Troxerutin improves cognitive function and forkhead box F2 expression in the hippocampus via modulating the microbial composition and the intestinal barrier function in diabetes mellitus mice.

Recent studies have found that gut microbes may affect blood-brain barrier (BBB) integrity. This study was to investigate the relationship between gut microbes and forkhead box F2 (FOXF2) and the mechanism of troxerutin improving diabetic cognitive dysfunction (DCD). Diabetic mice were used in this study for the prophylactic application of troxerutin (60 mg/kg/d) for 8 weeks. The cognitive function was assessed using the Morris water maze (MWM) and novel object recognition (NOR) tasks, and the changes of intestinal microbial composition were observed through 16S rRNA gene sequencing. The content of short-chain fatty acids (SCFAs) in feces was determined by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and the intestinal barrier function was assessed by enzyme-linked immunosorbent assay (ELISA) and western blotting. Troxerutin up-regulated FOXF2 expression in the hippocampus of mice, improving DCD. Meanwhile, it reversed the intestinal microbial composition (increased the abundance of the phylum Bacteroidota, as well as fecal propionic acid and butyric acid levels) and improved the intestinal barrier (increased the level of claudin-1 and significantly reduced the circulating lipopolysaccharide binding protein (LBP) levels). When intestinal microorganisms were removed with an antibiotic cocktail, the improvement of hippocampal FOXF2 expression and DCD by troxerutin attenuated accordingly, suggesting that troxerutin improved DCD by up-regulating the expression of hippocampal FOXF2 through the regulation of intestinal microbial composition and the intestinal barrier. In summary, troxerutin improved DCD by up-regulating the expression of hippocampal FOXF2 through the regulation of intestinal microbial composition and the intestinal barrier.

Improvement of actin dynamics and cognitive impairment in diabetes through troxerutin-mediated downregulation of TRPM7/CaN/cofilin.

Diabetic cognitive impairment is a central nervous complication of diabetes mellitus. Its specific pathogenesis is unknown, and no effective treatment strategy is currently available. An imbalance in actin dynamics is an important mechanism underlying cognitive impairment. Transient receptor potential channel 7 (TRPM7) mediates actin dynamics imbalance through calcineurin (CaN) and cofilin cascades involved in various neurodegenerative diseases. We previously demonstrated that TRPM7 expression is increased in diabetic cognitive impairment, and troxerutin has been shown to ameliorate diabetic cognitive impairment. However, the relationship between troxerutin and TRPM7 remains unclear. In this study, we hypothesize that troxerutin may improve diabetic cognitive impairment by enhancing actin dynamics through downregulation of the TRPM7/CaN/cofilin pathway. To test this hypothesis, we divided db/m and db/db mice into the following groups: normal control group (NC), normal + troxerutin group (NT), diabetic group (DM), diabetic + troxerutin group (DT) and diabetic + troxerutin + bradykinin group (DTB). The results showed that diabetic mice exhibited cognitive impairment at 17 weeks of age, TRPM7, CaN, cofilin and G-actin were highly expressed in the CA1 region of hippocampus, while p-cofilin and F-actin expression decreased. Furthermore, hippocampal neuronal cellsshowed varying degrees of damage. The length of synaptic active zone, the width of synaptic cleft, and the number of synapses per high-power field were decreased. Troxerutin intervention alleviated these manifestations in the DT group; however, the effect of troxerutin was weakened in the DTB group. In conclusion, our findings suggest that diabetes leads to cognitive impairment, activation of the TRPM7/CaN/cofilin pathway, actin dynamics imbalance, and destruction of hippocampal neuronal cells and synapses. Troxerutin can downregulate TRPM7/CaN/cofilin, improve actin dynamics imbalance, and ameliorate cognitive impairment in diabetic mice. This study provides a new avenue for exploring and treating cognitive impairment in diabetes.

The dynamic changes of psychosomatic symptoms in three waves of COVID-19 outbreak and fatigue caused by enduring pandemic in China.

BACKGROUND: Two years have passed since the 2019 novel coronavirus disease (COVID-19) was first reported. The persistent pandemic might lead to severe psychosomatic problems and fatigue. In addition, the recent rapid rising COVID-19 cases in China have become a trending issue. Therefore, this study aimed to investigate the dynamic changes in psychosomatic problems at the initial and current stages of the pandemic. METHODS: Three waves of cross-sectional online survey were conducted during the initial COVID outbreak in China. The psychosomatic symptom scale (PSSS), perceived stress scale (PSS), and pandemic fatigue scale (PFS) were used to assess the psychosomatic problems, stress, and fatigue. RESULTS: 4317, 1096, and 2172 participants completed the first, second, and third surveys. The prevalence of psychosomatic disorder was 22 %, 28 %, and 39 %, respectively. The network structure of PSSS symptoms has not significantly changed as the pandemic progresses. However, the global strength of the PSSS networks, indicating the overall connectivity, in the third wave was significantly higher than in the first wave (s = 0.54, P = 0.007). The most central symptoms in the first and third wave networks were depressed mood and tiredness. The PFS score was higher in the people concerned with indirect impact than those concerned with health (P < 0.001). PFS has positive relationships with PSSS and PSS score (R = 0.41, P < 0.001 and R = 0.35, P < 0.001, respectively). CONCLUSIONS: The persistence of the pandemic caused critical psychosomatic issues, stress, and indirect burden over time, leading to inevitable fatigue. People endured needing immediate attention to prevent or reduce psychosomatic disorders.

Acute intermittent porphyria: prevalence of pathogenic HMBS variants in China, and epidemiological survey in Hebei Province, China.

Background: Acute intermittent porphyria (AIP) is a rare inherited disorder with extremely low prevalence. Early detection of patients with potential pathogenic hydroxymethylbilane synthase (HMBS) variants is crucial for clinical prognosis. This study was designed to investigate the prevalence of pathogenic HMBS variants in Chinese population. Methods: The China Metabolic Analysis Project (ChinaMAP) database was employed to predict the prevalence of pathogenic HMBS variants in the Chinese population according to the variant interpretation guidelines of The American College of Medical Genetics and Genomics (ACMG). And the prevalence of pathogenic HMBS variants in Mixed American (AMR), African/African American (AFR), and Non-Finnish European (NFE) populations were estimated based on the Genome Aggregation Database (gnomAD) genome V3.0 database according to the guidelines of ACMG. An epidemiological investigation of AIP was conducted in Hebei Province, China through collecting the annual newly-diagnosed AIP cases of inpatients in 32 comprehensive grade III A hospitals from January 2011 to December 2020 in Hebei, China. Results: A total of 5 pathogenic/likely pathogenic (P/LP) HMBS variants were identified and the prevalence of pathogenic HMBS variants was predicted to be 1/1,765. Furthermore, based on the gnomAD genome V3.0 database, the estimated prevalence of pathogenic HMBS variants was 1/1,367, 1/1,403, and 1/621 in AMR, AFR, and NFE populations, respectively. The distribution of these variants varied among different racial populations. Moreover, AIP patients were predominantly hospitalized in comprehensive grade III A tertiary hospitals in Hebei province over a 10-year period. A total of 39 patients were newly-diagnosed with AIP, and a majority of them were female (n=36). The annual incidence between 2011 and 2017 {0.03 [95% confidence interval (CI): 0.01 to 0.11] to 0.05 (95% CI: 0.07 to 0.14) per million population} was generally lower than [0.07 (95% CI: 0.03 to 0.17) to 0.08 (95% CI: 0.03 to 0.18) per million] in 2018 and thereafter. Conclusions: China has made great strides in the management of AIP. More nationwide epidemiological surveys and study of the prevalence rate of AIP patients in China are urgently required.

Identification and molecular analysis of 17 novel variants of hydroxymethylbilane synthase in Chinese patients with acute intermittent porphyria.

A partial deficiency of the heme biosynthetic enzyme hydroxymethylbilane synthase (HMBS) leads to acute intermittent porphyria (AIP), a severe neurovisceral, autosomal dominant disorder with low penetrance. Even though in-depth investigations of the HMBS variants have been carried out by researchers in Britain, France, Russia, and Sweden, this area remains uninvestigated in China owing to the rarity and lack of clinical understanding of the disease. In this study, 78 unrelated AIP patients revealed 48 different HMBS variants, of which 17 were novel. These included 22 missense variants, 9 splicings, 5 nonsense variants, 10 small deletions, 1 repeat insertion, and 1 complex deletion-insertion variant. The variant c.673C > T, found in 10 unrelated patients, was the most frequent variant, followed by the variant c.517C > T, found in 7 unrelated patients. We performed western blotting and immunofluorescence staining with four novel variants (c.653G > A, c.597dupC, c.726-727del, and c.1045_1046delAA) to detect the expression levels of mutant HMBSs. The results showed a variant-mediated decrease in the mutant-HMBS level, suggesting that the variant resulted in impaired gene product functions. Moreover, the in vitro functional verification in this study provided PS3_moderate evidence for American College of Medical Genetics and Genomics (ACMG) to grade the pathogenicity of novel variants in AIP.

Infectious disease pandemic and permanent volatility of international stock markets: A long-term perspective.

Understanding the impact of infectious disease pandemic on stock market volatility is of great concerns for investors and policy makers, especially during recent new coronavirus spreading period. Using an extended GARCH-MIDAS model and a newly developed Infectious Disease Equity Market Volatility Tracker (EMV-ID), we investigate the effects of infectious disease pandemic on volatility of US, China, UK and Japan stock markets through January 2005 to April 2020. The empirical results show that, up to 24-month lag, infectious disease pandemic has significant positive impacts on the permanent volatility of international stock markets, even after controlling the influences of past realized volatility, global economic policy uncertainty and the volatility leverage effect. At different lags of eruptions in infectious disease pandemic, EMV-ID has distinct effects on various stock markets while it has the smallest impact on permanent volatility of China's stock market.

Acute intermittent porphyria: focus on possible mechanisms of acute and chronic manifestations.

Porphyrias are a group of inherited metabolic diseases that include eight types, each of which is caused by a mutation that affects an enzyme of the heme biosynthetic pathway. When an enzyme defect has physiological significance, it leads to overproduction of pathway precursors prior to the defective step. The partial absence of the third enzyme in the heme biosynthetic pathway, porphobilinogen deaminase (PBGD) also known as hydroxymethylbilane synthase (HMBS), results in acute intermittent porphyria (AIP), which affects mainly women. Subjects who had AIP symptoms were deemed to have manifest AIP (MAIP). Clinical manifestations are usually diverse and non-specific. Acute AIP episodes may present with abdominal pain, nausea, and vomiting, and repeated episodes may result in a series of chronic injuries. Therefore, studying the mechanisms of acute and chronic manifestations of AIP is of great significance. This review aims to summarize the possible mechanisms of acute and chronic manifestations in patients with AIP.

Recent advances in the epidemiology and genetics of acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a dominant inherited disorder with a low penetrance that is caused by mutations in the gene coding for hydroxymethylbilane synthase (HMBS). Information about the epidemiology and molecular genetic features of this rare disorder is crucial to clinical research, and particularly to the evaluation of new treatments. Variations in the prevalence and penetrance of AIP in various studies may due to the different inclusion criteria and methods of assessment. Here, the prevalence and penetrance of AIP are analyzed systematically, and the genetic traits of different populations and findings regarding the genotype-phenotype correlation are summarized. In addition, quite a few studies have indicated that AIP susceptibility was affected by other factors, such as modifying genes. Findings regarding possible modifying genes are documented here, helping to reveal the pathogenesis of and treatments for AIP. The status of research on AIP in China reveals the lack of epidemiological and genetic studies of the Chinese population, a situation that needs to be promptly remedied.

Therapeutic strategies for acute intermittent porphyria.

Acute intermittent porphyria (AIP) is an autosomal dominant disease caused by mutations in porphobilinogen deaminase (PBGD), the third enzyme of the heme synthesis pathway. Symptoms of AIP usually manifest as intermittent acute attacks with occasional neuropsychiatric crises. The management of AIP includes treatment of acute attacks, prevention of attacks, long-term monitoring and treatment of chronic complications. Intravenous injection of heme is the most effective method of treating acute attacks. Carbohydrate loading is used when heme is unavailable or in the event of mild attacks. Symptomatic treatment is also needed during attacks. Prevention of attacks includes eliminating precipitating factors, heme prophylaxis and liver transplantation. New treatment options include givosiran (siRNA) to down-regulate ALA synthase-1 (ALAS1) and the messenger RNA of PBGD (PBGD mRNA) delivered to the liver cells of patients with AIP. Long-term monitoring of chronic complications includes regular liver-kidney function and hepatocellular carcinoma (HCC) screening.

The challenge of managing comorbidities: a case report of primary Sjogren's syndrome in a patient with acute intermittent porphyria.

Acute intermittent porphyria (AIP) is a rare inherited metabolic disease associated with heme metabolism. Primary Sjogren's syndrome (PSS) is a common autoimmune disease. The combined presence of AIP and PSS complicates treatment. A rare case of concomitant AIP and PSS is reported in this paper. A 30-year-old woman with AIP had recurrent acute abdominal pain, nausea and vomiting, constipation, persistent chest, back, and waist pain, red urine, positivity for porphobilinogen (PBG) in urine and a pathogenic mutation of the HMBS gene. Two and a half years after she was diagnosed with AIP, she was diagnosed with PSS based on dryness of the eyes and mouth, the elevation of immunoglobulins (IgG and IgA) and positive results on an anti-SS-A antibody test, an anti-SS-B antibody test, Schirmer's test and a labial gland biopsy. A mutation in the HMBS gene was detected in the patient and her cousin, but the patient had more severe AIP and more severe symptoms (such as epilepsy and a limp), which may be related to the co-morbidity of PSS. According to her PSS activity score, the patient had an ESSDAI score of 9 and required systemic treatment. However, potential medications were limited by AIP, so mycophenolate mofetil was eventually added to delay the progression of the primary disease.

An extremely rare combination of acute intermittent porphyria and Turner syndrome.

A very rare case of acute intermittent porphyria (AIP) co-existing Turner syndrome (TS) is reported for the first time. A 32-year-old woman was diagnosed with AIP due to recurrent acute abdominal pain, red urine and pathogenic mutation of Hydroxymethyl synthetase (HMBS) gene. At the same time, TS was confirmed by Karyotype analysis results of 46,X,i(X)(q10), which accompanied by primary amenorrhea, elevated serum concentrations of follicle-stimulating hormone (FSH). Since the first attack of AIP, the patient has been increasingly depressed, and Psychiatry identified major depression. Duloxetine was chosen after careful deliberation, and the patient's mood stabilized. AIP had not recurred after half a year. Since sex hormones are the exacerbating factor of acute attack of AIP, sex hormone replacement therapy for TS was not administered. In conclusion, the conditions of AIP co-existing TS are complicate, and the treatment still needs to be improved by multiple disciplines in the follow-up.

Troxerutin attenuates cognitive decline in the hippocampus of male diabetic rats by inhibiting NADPH oxidase and activating the Nrf2/ARE signaling pathway.

Diabetes­associated cognitive decline is a recently identified a potential complication of diabetes. The present study was designed to examine the effects of troxerutin, a potent antioxidant, on cognitive function in rats with streptozotocin­induced diabetes and to further explore the potential underlying mechanisms. Cognitive functions were investigated by the Morris water maze test. The malondialdehyde (MDA) level and superoxide dismutase (SOD) activity in the hippocampus were assessed as the parameters of oxidative stress. Subunits of the NADPH oxidase (NOX) expression and nuclear factor erythroid 2­related factor 2/antioxidant responsive element (Nrf2/ARE) signaling pathway were detected to explore the potential underlying mechanisms. The water maze test revealed that troxerutin significantly improved cognitive impairment in diabetic rats. Troxerutin treatment attenuated oxidative stress in the hippocampus of diabetic rats, as evidenced by the decreased MDA level and the increased SOD activity. Moreover, troxerutin activated the Nrf2/ARE signaling pathway via Nrf2 nuclear translocation in the cells in the hippocampus of diabetic rats. Troxerutin elevated the expression levels of the antioxidant enzymes, heme oxygenase­1 (HO­1) and NAD(P)H:quinone oxidoreductase (NQO1), and decreased the expression levels of the NOX subunits, gp91phox, p47phox and p22phox. On the whole, these findings demonstrate that troxerutin exerts neuroprotective effects against diabetes­associated cognitive decline by suppressing oxidative stress in the hippocampus of rats with streptozotocin­induced diabetes. Troxerutin may thus prove to be a potential therapeutic medicine for the treatment of diabetes­associated cognitive decline.

DL-3-n-butylphthalide (NBP) ameliorates cognitive deficits and CaMKII-mediated long-term potentiation impairment in the hippocampus of diabetic db/db mice.

Objective: Diabetes-associated cognitive deficits is characterized by long-term potentiation (LTP) decline in the hippocampus. DL-3-n-butylphthalide (NBP) is a novel agent exerting protective effect against ischemic brain. However, the effects of NBP on diabetes-associated cognitive deficits and underlying mechanisms are not fully clear. This study was designed to evaluate the effects of NBP on the cognitive deficits through activating CaMKII-mediated LTP process and protecting neuron structure of hippocampus in diabetic db/db mice. Methods: Male db/db mice were randomly divided into db/db group (n = 8) and db/db+NBP group (n = 8, 120mg/Kg NBP by gavage). Male db/m mice (n = 8) were included as control group. All animals were treated for 6 weeks. Morris Water Maze test was carried out to evaluate cognitive function. Electrophysiological recordings were performed to test LTP level. HE-staining and electron microscopy of hippocampus were used to observe structure change of neurons and synapse. RT-PCR and Western blot were used to assess the expression of CaMKII, NR2B, and GluR1. Results: Type 2 diabetes mellitus caused LTP decline, and significantly decreased NR2B, CaMKII, and GluR1 expression. Histological analysis showed that disorganized pyramidal cells, as well as degraded neuron and synapse ultrastructure in db/db mice. NBP treatment restored LTP and its associated proteins in db/db mice. The structure changes of hippocampal cells were partly reversed by NBP intervention. Conclusion: These results suggest that NBP ameliorates cognitive deficits induced by type 2 diabetes mellitus through improving CaMKII-mediated LTP and cell ultrastructure in the hippocampus. NBP is a potential therapeutic agent for diabetes-associated cognitive deficits. Abbreviations: NBP: DL-3-n-butylphthalide; LTP: long-term potentiation; CaMKII: calcium/calmodulin-dependent protein kinase II; NR2B: N-methyl-D-aspartic acid receptor subtype 2B; GluR1: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subtype 1.

L-3-n-butylphthalide attenuates cognitive deficits in db/db diabetic mice.

Numerous epidemiological studies have shown that diabetes mellitus (DM) is associated with dementia and cognition decline. However, there is currently no effective treatment for diabetes-induced cognitive dysfunction. The neuroprotective effect of L-3-n-butylphthalide (L-NBP) has been demonstrated in vascular dementia animal models. The purpose of this study was to determine whether L-NBP can ameliorate cognitive deficits in db/db mice, a model of obesity and type 2 diabetes. The mice were administered with vehicle or L-NBP (120 mg/kg) by gavage daily for 6 weeks. Then, Morris water maze tasks were performed, and hippocampal LTP was recorded in vivo. Next, the synaptic structure of the CA1 hippocampus region was investigated via electron microscopy. Finally, the expression levels of MDA, SOD, 8-OHdG, and NADPH oxidase subunits gp91 and p67, as well as the expression of NF-κB p65, TNF-α, IL-1ß and caspase-3 were measured by Western blot, RT-PCR and ELISA. Treatment with L-NBP significantly attenuated the learning and memory deficits in db/db mice. Concomitantly, L-NBP also increased hippocampus synaptic plasticity, characterized by an enhanced in vivo LTP, and suppressed oxidative stress, as indicated by increased SOD activity and decreased MDA, 8-OHdG, and NADPH oxidase subunits p67 and gp91. L-NBP also significantly decreased NF-κB p65, TNF-α, IL-1ßand caspase-3 levels in the hippocampus. L-NBP significantly ameliorated cognitive decline in type 2 diabetic mice, and this effect was accompanied by an improvement in hippocampal plasticity and an amelioration of oxidative stress, inflammation and apoptosis cascades. Thus, L-NBP may be a promising therapeutic agent against DM-mediated cognitive dysfunction.

Prophylactic Use of Troxerutin Can Delay the Development of Diabetic Cognitive Dysfunction and Improve the Expression of Nrf2 in the Hippocampus on STZ Diabetic Rats.

BACKGROUND: With the change in lifestyle and the aging population, the incidence of cognitive dysfunction in diabetes mellitus is rising sharply. Oxidative stress is an important mechanism in the development of diabetic cognitive dysfunction. Nuclear factor E2-related factor 2 (Nrf2) is the core transcription factor of antioxidative stress. Early prevention and treatment of diabetic cognitive dysfunction can reduce the incidence of dementia and improve the quality of life of diabetic patients. AIM: This study was aimed at determining effect of troxerutin on the development of cognitive dysfunction and the expression level of Nrf2 in the hippocampus of streptozotocin (STZ) diabetic rats, when used in the early preventive stage. METHODS: An STZ-induced diabetic rat model was established (n = 30), and the animals were randomly divided into 2 groups: diabetic control group (DC, n = 15) and diabetic troxerutin intervention group (DT, n = 15). Another 10 normoglycemic rats were put into a normal control group (NC, n = 10). While the DT group was injected with troxerutin (60 mg/kg), the DC group and the NC group were injected with physiological saline for 12 weeks daily. Learning and memory behaviors were tested using the Morris water maze test. The superoxide dismutase (SOD) activity, malondialdehyde (MDA) content, mRNA level, and protein level of Nrf2 were measured. Data were collected and analyzed by the statistical software package SPSS 19.0, which included one-way analysis of variance with completely randomized design. RESULTS: Learning and memory levels were significantly improved in the DT group compared with the DC group. Moreover, in the DT group, the expression level of Nrf2 in the hippocampus was increased, activity of SOD was elevated, and MDA content was decreased. CONCLUSION: Prophylactic use of troxerutin delays the development of diabetic cognitive dysfunction and increases the expression level of Nrf2 in the hippocampus of STZ diabetic rats.

Effects of TRPM7/miR-34a Gene Silencing on Spatial Cognitive Function and Hippocampal Neurogenesis in Mice with Type 1 Diabetes Mellitus.

This study aimed to explore the effects of transient receptor potential melastatin 7 (TRPM7)/microRNA-34a (miR-34a) gene silencing on spatial cognitive function and hippocampal neurogenesis in mice with type 1 diabetes mellitus (T1DM). BALB/c mice were chosen to establish T1DM models and divided into five groups respectively: the negative control (NC), T1DM, T1DM + si-TRPM7, T1DM + si-miR-34a, and T1DM + si-TRPM7 + si-miR-34a groups. Morris water maze (MWM) test was adopted to observe behavioral alterations in mice. In all groups, changes in weight, fasting insulin, blood glucose, and insulin-related antibodies: insulin autoantibody (IAA), islet cell antibody (ICA), and glutamic acid decarboxylase antibody (GAD-Ab) were monitored. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to test TRPM7 and miR-34a expressions. Nissl staining was performed to detect neuron numbers in hippocampal tissues. Ultrastructure of hippocampal neurons was observed by transmission electron microscopy. TdT-mediated dUTP nick-end labeling (TUNEL) staining was used to assess cell apoptosis, and Western blotting was applied to examine expressions of apoptosis-related proteins. Compared to the NC group, the mice in the T1DM group had increased expressions of TRPM7 and miR-34a; decreased weight and fasting insulin; increased blood glucose and levels of ICA, IAA, and GAD-Ab; prolonged escape latency; less time spent in the target quadrant; incomplete neuronal structure; reduced neuron numbers; increased cell apoptosis and expressions of activated Bax, Cyt-c, and cleaved caspase-3; but reduced Bcl-2 expression. In comparison to the T1DM group, the T1DM + si-TRPM7, T1DM + si-miR-34a, and T1DM + si-TRPM7 + si-miR-34a groups showed increased weight and fasting insulin; reduced blood glucose and levels of ICA, IAA, and GAD-Ab; shortened escape latency; prolonged time spent in the target quadrant platform; intact neuronal structure; increased neuron numbers; repaired neurons; reduced cell apoptosis and expressions of activated Bax, Cyt-c, and cleaved caspase-3; but increased Bcl-2 expression. The T1DM + si-TRPM7 + si-miR-34a group underwent more obvious changes than the T1DM + si-TRPM7 and T1DM + si-miR-34a groups. Our results demonstrated that TRPM7/miR-34a gene silencing could improve spatial cognitive function and protect hippocampal neurogenesis in mice with T1DM.

Successful treatment of type B insulin resistance with mixed connective tissue disease by pulse glucocorticoids and cyclophosphamide.

Type B insulin resistance syndrome is a very rare condition caused by autoantibodies against the insulin receptor. We report the successful treatment of a patient with refractory type B insulin resistance with pulse glucocorticoids and cyclophosphamide. The medical record of a patient with type B insulin resistance was reviewed. A 36-year-old Chinese woman presented with menopause, weight loss and refractory hyperglycemia for 3 months, which could not be controlled by up to 972 of insulin units per day. Mixed connective tissue disease was diagnosed with high titers of antinuclear antibody, ribonucleoprotein antibody and interstitial lung disease. Type B insulin resistance was diagnosed with positive immunoprecipitation assay of anti-insulin-receptor antibodies in serum. We started one cycle of pulse methylprednisolone (1,000 mg/day for 3 days) then tapered to prednisone 1 mg/kg/day, and cyclophosphamide 0.4 g/week was added on. Three weeks after pulse glucocorticoid therapy, fasting glucose returned to 4.4 mmol/L. Fasting insulin decreased from 647.27 to 12.95 uIU/mL 6 weeks later. The patient had gained 15 kg during 20 months of uneventful following up, and glycated hemoglobin decreased from 10.1 to 5.1%.In this patient with type B insulin resistance, a combination of pulse glucocorticoids and cyclophosphamide was successful in inducing a complete remission. Close cooperation between endocrinologists and rheumatologists will ensure an individualized regimen for this rare condition.

Effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits in the hippocampus of streptozotocin-induced type 1 diabetes mellitus rats.

Increasing evidence demonstrates an association between diabetes and hippocampal neuron damage. This study aimed to determine the effects of troxerutin on cognitive deficits and glutamate cysteine ligase subunits (GCLM and GCLC) in the hippocampus of streptozotocin-induced type 1 diabetes mellitus (T1DM) rats. At 12weeks after streptozotocin injection, T1DM rats were randomly divided into 4 groups (n=15 each group) to receive no treatment (T1DM), saline (T1DM+saline), alpha-lipoic acid (T1DM+alpha-lipoic acid), and troxerutin (T1DM+troxerutin), respectively, for 6weeks. Meanwhile, 10 control animals (NC group) were assessed in parallel. Learning performance was evaluated by the Morris water maze. After treatment, hippocampi were collected for pathological examination by hematoxylin and eosin (H&E) staining. Next, hippocampal superoxide dismutase (SOD) activity, and malondialdehyde (MDA) and glutathione (GSH) levels were assessed. Finally, glutamate cysteine ligase catalytic (GCLC) and glutamate cysteine ligase modifier (GCLM) subunit mRNA and protein levels were quantified by reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively. Compared with T1DM and T1DM+saline groups, escape latency was overtly reduced in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Significantly increased GCLM and GCLC mRNA levels, GCLC protein amounts, SOD activity, and GSH levels, and reduced MDA amounts were observed in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. In T1DM and T1DM+saline groups, H&E staining showed less pyramidal cells in the hippocampus, with disorganized layers, karyopyknosis, decreased endochylema, and cavitation, effects relieved in T1DM+alpha-lipoic acid and T1DM+troxerutin groups. Troxerutin alleviates oxidative stress and promotes learning in streptozotocin-induced T1DM rats, a process involving GCLC expression.

Alteration of NPY in hypothalamus and its correlation with leptin and ghrelin during the development of T2DM in a rat model.

OBJECTIVES: This study aimed to investigate the alteration of Neuropeptide Y (NPY) in the hypothalamus and its correlation with insulin, leptin and ghrelin during the development of a rat model of type 2 diabetes mellitus. METHODS: The type 2 diabetes mellitus model was developed in diet-induced obesity (DIO) rats followed by the intraperitoneal injection of low-dose streptozotocin (STZ, 25 mg/kg). At four time points during the development of type 2 diabetes mellitus in rats, the fasting serum insulin, leptin, and plasma ghrelin were measured and the hypothalamic neuropeptide Y (NPY) content and mRNA expression were detected in the rats, which were divided into 4 groups: normal control (NC), DIO4W, DIO8W, and T2DM; the mRNA expression of OB-Rb, and GSH-R1a in the hypothalamus were also assayed. RESULTS: During the development of the type 2 diabetes mellitus rat model, both the fasting serum levels of insulin and leptin (ng/ml) elevated significantly and the fasting plasma ghrelin concentration decreased the hypothalamic NPY (pg/mg) content significantly. NPY mRNA increased significantly in a time-dependent fashion while both the OB-Rb and the GHS-R1a mRNA of the hypothalamus decreased significantly. Hypothalamic NPY concentration was positively correlated with the changes in serum insulin and leptin and negatively correlated with plasma ghrelin. CONCLUSIONS: During the development of the type 2 diabetes mellitus rat model, the hypothalamic NPY content and NPY mRNA expression increased in a time-dependent manner, which was positively correlated with the changes of the serum insulin and leptin and negatively correlated with the plasma ghrelin.

Effects of L-3-n-butylphthalide on cognitive dysfunction and NR2B expression in hippocampus of streptozotocin (STZ)-induced diabetic rats.

Diabetes mellitus is associated with rapid cognitive decline. Currently, there is no effective treatment for cognitive dysfunction induced by diabetes. L-3-n-Butylphthalide (L-NBP) is a nerve protective drug extracted from seeds of celery, which has been proved to improve learning and memory in vascular dementia animal models by improving microcirculation, protecting mitochondria and increasing long-term potentiation (LTP). NR2B, one of the subunits of N-methyl-D-aspartate receptor, has been proved to be an important factor for the formation of LTP. The study aimed to investigate the role of NR2B in cognitive dysfunction in the rats with type 1 diabetes and define the protective effects of L-NBP on cognition. A rat model of type 1 diabetes was established by a single intraperitoneal injection of streptozotocin at 60 mg/kg. Animals were randomly allocated to four groups: normal control (NC); diabetic control (DC); diabetic + low L-NBP (DL, administered L-NBP 60 mg/kg per day for 12 weeks); and diabetic + high L-NBP (DH, administered L-NBP 120 mg/kg per day, for 12 weeks). After 12 weeks, cognitive and memory changes were investigated in the Morris water maze. The expression of NR2B was assessed by real-time polymerase chain reaction, Western blotting, and immunohistochemistry. Our results indicated that the escape latency was significantly increased and the number of crossing platform was significantly decreased in DC group compared to NC group. Also, the expression of NR2B was significantly declined in DC group. However, compared to DC group, the expression of NR2B of the L-NBP-treated groups was significantly increased and the escape latency was shortened with the DH group being the most obvious. Therefore, L-NBP can improve the cognitive function by up-regulating the expression of NR2B in STZ-diabetic rats, which may provide the direction for future diabetic encephalopathy therapy.