoblastoma was detected on day 4 of life, which was resistant to chemotherapy, requiring surgical resection. He developed Wilms' tumour at 3 months of age, which also showed poor response to induction chemotherapy with vincristine and actinomycin D. Surgical resection of Wilms' tumour was followed by post-operative chemotherapy intensified with cycles containing cyclophosphamide, doxorubicin, carboplatin and etoposide, in addition to receiving flank radiotherapy. We report, for the first time, an uncommon association of hepatoblastoma and Wilms' tumour in BWS in early infancy. Early onset tumours may show resistance to chemotherapy. UPD(11p15) is likely associated with persistent CHI in BWS. Learning points: Long-acting somatostatin analogues are effective in managing persistent CHI in BWS. UPD(11)pat genotype may be a pointer to persistent and severe CHI. Hepatoblastoma and Wilms' tumour may have an onset within early infancy and early tumour surveillance is essential. Tumours associated with earlier onset may be resistant to recognised first-line chemotherapy.
PubMed: 30817313
DOI: 10.1530/EDM-18-0146 -
British Journal of Pharmacology Nov 2019CD34 haematopoietic stem/progenitor cells have revascularization potential and are now being tested for the treatment of ischaemic vascular diseases in clinical trials....
BACKGROUND AND PURPOSE
CD34 haematopoietic stem/progenitor cells have revascularization potential and are now being tested for the treatment of ischaemic vascular diseases in clinical trials. We tested the hypothesis that mitochondrial depolarization stimulates the reparative functions of CD34 cells.
EXPERIMENTAL APPROACH
Peripheral blood was obtained from healthy individuals (n = 63), and mononuclear cells (MNCs) were separated. MNCs were enriched for lineage negative cells, followed by isolation of CD34 cells. Vascular repair-relevant functions of CD34 cells, proliferation and migration, were evaluated in the presence and absence of diazoxide. Mitochondrial membrane potential, ROS and NO levels were evaluated by flow cytometry by using JC-1, mitoSOX and DAF-FM respectively.
KEY RESULTS
Diazoxide stimulated the proliferation and migration of CD34 cells that were comparable to the responses induced by stromal-derived factor-1α (SDF) or VEGF. Effects of diazoxide were blocked by either 5-hydroxydecanoate (5HD), a selective mitochondrial ATP-sensitive potassium channel (mitoK ) inhibitor, or by L-NAME. Diazoxide induced mitochondrial depolarization, and NO and cGMP generation that were 5HD-sensitive. The generation of NO and cGMP by diazoxide was blocked by an endothelial NOS (eNOS)-selective inhibitor, NIO, but not by a neuronal (n)NOS-selective inhibitor, N -propyl-L-arginine (NPA). A Ca chelator, BAPTA, Akt inhibitor, triciribine, or PI3K inhibitor, LY294002, inhibited the NO release induced by diazoxide. Phosphorylation of eNOS at Ser and dephosphorylation at Thr were increased. Diazoxide-induced ROS generation and phosphorylation of eNOS at Ser were reduced by NPA.
CONCLUSION AND IMPLICATIONS
Diazoxide stimulates vascular repair-relevant functions of CD34 cells via the mitoK -dependent release of NO and ROS.
LINKED ARTICLES
This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.
Topics: Antigens, CD34; Cell Movement; Cell Proliferation; Cells, Cultured; Cyclic GMP; Diazoxide; Hematopoietic Stem Cells; Humans; Mitochondria; Nitric Oxide; Reactive Oxygen Species
PubMed: 30367728
DOI: 10.1111/bph.14529 -
Cureus Dec 2022Background and objective Neonatal hypoglycemia (NH) is one of the most common causes of admission to the neonatal intensive care unit (NICU). Persistent NH despite...
Background and objective Neonatal hypoglycemia (NH) is one of the most common causes of admission to the neonatal intensive care unit (NICU). Persistent NH despite adequate feeding and intravenous dextrose may often require medications to maintain normal blood glucose levels (BGL). Several medications are used in the management of persistent NH, such as glucagon, diazoxide, and octreotide. In this study, we aimed to determine the factors that predict the need for medications to treat persistent NH. Methods This was a retrospective cohort study conducted at the Sultan Qaboos University Hospital (SQUH), Muscat, Oman. Infants admitted to the NICU between 2015 and 2019 with hypoglycemia (capillary blood glucose <2.6 mmol/l) were eligible to be included in the study. A prespecified dataset was collected from electronic patient records, including birth weight (BW), APGAR scores, gestational age, BGL, maternal risk factors such as diabetes mellitus (DM), hypertension, or antenatal use of medications, and the NICU management during admission. Data analysis was performed using SPSS Statistics for Windows, version 27.0 (IBM Corp., Armonk, NY). Results A total of 89 neonates were admitted due to NH during the study period. Of them, 10 (11.2%) patients had received medication (diazoxide). Use of medication for persistent NH was significantly associated with maternal gestational diabetes/diabetes mellitus (GDM/DM) status (p=0.041), higher BW (p=0.001), and large for gestational age [LGA (defined as BW >90th percentile)] (p=0.014), severe hypoglycemia (mean glucose level of 1-1.5 mmol/l) at two hours of life and at admission, and elevated maximum glucose infusion rate (GIR). GIR for the medication-requiring cohort was 12.95 mg/kg/min and that for the non-medication-requiring cohort was 6.77 mg/kg/min (p<0.001). Conclusion Based on our findings, the need for using certain medications to treat persistent NH, such as diazoxide in neonates admitted with NH, can be predicted by factors such as maternal GDM/DM status, BW >90th percentile, very low BGL at two hours of age and on admission, and elevated GIR. Elevated maximum GIR was a leading indicator for using medications in the treatment of NH.
PubMed: 36620829
DOI: 10.7759/cureus.32197