Background: Myo-inositol has emerged as one of the preventive therapies for the development of gestational diabetes mellitus in at-risk populations. This systematic review and meta-analysis was conducted to determine the efficacy and safety of myo-inositol in decreasing the incidence of gestational diabetes in overweight and obese pregnant women. Methodology: This meta-analysis was conducted using the standard Cochrane methodology and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines. Inclusion criteria were randomized controlled trials (RCTs) that enrolled overweight and obese pregnant women and used myo-inositol supplementation. The primary outcome was the incidence of gestational diabetes mellitus at 24-28 weeks. Secondary outcomes included cesarean section rate, the incidence of pregnancy-induced hypertension, macrosomia and preterm delivery. Risk ratios (RRs) and 95% confidence intervals (CIs) were used for dichotomous data. Results: Six RCTs were included. Compared to standard micronutrient supplementation, standard dose of myo-inositol (4 g) may reduce the incidence of GDM (RR 0.54; CI [0.30, 0.96]; n = 887 women), but the certainty of evidence is low to very low. With low-dose myo-inositol however, evidence is uncertain about its benefit on the incidence of gestational diabetes mellitus in overweight and obese women with RR 0.71; CI [0.14, 3.50]. No adverse effects were noted. For the secondary outcomes, standard dose myo-inositol appears to reduce the incidence of pregnancy-induced hypertension and preterm delivery, but the certainty of evidence is low to very low. Conclusion Current evidence is uncertain on the potential benefit of myo-inositol supplementation in overweight and obese pregnant women. While studies show that 4 g myo-inositol per day may decrease the incidence of GDM, pregnancy-induced hypertension and pre-term birth with no associated risk of serious adverse events, the certainty of evidence is low to very low. Future high-quality trials may provide more compelling evidence to support practice recommendations.
Diabetes, Gestational ; Obesity ; Inositol Phosphates

OBJECTIVE: To compare the analgesic effect of Jin Ling Zi Powder (JLZ) and its two single herbs. METHODS: The hot plate method was used to induce pain. Totally 36 mice were randomly divided into 6 groups by a complete random design, including control, model, aspirin (ASP, 0.14 g/kg body weight), JLZ (14 g/kg body weight), Corydalis yanhusuo (YHS, 14 g/kg body weight), and Toosendan Fructus (TF, 14 g/kg body weight) groups, 6 mice in each group. The mice in the control and model groups were given the same volume of saline, daily for 2 consecutive weeks. At 30, 60, 90, and 120 min after the last administration, the pain threshold of mice in each group was measured, and the improvement rate of pain threshold was calculated. Serum endogenous metabolites were analyzed by gas chromatography-mass spectrometry (GC-MS). RESULTS: There was no statistical difference in pain threshold among groups before administration (P>0.05). After 2 weeks of administration, compared with the model group, the pain threshold in JLZ, YHS, TF and ASP groups were increased to varying degrees (P<0.05). JLZ had the best analgesic effect and was superior to YHS and TF groups. A total of 14 potential biomarkers were screened in serum data analysis and potential biomarkers levels were all reversed to different degrees after the treatment with JLZ and its single herbs. These potential biomarkers were mainly related to glyoxylate and dicarboxylate metabolism, glycine, serine and threonine metabolism, valine, leucine and isoleucine biosynthesis, aminoacyl-tRNA biosynthesis and inositol phosphate metabolism. CONCLUSIONS The analgesic mechanism of JLZ and YHS was mainly due to the combination of glycine and its receptor, producing post-synaptic potential, reducing the excitability of neurons, and weakening the afferent effect of painful information.
Animals ; Mice ; Analgesics/therapeutic use* ; Aspirin/pharmacology* ; Biomarkers ; Body Weight ; Drugs, Chinese Herbal/therapeutic use* ; Glycine ; Glyoxylates ; Inositol Phosphates ; Isoleucine ; Leucine ; Metabolomics/methods* ; Powders ; RNA, Transfer ; Serine ; Threonine ; Valine

BACKGROUND: Recent research has shown that reactive oxygen species (ROS) play a significant role in the development and persistence of neuropathic pain through central sensitization via N-methyl-D-aspartate (NMDA) receptor activation. In the present study, we examined whether the intraperitoneal administration of vitamins C and E alone or together could alleviate mechanical allodynia in a chronic post-ischemia pain (CPIP) rat model. METHODS: Vitamins C and E were administered intraperitoneally to 48 male Sprague Dawley rats once per day for 3 days before hindpaw ischemia-reperfusion (I/R) injury was induced. On the third day, the CPIP rat model was produced by inducing ischemia in the left hindpaw by applying an O-ring for 3 h, followed by reperfusion. Three days after reperfusion, hindpaw mechanical allodynia was assessed by measuring the withdrawal response to von Frey filament stimulation. The rats were sacrificed immediately after behavioral testing to determine the phosphorylated NMDA receptor subunit 1 (pNR1) and extracellular-signal-regulated kinases (pERK) levels in the spinal cord. RESULTS: When the antioxidant vitamins C and E were administered intraperitoneally to CPIP rats, I/R injury-induced mechanical allodynia was attenuated, and pNR1 and pERK levels were decreased in the rat spinal cord. Additionally, the co-administration of both vitamins had an increased antiallodynic effect. CONCLUSIONS: The reduced phosphorylated NR1 and ERK levels indicate that vitamins C and E inhibit the modulation of spinal cord neuropathic pain processing. Co-administration of vitamins C and E had a greater antiallodynic effect.
Animals ; Antioxidants ; Ascorbic Acid* ; Central Nervous System Sensitization ; Complex Regional Pain Syndromes ; Humans ; Hyperalgesia ; Inositol Phosphates ; Ischemia ; Male ; Mitogen-Activated Protein Kinases ; Models, Animal* ; N-Methylaspartate ; Neuralgia ; Phosphotransferases ; Prostaglandins E ; Rats* ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Receptors, N-Methyl-D-Aspartate ; Reperfusion ; Reperfusion Injury ; Spinal Cord ; Vitamin E* ; Vitamins*

Previously, we reviewed biological evidence that mercury could induce autoimmunity and coronary arterial wall relaxation as observed in Kawasaki syndrome (KS) through its effects on calcium signaling, and that inositol 1,4,5-triphosphate 3-kinase C (ITPKC) susceptibility in KS would predispose patients to mercury by increasing Ca2+ release. Hg2+ sensitizes inositol 1,4,5-triphosphate (IP3) receptors at low doses, which release Ca2+ from intracellular stores in the sarcoplasmic reticulum, resulting in delayed, repetitive calcium influx. ITPKC prevents IP3 from triggering IP3 receptors to release calcium by converting IP3 to inositol 1,3,4,5-tetrakisphosphate. Defective IP3 phosphorylation resulting from reduced genetic expressions of ITPKC in KS would promote IP3, which increases Ca2+ release. Hg2+ increases catecholamine levels through the inhibition of S-adenosylmethionine and subsequently catechol-O-methyltransferase (COMT), while a single nucleotide polymorphism of the COMT gene (rs769224) was recently found to be significantly associated with the development of coronary artery lesions in KS. Accumulation of norepinephrine or epinephrine would potentiate Hg2+-induced calcium influx by increasing IP3 production and increasing the permeability of cardiac sarcolemma to Ca2+. Norepinephrine and epinephrine also promote the secretion of atrial natriuretic peptide, a potent vasodilator that suppresses the release of vasoconstrictors. Elevated catecholamine levels can induce hypertension and tachycardia, while increased arterial pressure and a rapid heart rate would promote arterial vasodilation and subsequent fatal thromboses, particularly in tandem. Genetic risk factors may explain why only a susceptible subset of children develops KS although mercury exposure from methylmercury in fish or thimerosal in pediatric vaccines is nearly ubiquitous. During the infantile acrodynia epidemic, only 1 in 500 children developed acrodynia whereas mercury exposure was very common due to the use of teething powders. This hypothesis mirrors the leading theory for KS in which a widespread infection only induces KS in susceptible children. Acrodynia can mimic the clinical picture of KS, leading to its inclusion in the differential diagnosis for KS. Catecholamine levels are often elevated in acrodynia and may also play a role in KS. We conclude that KS may be the acute febrile form of acrodynia.
Acrodynia ; Arterial Pressure ; Autoimmunity ; Calcium ; Calcium Signaling ; Catechol O-Methyltransferase ; Catecholamines ; Child ; Coronary Vessels ; Diagnosis, Differential ; Epinephrine ; Heart Rate ; Humans ; Hydrazines ; Hypertension ; Inositol ; Inositol 1,4,5-Trisphosphate ; Inositol 1,4,5-Trisphosphate Receptors ; Inositol Phosphates ; Mucocutaneous Lymph Node Syndrome ; Norepinephrine ; Permeability ; Phosphorylation ; Polymorphism, Single Nucleotide ; Powders ; Relaxation ; Risk Factors ; S-Adenosylmethionine ; Sarcolemma ; Sarcoplasmic Reticulum ; Tachycardia ; Thimerosal ; Thrombosis ; Tooth ; Tooth Eruption ; Vaccines ; Vasoconstrictor Agents ; Vasodilation

BACKGROUND: Recent studies indicate that reactive oxygen species (ROS) are involved in persistent pain, including neuropathic and inflammatory pain. Since the data suggest that ROS are involved in central sensitization, the present study examines the levels of activated N-methyl-D-aspartate (NMDA) receptors in the dorsal horn after an exogenous supply of three antioxidants in rats with chronic post-ischemia pain (CPIP). This serves as an animal model of complex regional pain syndrome type-I induced by hindpaw ischemia/reperfusion injury. METHODS: The application of tight-fitting O-rings for a period of three hours produced CPIP in male Sprague-Dawley rats. Allopurinol 4 mg/kg, allopurinol 40 mg/kg, superoxide dismutase (SOD) 4,000 U/kg, N-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg and SOD 4,000 U/kg plus L-NAME 10 mg/kg were administered intraperitoneally just after O-ring application and on the first and second days after reperfusion. Mechanical allodynia was measured, and activation of the NMDA receptor subunit 1 (pNR1) of the lumbar spinal cord (L4-L6) was analyzed by the Western blot three days after reperfusion. RESULTS: Allopurinol reduced mechanical allodynia and attenuated the enhancement of spinal pNR1 expression in CPIP rats. SOD and L-NAME also blocked spinal pNR1 in accordance with the reduced mechanical allodynia in rats with CPIP. CONCLUSION: The present data suggest the contribution of superoxide, produced via xanthine oxidase, and the participation of superoxide and nitric oxide as a precursor of peroxynitrite in NMDA mediated central sensitization. Finally, the findings support a therapeutic potential for the manipulation of superoxide and nitric oxide in ischemia/reperfusion related pain conditions.
Allopurinol ; Animals ; Antioxidants ; Blotting, Western ; Central Nervous System Sensitization ; Horns ; Humans ; Hyperalgesia ; Inositol Phosphates ; Male ; Models, Animal ; N-Methylaspartate ; NG-Nitroarginine Methyl Ester ; Nitric Oxide ; Peroxynitrous Acid ; Prostaglandins E ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species ; Reperfusion ; Reperfusion Injury ; Spinal Cord ; Superoxide Dismutase ; Superoxides ; Xanthine Oxidase

BACKGROUND: Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes including complex regional pain syndromes (CRPS). Underlying mechanisms for the development of such pain are still a matter of investigation. Several studies suggest that activation of the N-methyl-D-aspartate (NMDA) receptor is essential for central sensitization as a base for persistent pain. The aim is to assess whether alteration of NMDA receptor expression correlates with the contralateral allodynia in the chronic post-ischemia pain (CPIP) model rats representing CRPS-Type I. METHODS: Application of a tight-fitting tourniquet for a period of 3 hours before reperfusion produced CPIP in male Sprague-Dawley rats. The mechanical paw withdrawal thresholds to von Frey stimuli (using a dynamic plantar aesthesiometer) were measured as pain indicators in ipsilateral and contralateral hindpaws. Phosphorylation of the NMDA receptor 1 subunit (pNR1), assessed with Western blot, was measured in the contralateral L4-6 spinal cord. RESULTS: Ipsilateral and contralateral mechanical allodynia is present at 4 hours after reperfusion, peaked at 3 days, and continued for 7 days after reperfusion. The relative density of pNR1 of CPIP rats significantly decreased in the contralateral L4-6 spinal cord compared to baseline value (P < 0.05). There was significant correlation between paw withdrawal threshold and the relative density of pNR1 (ipsilateral; R2 = 0.75, P < 0.01, contralateral; R2 = 0.60, P < 0.01). CONCLUSIONS: These data suggest that pNR1 is correlated to the contralateral mechanical allodynia in CPIP rats.
Animals ; Blotting, Western ; Central Nervous System Sensitization ; Complex Regional Pain Syndromes ; Humans ; Hyperalgesia ; Inositol Phosphates ; Male ; N-Methylaspartate ; Phosphorylation ; Prostaglandins E ; Rats ; Rats, Sprague-Dawley ; Reperfusion ; Specific Gravity ; Spinal Cord ; Tourniquets

BACKGROUND: It is well known that the GABAergic inhibitory interneuronal system plays an important role in modulation of the noxious stimulation transmitted from the primary afferent input. Some studies have revealed the role that the GABA inhibitory interneuronal system plays in the modulation of pain transmission and the changes in the GABAergic interneurons that occur during the neuropathic pain. This study was conducted to evaluate the apoptosis of the GABAergic interneuron, which is assumed to contribute to neuropathic pain. METHODS: Male Sprague-Dawley rats weighing 290-310 g were used to create a CPIP (chronic post-ischemic pain) model, which was made by placing a tourniquet on the left hindpaw of the rats. The tourniquet was maintained for 3 hours, after which it was released to allow reperfusion. Thirty minutes prior to reperfusion, N-acetyl-L-cysteine (NAC group) or normal saline (control group) was injected. After reperfusion, mechanical allodynia and cold allodynia were measured. In addition, the release of cytochrome c into the cytosol was evaluated through western blot or immunohistochemistry of the spinal cord. RESULTS: Mechanical and cold allodynia developed and the number of GABA interneurons was reduced in the control group. Additionally, The cytochrome c from the GABA interneuron was released into the cytosol in the control group, but the amount released was reduced in response to treatment with NAC. CONCLUSIONS: The results of this study showed that the GABA interneuron in the Rexed laminae I, II released cytochrome c into the cytosol in CPIP neuropathic pain model, which is known to lead to apoptosis. However, treatment with N-acetyl-L-cysteine prevented this process.
Acetylcysteine ; Animals ; Apoptosis ; Blotting, Western ; Cold Temperature ; Complex Regional Pain Syndromes ; Cytochromes c ; Cytosol ; gamma-Aminobutyric Acid ; Horns ; Humans ; Hyperalgesia ; Immunohistochemistry ; Inositol Phosphates ; Interneurons ; Ischemia ; Male ; Neuralgia ; Prostaglandins E ; Rats ; Rats, Sprague-Dawley ; Reperfusion ; Spinal Cord ; Tourniquets

BACKGROUND: Chronic post-ischemia pain (CPIP) model is reported to represent the complex regional pain syndrome type I. The administration of non-specific free radical scavengers reduced mechanical allodynia, but it is not evident which type of free radical is responsible for the development of CPIP. This study was investigated to elucidate the role of superoxide on the development of CPIP and the relationship with the expression of c-fos gene. METHODS: Male Sprague-Dawley rats weighing 290-310 g were housed in one cage with food and water ad libitum. CPIP model was made by placing a tourniquet on the left hindpaw of rats. The tourniquet maintained for 3 hours, then released to allow reperfusion. Thirty minutes before reperfusion, superoxide dismutase (SOD) or normal saline (control group) was injected. Mechanical allodynia and cold allodynia were measured at 1, 3, 5, 7, 14 and 28 days after reperfusion and compared. Also, spinal cord was harvested and the expression of c-fos gene was measured through the real time reverse transcription polymerase chain reaction. RESULTS: Superoxide dismutase reduced mechanical allodynia (1, 3, 5 and 14 day) and cold allodynia (1, 3 and 7 day) compared with control rats in left hindpaw. Expression of c-fos was significantly reduced in the SOD rats at the day 14 and 28 compare to the control rats. CONCLUSIONS: The administration of superoxide dismutase suppressed the allodynia and c-fos gene expression of CPIP model rats and it may be suggested that the superoxide has an important role in the development of CPIP.
Animals ; Cold Temperature ; Free Radical Scavengers ; Genes, fos ; Humans ; Hyperalgesia ; Inositol Phosphates ; Male ; Prostaglandins E ; Rats ; Rats, Sprague-Dawley ; Reperfusion ; Reperfusion Injury ; Reverse Transcription ; Spinal Cord ; Superoxide Dismutase ; Superoxides ; Tourniquets ; Water

Radiotherapy would be the choice of treatment for human cancers, because of high cost-effectiveness. However, a certain population of patients shows a resistance to radiotherapy and recurrence. In an effort to increase the efficacy of radiotherapy, many efforts were driven to find the genes causing the unresponsiveness to ionizing radiation. In this paper, we compared the gene expression profiles of two lung cancer cell lines, H460 and H1299, which showed differential responses to ionizing radiations. Each cell were irradiated at 2 Gy, and harvested after 0, 2, 4, 8, 12 and 24 hours to examine the expressions. Two-way ANOVA analysis on time-series experiments of two cells could select 2863 genes differentially expressed upon ionizing radiation among 32,321 genes in microarray (p<0.05). We classified these genes into 21 clusters by SOM clustering according to the interaction between cell types and time. Two SOM clusters were enriched with apoptosis-related genes in pathway analysis. One cluster contained higher levels of phosphatidyl inositol 3-phosphate kinase (PI3K) subunits in H1299, radio resistant cells than H460, radiosensitive cells. TRAIL receptors were expressed in H460 cells while the decoy receptor for TRAIL was expressed in H1299 cells. From these results, we could characterize the differential responsiveness to ionizing radiation according to their differential expressions of apoptosis-related genes, which might be the candidates to increase the power of radiotherapy.
Apoptosis ; Cell Line ; Humans ; Inositol Phosphates ; Lung ; Lung Neoplasms ; Phosphatidylinositols ; Phosphotransferases ; Radiation, Ionizing ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; Recurrence ; Transcriptome

Radiotherapy would be the choice of treatment for human cancers, because of high cost-effectiveness. However, a certain population of patients shows a resistance to radiotherapy and recurrence. In an effort to increase the efficacy of radiotherapy, many efforts were driven to find the genes causing the unresponsiveness to ionizing radiation. In this paper, we compared the gene expression profiles of two lung cancer cell lines, H460 and H1299, which showed differential responses to ionizing radiations. Each cell were irradiated at 2 Gy, and harvested after 0, 2, 4, 8, 12 and 24 hours to examine the expressions. Two-way ANOVA analysis on time-series experiments of two cells could select 2863 genes differentially expressed upon ionizing radiation among 32,321 genes in microarray (p<0.05). We classified these genes into 21 clusters by SOM clustering according to the interaction between cell types and time. Two SOM clusters were enriched with apoptosis-related genes in pathway analysis. One cluster contained higher levels of phosphatidyl inositol 3-phosphate kinase (PI3K) subunits in H1299, radio resistant cells than H460, radiosensitive cells. TRAIL receptors were expressed in H460 cells while the decoy receptor for TRAIL was expressed in H1299 cells. From these results, we could characterize the differential responsiveness to ionizing radiation according to their differential expressions of apoptosis-related genes, which might be the candidates to increase the power of radiotherapy.
Apoptosis ; Cell Line ; Humans ; Inositol Phosphates ; Lung ; Lung Neoplasms ; Phosphatidylinositols ; Phosphotransferases ; Radiation, Ionizing ; Receptors, TNF-Related Apoptosis-Inducing Ligand ; Recurrence ; Transcriptome