Clinical and genetic analysis of five pedigree with maturity-onset diabetes of the young type 2 / 中华内分泌代谢杂志

Objective:To explore the clinical and molecular genetic characteristics of patients with maturity-onset diabetes of the young type 2(MODY2).Methods:Clinical data and laboratory results were collected from five MODY2 patients and their family members diagnosed in the Department of Endocrinology, Genetics, and Metabolism of Xi ′an Children′s Hospital in the recent two years. Whole exome sequencing was carried out on every proband to identify potential variants, then the suspected variants were verified with Sanger sequencing in family numbers.Results:Among the 5 probands, except for proband 4 who presented with polydipsia and polyuria, hyperglycemia in the rest of the children was accidentally identified. Urine routine, urinary protein, and blood lipid of the five probands were all normal, and HbA 1C was between 5.96% and 8.15%. Moreover, an important discovery in this study was that proband 5 had insulin resistance(IRS), which was different from previous studies. It was confirmed by genetic analysis that a glucokinase(GCK) gene variant existed in every MODY2 pedigree. There were four GCK variants in this study, including c. 146C>T(p.T49I), c. 1237T>G(p.Y413D), c. 683C>T(p.T228M) and c. 952G>T(p.G318W), among which the C. 1237T>G(P.y413d) and C. 952G>T(P.G318W) had not been reported till now. All probands received lifestyle intervention, and the blood glucose control was relatively stable. Conclusion:There is MODY2 patient complicated with IRS. MODY2 patients can be controlled well by lifestyle interventions. In addition, we discovered two novel variants of GCK, which extend the mutation spectrum of this gene.

Clinical and genetic analysis of an infant with permanent neonatal diabetes mellitus due to novel variant of insulin gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for an infant with permanent neonatal diabetes mellitus (PNDM).@*METHODS@#Clinical data of the child was collected. Targeted capture-next generation sequencing was carried out to identify the potential variants. Candidate variant was verified by Sanger sequencing of her family members.@*RESULTS@#The child was a 4-month-and-26-day female featuring onset of ketoacidosis accompanied with fasting blood glucose of 24.4 mmol/L, positive urine glucose, decreased serum C-peptide, HbA1c of 9.58%, and negative diabetes autoantibody. Genetic testing revealed that she has carried a heterozygous c.314T>G (p.L105R) variant of the INS gene. Sanger sequencing verified that neither of her parents has carried the same variant, which was also unreported in the literature. The variant was classified as likely pathogenic based on the ACMG guidelines.@*CONCLUSION@#The c.314T>G (P.L105R) variant of the INS gene probably underlay the genetic etiology in this child. Genetic testing should be conducted for children with suspected PNDM for early diagnosis and appropriate treatment.

Clinical and genetic analysis of a patient with primary distal renal tubular acidosis due to variants of ATP6V0A4 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical features and genetic etiology of a patient with primary distal renal tubular acidosis (dRTA).@*METHODS@#A child who was diagnosed with primary dRTA at the Xi'an Children's Hospital in April 2021 due to poor appetite and persistent crying was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was carried out for the child. Candidate variants were validated by Sanger sequencing of his family members.@*RESULTS@#The child, a 1-month-and-18-day male, had featured poor appetite, persistent crying, poor weight gain and dehydration. Laboratory examination has suggested metabolic acidosis, hyperchloremia, hypokalemia, abnormal alkaline urine and anemia. Ultrasonographic examination of the urinary system revealed calcium deposition in renal medulla. DNA sequencing revealed that he has harbored compound heterozygous variants of the ATP6V0A4 gene, namely c.1363dupA (p.M455NfsX14) and c.2257C>T (p.Q753X), which were respectively inherited from his father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were classified as pathogenic (PVS1+PM3+PM2_Supporting).@*CONCLUSION@#The compound heterozygous variants of c.1363dupA (p.M455NfsX14) and c.2257C>T (p.Q753X) of the ATP6V0A4 gene probably underlay the pathogenesis of primary dRTA in this patient. Discovery of the c.2257C>T (p.Q753X) variant has also expanded the mutational spectrum of the ATP6V0A4 gene.

Analysis of clinical phenotype and genotype of cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome caused by a novel variant of SNAP29 gene / 中华神经科杂志

Objective:To investigate the clinial phenotype and genetic characteristics of a child with cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma (CEDNIK) syndrome and to improve the clinicians′ understanding of this disease.Methods:Clinical data of the child with CEDNIK syndrome diagnosed in Department of Endocrinology, Genetics and Metabolism, Xi′an Children′s Hospital in June 2020 were collected. Whole exome sequencing was carried out to identify the potential variants of SNAP29 gene. Suspected variants were verified by Sanger sequencing of family numbers. The literature about the cases of CEDNIK syndrome were reviewed.Results:The proband is a boy, who was aged 1 year and 4 months, had the manifestations of psychomotor retardation, microcephaly, feeding difficulties, severe malnutrition, recurrent respiratory tract infection, binocular esotropia, sensorineural deafness, cutaneous ichthyosis and keratosis, left cryptorchidism. Brain magnetic resonance imaging indicated congenital dysplasia. Whole exome sequencing identified a homozygous variant of c.383dupT (p.E129Rfs *5) in the SNAP29 gene of the proband, and the heterozygous variation was observed at the same locus in his parents, which conformed to the autosomal recessive inheritance. This mutataion was determined as a pathogenic mutation according to the guidelines of American College of Medical Genetics and Genomics. Literature retrieval showed currently a total of 29 cases of CEDNIK syndrome were reported, containing 8 types of SNAP29 gene mutation. However, there was no Chinese case reported. And the c.383dupT (p.E129Rfs *5) mutation found in this study was a novel one which had not been reported yet. Conclusion:The phenotype of the proband is generally consistent with the CEDNIK syndrome and the novel c.383dupT (p.E129Rfs *5) mutation of SNAP29 gene is the genetic cause.

Clinical and genetic analysis of five patients with familial male-limited precocious puberty / 中华内分泌代谢杂志

Objective:To analyze the clinical and genetic characteristics of five patients with familial male-limited precocious puberty(FMPP).Methods:The clinical data, laboratory and imaging results of the five patients with FMPP were collected. Whole exome sequencing was carried out to identify the potential variants. Suspected variants were verified by Sanger sequencing of family numbers.Results:Of the five patients, four were children and one was an adult. All the four children presented to hospital with premature sexual development at age less than 4 years. Serum testosterone was elevated, luteinizing hormone(LH) and follicle stimulating hormone(FSH) basal values were at prepubertal levels, and gonadotropin-releasing hormone(GnRH) stimulation test suggested peripheral precocious puberty. Genetic analysis revealed the mutations of LHCGR genes in all the five patients. Patients 1, 2, 3, and 4 carried the same heterozygous mutation c. 1713G>C(p.M571I), and the patient 5 carried the c. 1741T>C(p.C581R)variation. The four children were treated with anti-androgen preparations and the third-generation aromatase inhibitors, all of which were effective.Conclusion:The c. 1713G>C mutation of LHCGR gene is a novel one which expands the mutation spectrum of LHCGR gene. Combined treatment with bicaluamide and the third generation aromatase inhibitors can improve clinical symptoms and delay epiphyseal closure in children with FMPP.

Expression and functional SNP loci screen of ATM from coal worker's pneumoconiosis / 中华劳动卫生职业病杂志

Objective: To detect of gene expression and genotype of the ataxia telangiectasia mutated (ATM) from coal workers' pneumoconiosis (CWP) , It is explored whether CWP is related to ATM gene. Methods: In October 2020, the relevant information of 264 subjects who received physical examination or medical treatment in the Department of occupational diseases of Guiyang public health treatment center from January 2019 to September 2020 was collected. Through the occupational health examination, 67 healthy people with no history of exposure to occupational hazards were selected as the healthy control group; The coal miners with more than 10 years of coal dust exposure history and small shadow in the lung but not up to the diagnostic criteria were the dust exposure control group, a total of 66 people; The patients with the same history of coal dust exposure and confirmed stage I were coal worker's pneumoconiosis stage I group, a total of 131 people. The expression of ATM was detected by QRT PCR. ATM rs189037 and rs1801516 were genotyped by massarray. Results: There was significant difference in the expression of ATM among the groups (P<0.05) ; Compared with the healthy control group, the expression of ATM in the dust exposed control group was significantly increased (P<0.05) . With the occurrence and development of CWP, the GG of rs189037 wild type decreased, the GA of mutant heterozygote and AA of homozygote increased, but the difference was not statistically significant (P>0.05) ; Rs1801516 wild type GG and mutant heterozygote GA had no significant changes (P>0.05) . There were significant differences in age, neutrophils and basophils among rs189037 groups (all P<0.05) . There were no significant differences in blood pressure, eosinophils, lymphocytes, monocytes, smoking and drinking history among rs189037 groups (all P>0.05) . Compared with wild-type GG, the or of mutant heterozygotes and homozygotes increased, but the differences were not statistically significant (P>0.05) . Conclusion: ATM gene may be one of the early activation genes of CWP and rs189037 may be the functional loci which affects gene expression. ATM gene is related to inflammatory response, Neutrophils and basophils have an impact on the development of CWP.

Regulation of Hypnotic Active Components of Cnidii Fructus on Melatonin Synthesis Rate-limiting Enzyme AANAT in Rats with PCPA-induced Insomnia / 中国实验方剂学杂志

Objective:To observe the effects of Cnidii Fructus hypnotic active components （CHC） on the behaviors of rats with p-chlorophenylalanine （PCPA）-induced insomnia and melatonin （MT） synthesis rate-limiting enzyme arylalkylamine <italic>N</italic>-acetyltransferase （AANAT）， and explore the protective mechanism of CHC on the pineal gland. Method:Male SD rats of SPF grade were randomly divided into a blank control group， a model group， a MT group， and high-， medium-， and low-dose CHC groups with 10 rats in each group. Except for the blank control group， other groups received 4.5% PCPA suspension at 10 mL·kg^-1， intragastric administration， for two consecutive days. After PCPA model of insomnia was established， normal and model groups were gavaged at the same volume of 2% Tween-80， MT control group （10 mg·kg^-1）， CHC was high， medium and low （60， 30， 15 mg·kg^-1）， 10 mL·kg^-1， once a day， for consecutive 7 days. Four days after administration， open field， elevated cross maze， and pentobarbital sodium-induced sleep tests were conducted， respectively. Serum MT was detected by enzyme-linked immunosorbent assay. The mRNA expression level of AANAT was determined by real-time fluorescence-based quantitative polymerase chain reaction （Real-time PCR）. The expression of AANAT protein in the pineal gland was detected by Western blot. Result:Compared with the results in the blank control group， the total distance of open field activity and standing times and duration in the central area were increased （<italic>P</italic><0.05， <italic>P</italic><0.01）， the proportions of open arm entry （OE%） and open arm time （OT%） were decreased （<italic>P</italic><0.05）， and the sleep latency was prolonged （<italic>P</italic><0.01） in the model group. Compared with the model group， no significant difference was observed in the low-dose CHC group， while other groups exhibited reduced total distance of activity （<italic>P</italic><0.05， <italic>P</italic><0.01）， elevated OE% （<italic>P</italic><0.05）， shortened sleep latency， and prolonged sleep time （<italic>P</italic><0.05， <italic>P</italic><0.01）. Compared with the serum MT in the blank control group， that in the model group was decreased （<italic>P</italic><0.01）. Compared with the model group， no significant difference was observed in the low-dose CHC group， while other groups displayed increased serum MT （<italic>P</italic><0.05）. The mRNA and protein expression of AANAT was decreased in the model group as compared with that in the blank control group （<italic>P</italic><0.01）. Compared with the model group， the MT group and the high-dose CHC group showed up-regulated expression （<italic>P</italic><0.05）. Conclusion:CHC improved the behavioral indexes of PCPA-induced insomnia， increased the synthesis and secretion of MT in pineal cells， and elevated the serum MT level， which was related to the up-regulation of the mRNA and protein expression of AANAT in the pineal gland.

Identification of a novel variant of SRD5A2 gene in a child featuring steroid 5α-reductase type 2 deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical characteristics and genetic basis of a child with 5α-reductase type 2 deficiency.@*METHODS@#Clinical data of the child was retrospectively analyzed. Targeted capture-next generation sequencing and Sanger sequencing were carried out to detect potential variants.@*RESULTS@#The patient's main features included micropenis and hypospadia. He was found to harbor compound heterozygous c.680G>A (p.R227Q) and c.3G>T (p.M1I) variants of the SRD5A2 gene. Among these, c.680G>A (p.R227Q) was inherited from his father and was a known pathogenic mutation, while c.3G>T (p.M1I) was inherited from his mother and was unreported previously.@*CONCLUSION@#The compound heterozygous variants of the SRD5A2 gene probably underlay the disease in this child, who was eventually diagnosed with 5α-reductase 2 deficiency.

A novel dammarane-type saponin from Gynostemma pentaphyllum and its neuroprotective effect / 中国中药杂志

One new and two known dammarane-type saponins were isolated from the leaves of Gynostemma pentaphyllum using various chromatographic methods. Their structures were identified by HR-ESI-MS,~( 1)H-NMR, ~(13)C-NMR, 2 D-NMR spectra as 2α,3β,12β,20,24(S)-tetrahdroxydammar-25-en-3-O-[β-D-glucopyranosyl(1→2)-β-D-glucopyranosyl]-20-O-β-D-xylopyranosyl(1→6)-β-D-glucopyranoside(1, a new compound, namely gypenoside J5) and 2α,3β,12β,20,24(R)-tetrahdroxydammar-25-en-3-O-[β-D-glucopyranosyl(1→2)-β-D-glucopyranosyl]-20-O-β-D-xylopyranosyl(1→6)-β-D-glucopyranoside(2) and 2α,3β,12β,20-tetrahydroxy-25-hydroperoxy-dammar-23-en-3-O-[β-D-glucopyranosyl(1→2)][β-D-glucopyranosyl]-20-O-[β-D-xylopyranosyl(1→6)]-β-D-glucopy-ranoside(3), respectively. Compounds 1 and 2 were a pair of C-24 epimers. All compounds showed weak cytotoxicity agxinst H1299, HepG2, PC-3, SH-SY5 Y cancer cell lines. However, they exerted protective effect against SH-SY5 Y cellular damage induced by H_2O_2 dose-dependently, of which compound 1 displayed the strongest antioxidant effect. The present study suggested that G. pentaphyllum has antioxidative potential and the saponins from G. pentaphyllum are considered as the active compounds with neuroprotecitve effect.

Effect of Isopimpinellin on Expression of Inhibitory Neurotransmitter and Receptor Genes in Primary Hippocampal Neurons / 中国实验方剂学杂志

Objective:To observe the effect of isopimpinellin on primary hippocampal neuron cells γ-aminobutyric acid (GABA), 5-hydroxytryptamine (5-HT) and receptor genes expressions, in order to explore its hypnotic mechanism. Method:The primary hippocampal neurons of neonatal Sprague-Dawley rats were cultured in vitro. And subsequent experiments were conducted in the optimal state of cell growth, and the purity was identified by immunohistochemistry of neuron-specific enolase. Hippocampal neurons were randomly divided into five groups, namely blank control group, diazepam group (25 mg·L-1), and low-dose (5 mg·L-1), moderate-dose (10 mg·L-1) and high-dose (20 mg·L-1) isopimpinellin groups. Early apoptosis of hippocampus neuron cells were detected using flow cytometry technique after 24 h administration, and the changes in the levels of GABA and 5-HT were detected using enzyme-linked immunosorbent. The changes in mRNA expressions of receptor genes relating to gamma-aminobutyric acid type A receptor(GABAA) genes GABRA1,GABRA5,GABBR1, gamma-aminobutyric acid type B receptor genes (GABAB) GABRB2, 5-hydroxytryptamine 1A receptor (5-HT1A)5-HT1A(A),5-HT1A(B),5-HT1A(C) were detected by real-time quantitative PCR(Real-time PCR). Result:On the 7th day, the hippocampal neurons grew in a good condition, and the purity was above 90%. Apoptosis rates of hippocampal neurons in the low-dose and moderate-dose groups were significantly lower than that in the blank control group (PP1,GABRA5,5-HT1A(A),5-HT1A(C) in the moderate-dose and high-dose isopimpinellin groups were significantly higher than those in the blank control group (PP1,5-HT1A(B) in the low-dose, moderate-dose and high-dose isopimpinellin groups were significantly higher than those in the blank control group (PPConclusion:The hypnotic mechanism of isopimpinellin may be related to the inhibition of hippocampal neuron apoptosis, the increase of the content of inhibitory neurotransmitter GABA, and the up-regulation of GABA and 5-HT-related receptor genes.

Comparation on effect between Phellodendri Chinensis Cortex and Coptis Rhizoma on organism metabolism in mice / 中草药

Objective: To compare the effect of Phellodendri Chinensis Cortex (HB) and Coptis Rhizoma (HL) on organism metabolism in mice and explore the regulation of both HB and HL on the endogenous metabolism in mice. Methods: 1H-NMR, based on metabolomic approach coupled with multivariate statistical analysis method, was used to investigate the intervention differences between HB and HL on endogenous metabolites in the serum and liver of normal mice after drug administration. Results: The changes of organism endogenous metabolites in both HB and HL treated groups were similar, but the differences also existed. Compared with the control group, the levels of 3-HB, NAG, glycerin, choline, α-glucose,and β-glucose in serum and those of glutamate, glycogen, adenosine, GSSG, betaine, and other metabolites in liver were changed in the two drug treated groups in a different change range. These changes of endogenous metabolites involved in glycometabolism, lipid metabolism, and other pathways. Conclusion: This study provides a scientific basis for the comparative analysis of drug function between HB and HL, which has both the similarities and differences.

Comparison of chemical composition between raw and vinegar-baked Paeoniae Radix Alba using NMR based metabolomic approach / 药学学报

To compare the chemical change of Paeoniae Radix Alba (PRA) after vinegar-baking processing, as well as the effect of vinegar types exerted on the processing, 1H NMR-based metabolomic approach combined with multivariate statistical analysis was used to investigate the different metabolites between the raw and two vinegar-baked PRA. More than thirty metabolites were identified in the 1H NMR spectrum of PRA, and the multivariate statistical analysis showed that raw and two vinegar-baked PRA could be separated obviously. After vinegar-baking, the contents of isoleucine, lactate, alanine, arginine, albiflorin, and 5-hydroxymethyl furfural (5-HMF) elevated, while those of sucrose, paeoniflorin and its analogues (calculated by benzoate) decreased. The chemical compositions of two vinegar-baked PRA were also different. Shanxi vinegar- baked PRA showed higher levels of leucine, isoleucine, valine, and albiflorin, while rice vinegar-baked PRA contained more sucrose and paeoniflorin's analogues (calculated by benzoate). And the chemical changes in Shanxi vinegar-baked PRA were greater than those of rice vinegar-baked PRA. The results revealed the chemical differences between raw and vinegar-baked PRA, as well as the influence of vinegar type on processing, in a holistic manner, the results obtained suggested that the correlations between the chemical change and the drug action after processing, as well as the vinegar type used in processing, should be further studied.

Discrimination of patients with Xiao-Chaihu Tang syndrome using 1H NMR metabonomics and partial least square analysis / 药学学报

1H NMR metabonomics approach was used to reveal the chemical difference of urine between patients with Xiao-Chaihu Tang syndrome (XCHTS) and healthy participants (HP). The partial least square method was used to establish a model to distinguish the patients with Xiao-Chaihu-Tang syndrome from the healthy controls. Thirty-four endogenous metabolites were identified in the 1H NMR spectrum, and orthogonal partial least squares discriminant analysis showed the urine of patients with Xiao-Chaihu Tang syndrome and healthy participants could be separated clearly. It is indicated that the metabolic profiling of patients with Xiao-Chaihu Tang syndrome was changed obviously. Fifteen metabolites were found by S-pot of OPLS-DA and VIP value. The contents of leucine, formic acid, glycine, hippuric acid and uracil increased in the urine of patients, while threonine, 2-hydroxyisobutyrate, acetamide, 2-oxoglutarate, citric acid, dimethylamine, malonic acid, betaine, trimethylamine oxide, phenylacetyl glycine, and uridine decreased. These metabolites involve the intestinal microbial balance, energy metabolism and amino acid metabolism pathways, which is related with the major symptom of Xiao-Chaihu Tang syndrome. The patients with Xiao-Chaihu Tang syndrome could be identified and predicted correctly using the established partial least squares model. This study could be served as the basis for the accurate diagnostic and reasonable administration of Xiao-Chaihu-Tang syndrome.

Comparison on chemical constituents between Paeoniae Alba Radix and Paeoniae Rubra Radix using NMR based metabolomic approach / 中草药

Objective: To compare the chemical constituents of Paeoniae Alba Radix and Paeoniae Rubra Radix, and to provide a basis for quality evaluation. Methods: NMR-based metabolomic approach combined with multivariate statistical analysis was used to investigate the differential metabolites between Paeoniae Alba Radix and Paeoniae Rubra Radix. Results: Thirty-two metabolites were identified in the 1H-NMR spectra, and the multivariate statistical analysis showed that Paeoniae Alba Radix and Paeoniae Rubra Radix could be separated clearly. Paeoniae Alba Radix contained more arginine, threonine, acetic acid, aspartic acid, glutamine, GABA, citric acid, succinate, lactate, albiflorin, 6-O-galloyl albiflorin, 1, 2, 3, 4, 6-pentagalloyglucose, and gallic acid, while Paeoniae Rubra Radix contained more alanine, α-glucose, sucrose, paeoniflorin, catechin, β-sitosterol, fatty acid, and paeonol. In addition, the Pearson correlations between differential metabolites of Paeoniae Alba Radix and Paeoniae Rubra Radix also showed apparent differences. Conclusion: The results reveal the chemical differences between Paeoniae Alba Radix and Paeoniae Rubra Radix in a holistic way, and provide a scientific basis for assessing the quality of Paeoniae Alba Radix and Paeoniae Rubra Radix, as well as the correlations between the chemical constituents and pharmacological efficacy.

Protective effect of baicalin against rotenone induced injury on PC12 cells / 中国中药杂志

<p><b>OBJECTIVE</b>To explore the protective effect of baicalin against rotenone-induced injury on PC12 cells, and the po-tential mechanism of action action was also explored.</p><p><b>METHOD</b>PC12 cells were injured by rotenone and were treated with different concentrations (0.1, 1, 10 μmol x L(-1)) of baicalin at the same time. Cell viability was analyzed by MTT, and morphology was observed by phase-contrast microscopy. The cell apoptosis was detected by flow cytometry by Annexin V-FITC/PI staining. The intracellular ROS level was determined by fluorescence microscope with DCF-DA staining. The expression of Bcl-2, Bax and Caspase-3 was analyzed by Western blot.</p><p><b>RESULT</b>The viability of PC12 cells exposure to rotenone for 24 hour was gradually decreased with dose escalating and 1.5 μmol x L was adopted to do the following experiment. Baicalin increased cell viability, improved cell morphology and decreased intracellular ROS level. Moreover, FACS indicated baicalin attenuated the apoptosis induced by rotenone significantly. Western blot showed that Bcl-2, Bax and Caspase-3 expression in rotenone-induced PC12 cells was reversed by baicalin.</p><p><b>CONCLUSION</b>This study has demonstrated that baicalin protects PC12 cells against rotenone-induced apoptosis, at least in part, by scavenging excessive ROS and inhibiting the mitochondrion-dependent apoptotic pathway.</p>

Leptin: molecular mechanisms, systemic pro-inflammatory effects, and clinical implications / Leptina: mecanismos moleculares, efeitos pró-inflamatórios sistêmicos e implicações clínicas

Leptin, the adipokine produced mainly by the white adipose tissue, plays important roles not only in the regulation of food intake, but also in controlling immunity and inflammation. It has been widely demonstrated that the absence of leptin leads to immune defects in animal and human models, ultimately increasing mortality. Leptin also regulates inflammation by means of actions on its receptor, that is widely spread across different immune cell populations. The molecular mechanisms by which leptin determines its biological actions have also been recently elucidated, and three intracellular pathways have been implicated in leptin actions: JAK-STAT, PI3K, and ERK 1/2. These pathways are closely regulated by intracellular proteins that decrease leptin biological activity. In this review, we discuss the molecular mechanisms by which leptin regulates immunity and inflammation, and associate those mechanisms with chronic inflammatory disorders. Arq Bras Endocrinol Metab. 2012;56(9):597-607.

A leptina, uma adipocina produzida principalmente pelo tecido adiposo branco, tem um papel importante não somente na regulação da ingestão alimentar, mas também no controle da imunidade e da inflamação. Já foi amplamente demonstrado que a ausência de leptina causa deficiências imunológicas em modelos animais e em humanos, levando ao aumento da mortalidade. A leptina também regula a inflamação por meio da ação em seu receptor, amplamente distribuído em diversos tipos de células do sistema imunológico. Os mecanismos moleculares pelos quais a leptina determina suas ações biológicas foram recentemente elucidados, e três cascatas intracelulares são ativadas pela leptina: JAK-STAT, PI3K e ERK 1/2. Essas cascatas são reguladas por proteínas intracelulares, reduzindo as ações da leptina. Nesta revisão, são discutidos os mecanismos moleculares pelos quais a leptina regula a imunidade e a inflamação, associando-os a enfermidades inflamatórias crônicas. Arq Bras Endocrinol Metab. 2012;56(9):597-607.

Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy / Deficiência congênita de leptina: diagnóstico e efeitos da terapia de reposição

To describe our 10-year experience in treating leptin-deficient humans. Three adults and one boy presented with childhood-onset morbid obesity, hypogonadism and family history of obesity and early death. Serum leptin was inappropriately low. A recessive C105T leptin gene mutation was identified. Metabolic and endocrine assessments were conducted, before and while on and off leptin. The adults' body mass index decreased from 51.2 ± 2.5 to 29.5 ± 2.8 kg/m². Serum lipids normalized, insulin resistance decreased, and one of the initially diabetic females became normoglycemic. Hypogonadotropic hypogonadism was reversed, and other changes were observed in the adrenal, sympathetic, somatotropic and thyroid functions. Leptin replacement therapy reverses endocrine and metabolic alterations associated with leptin deficiency. Some of these results may be extrapolated to other diseases.

Descrever nossa experiência de 10 anos tratando pacientes deficientes em leptina. Três adultos e um menino apresentaram obesidade mórbida com início na infância, hipogonadismo e história familiar de obesidade e morte precoce. A leptina sérica era inapropriadamente baixa. A mutação recessiva C105T no gene da leptina foi identificada. Avaliações metabólicas e endócrinas foram realizadas antes e durante o tratamento. O índice de massa corporal dos adultos baixou de 51,2 ± 2,5 para 29,5 ± 2,8 kg/m². Houve normalização dos lipídios séricos, a resistência insulínica diminuiu e a paciente que era diabética se tornou normoglicêmica. O hipogonadismo hipogonadotrópico foi revertido e outras alterações foram observadas nas funções adrenal, simpática, somatotrópica e tireoidiana. A reposição de leptina reverte as alterações endócrinas e metabólicas associadas com a deficiência de leptina. Alguns desses resultados podem ser extrapolados para outras doenças.

Pathophysiological basis of cardiovascular disease and depression: a chicken-and-egg dilemma / Bases fisiopatológicas da doença cardiovascular e depressão: um dilema do ovo e da galinha

OBJECTIVE: To describe the pathophysiological basis linking cardiovascular disease (CVD) and depression; to discuss the causal relationship between them, and to review the effects of antidepressant treatment on cardiovascular disease. METHOD: A review of the literature based on the PubMed database. DISCUSSION: Depression and cardiovascular disease are both highly prevalent. Several studies have shown that the two are closely related. They share common pathophysiological etiologies or co-morbidities, such as alterations in the hypothalamic-pituitary axis, cardiac rhythm disturbances, and hemorheologic, inflammatory and serotoninergic changes. Furthermore, antidepressant treatment is associated with worse cardiac outcomes (in case of tricyclics), which are not observed with selective serotonin reuptake inhibitors. CONCLUSION: Although there is a strong association between depression and cardiovascular disease, it is still unclear whether depression is actually a causal factor for CVD, or is a mere consequence, or whether both conditions share a common pathophysiological etiology. Nevertheless, both conditions must be treated concomitantly. Drugs other than tricyclics must be used, when needed, to treat the underlying depression and not as mere prophylactic of cardiac outcomes.

OBJETIVO: Descrever as bases fisiopatológicas que servem de elo entre doenças cardiovasculares e depressão; discutir as relações de causalidade dentre tais entidades e os efeitos do tratamento com antidepressivos sobre doenças cardiovasculares. MÉTODO: Uma revisão da literatura baseada no banco de dados PubMed. DISCUSSÃO: A depressão e doenças cardiovasculares são duas doenças altamente prevalentes. Vários estudos mostraram que ambas as doenças são intimamente ligadas. Elas apresentam etiologias ou comorbidades em comum, tais como alterações no eixo hipotalâmico-pituitário, distúrbios de ritmo cardíaco e alterações hemorreológicas, inflamatórias e serotoninérgicas. Além disso, o tratamento com antidepressivos está associado com pior prognóstico cardíaco (no caso de tricíclicos), o que não é observado com inibidores seletivos da recaptação da serotonina. CONCLUSÃO: Apesar de haver uma forte associação entre depressão e doenças cardiovasculares, é ainda incerto se a depressão é na verdade o fator causal para doenças cardiovasculares, uma mera consequência, ou se ambas as condições dividem uma etiologia fisiopatológica em comum. De qualquer maneira, ambas as doenças devem ser tratadas concomitantemente. Para evitar comprometimento cardíaco, drogas não-tricíclicas devem ser usadas, quando necessário, para o tratamento da depressão e não como meros profiláticos de eventos cardíacos.

Different glutamate receptor mechanisms in long-term depression induced by different stimulus patterns in the CA1 area of adult rat hippocampus / 生理学报

Previous reports suggested that a novel stimulus pattern of multi-train stimulus at low-frequency (2-Hz or 5-Hz) could induce stable long-term depression (LTD) in the CA1 area of adult rat hippocampus. In the present study, in order to determine the mechanism in LTD induced by the two novel tetanus patterns, changes in the population spikes (PS) in the hippocampal CA1 area of adult rats following the multi-train stimulus in the presence of AP5 [antagonist of N-methyl-D-aspartate receptors (NMDARs)] or MCPG [antagonist of type I/II metabotropic glutamate receptors (mGluRs)] were recorded. The results showed that both AP5 and MCPG inhibited the LTD induced by 2-Hz multi-train stimulus. The mean amplitude of population spikes (PSA) normalized to the baseline was (96.0±3.5)% after applying AP5 (n=10) and (95.7±4.1)% after applying MCPG (n=8), respectively, measured at 20 min post-tetanus. While 5-Hz multi-train tetanus failed to induce LTD in the presence of MCPG. The mean PSA was (73.6±4.4)% (n=10) and (98.2±8.9)% (n=8) in the presence of AP5 and MCPG, respectively, measured at 35 min post-tetanus. So it is suggested that LTD induced by 2-Hz multi-train tetanus involves co-activation of NMDARs and mGluRs, while LTD induced by 5-Hz multi-train tetanus is only related to activation of mGluRs.

Thyroid Hormone Disrupting Activities of Tetrabromobisphenol-A:a Review / 环境与健康杂志

Tetrabromobisphenol A(TBBPA)is supposed to have potential thyroid disrupting activities due to its similar structure to thyroid hormones.TBBPA has been proved to show thyroid disrupting effects in vivo and in vitro studies.TBBPA might disrupt thyroid hormone system through transthyretin- and thyroid receptor-mediated pathways.The ability of TBBPA inducing the production of reactive oxygen species might be the extension of its thyroid disrupting activities.The thyroid disrupting effects of TBBPA might be closely related to its oxidative stress,reproduction toxicity and neurotoxicity.More experiments are required for the effects of TBBPA on the aquatic and amphibian animals.