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Biomedical subjects

Yi Feng

Publications and source records attributed to Yi Feng.

At least 19 recordsLinked to original sources

Mitochondrial Function-Related Genes in Sleep Disorders: A Multi-Omics Mendelian Randomization Study.

Mitochondrial dysfunction is linked to sleep disorders in previous report, but the potential roles of specific genes remain unclear. This study aimed to dissect different subtype-specific genetic associations and their underlying mechanisms. A multi-omics Summary-data-based Mendelian Randomization (SMR) approach was performed to identify potential causal links between mitochondrial function-related genes and sleep disorders. We integrated GWAS data from FinnGen database (the discovery set), independent GWAS datasets (covering different sleep-disorder subtypes and used for validation), and cis-QTLs (including mQTLs, eQTLs, and pQTLs) to perform systematic exploration. Specially, we performed targeted validation of tissue-specific effects, leveraging gene expression data from disease-relevant brain regions within the GTEx database. Our SMR analysis identified mitochondrial function-related genes potentially modulating sleep disorders across biological layers, initially identifying 102 genes at the methylation level, 48 at the gene expression level, and 6 at the protein abundance level. Integrative analysis subsequently prioritized DCXR and ACADVL and revealed their distinct, subtype-specific associations. DCXR exhibited a protective role in sleep apnea while ACADVL showed a paradoxical risk conferring role in daytime sleepiness. In addition, the analysis identified an epigenetic regulatory mechanism for DCXR in which its expression and protein levels are modulated by DNA methylation. Finally, validation in brain-hypothalamus tissue confirmed DCXR as a significant potential protective factor (OR = 0.929, 95% CI: 0.887-0.973, P_HEIDI = 0.999, FDR = 0.2449). Our findings implicate key mitochondrial genes, particularly DCXR and ACADVL, in the pathophysiology of specific sleep disorder subtypes, highlighting potential avenues for precision medicine. Clinical trial number: Not applicable.

Humans↗

Two-sample Mendelian randomization study of gut microbiota and inflammatory proteins: Predictive, preventive, and personalized treatment for migraine.

The human gut microbiota is increasingly recognized as a significant factor in the pathogenesis of migraine, potentially via inflammatory pathways. Identifying specific human gut microbiota components associated with migraines, along with the investigation of particular inflammatory proteins, is essential for advancing primary prediction, targeted prevention, and personalized treatment strategies for migraines. We conducted a two-sample Mendelian randomization study using publicly available summary statistics from genome-wide association studies. Data for 473 human gut microbiota taxa were obtained from the Finnish national health survey conducted by the National Institute for Health and Welfare study (FINRISK, n = 5959 European participants). Genome-wide association study data (https://www.ebi.ac.uk/gwas/) for 91 circulating inflammatory proteins were obtained from 14,824 participants across 11 cohorts using the Olink Target 96 Inflammation panel. Migraine outcome data were obtained from the FinnGen R12 release, with cases defined using ICD-10 code G43. All genome-wide association study analyses were adjusted for sex, age, genotyping batch, and 10 genetic principal components to control population stratification (genomic inflation factors: 1.00–1.05). Inverse variance-weighted Mendelian randomization was the primary analysis method, with Mendelian randomization-Egger, weighted median, and mode-based methods as sensitivity analyses. Two-step Mendelian randomization mediation analysis quantified the proportion of the effects of human gut microbiota on migraine that are mediated through inflammatory proteins. Thirty-seven bacterial genera were found to be associated with migraine using the inverse variance-weighted method. Of these, 18 genera exhibited a negative association, while 19 genera demonstrated a positive association with migraine risk. Additionally, eight inflammatory proteins were found to increase the risk of migraine. Among human gut microbiota, four were observed to reduce inflammatory protein levels, whereas another four were associated with increased inflammatory protein levels. Additionally, five gut microbiota were identified to influence migraine through inflammatory proteins in both Mendelian randomization analyses. Specifically, Actinobacteria, Brachyspiraceae, CAG-269 sp001915995, and Paraglaciecola were found to affect migraine outcomes via inflammatory proteins, with mediation proportions of 12%, 19%, 15.5%, and 6.7%, respectively. Lawsonibacter sp002161175 was identified to influence migraine risk through Oncostatin-M and SLAM, with mediation proportions of 15.6% and 11.3%, respectively. Our study elucidated the role of specific human gut microbiota alterations in the pathogenesis of migraine and highlighted the mediating effects of inflammatory proteins. Targeting these particular human gut microbiota alterations offers a promising strategy for predictive, preventive, and personalized medicine in migraine management, resulting in substantial clinical advancements.

causality↗

Cloning and identification of novel cellulase genes from uncultured microorganisms in rabbit cecum and characterization of the expressed cellulases.

A metagenomic cosmid library was prepared in Escherichia coli from DNA extracted from the contents of rabbit cecum and screened for cellulase activities. Eleven independent clones expressing cellulase activities (four endo-beta-1,4-glucanases and seven beta-glucosidases) were isolated. Subcloning and sequencing analysis of these clones identified 11 cellulase genes; the encoded products of which shared less than 50% identities and 70% similarities to cellulases in the databases. All four endo-beta-1,4-glucanases and all seven beta-glucosidases, respectively, belonged to glycosyl hydrolase family 5 (GHF 5) and family 3 (GHF 3) and formed two separate branches in the phylogenetic tree. Ten of the 11 cloned cellulases exhibited highest activities at pH 5.5 approximately 7.0 and 40 approximately 55 degrees C, a condition similar to that in the rabbit cecum. All the four endo-beta-1,4-glucanases could hydrolyze a wide range of beta-1,4-, beta-1,4/beta-1,3- or beta-1,3/beta-1,6-linked polysaccharides. One endo-beta-1, 4-glucanase gene, umcel5G, was overexpressed in E. coli, and the purified recombinant enzyme was characterized in detail. The enzymes cloned in this work represented at least some of the cellulases operating efficiently in the rabbit cecum. This work provides the first snapshot on the cellulases produced by bacteria in rabbit cecum.

Animals↗

Epidemiology, clinical and laboratory characteristics of currently alive HIV-1 infected former blood donors naive to antiretroviral therapy in Anhui Province, China.

BACKGROUND: Unregulated commercial blood/plasma collection among farmers occurred between 1992 and 1995 in central China and caused the second major epidemic of human immunodeficiency virus type 1 (HIV-1) infection in China. It is important to characterize HIV-1-infected former blood donors and to study characteristics associated with disease progression for future clinical intervention and vaccine development. METHODS: A cross-sectional study was performed on HIV-1-infected former blood donors (FBDs) and age-matched HIV-seronegative local residents. Demographic, epidemiologic, clinical and key laboratory data were collected from all study participants. Both unadjusted and adjusted multivariate linear regressions were employed to analyze the association of the decrease of CD4(+) T-cell counts with other characteristics. RESULTS: Two hundred and ninety-four HIV-1-infected FBDs and 59 age-matched HIV-seronegative local residents were enrolled in this study. The unregulated blood/plasma collection occurred more than a decade (10.8 - 12.8 years) ago, which caused the rapid spread of HIV-1 infection and the high prevalence of co-infection with hepatitis C virus (HCV, 89.5%); hepatitis B virus (HBV) co-infection was observed in only 11 HIV(+)participants (3.7%). Deterioration in both clinical manifestation and laboratory parameters and increase of viral loads were observed in parallel with the decrease of CD4(+) T-cell counts. The decrease of total lymphocyte counts (P < 0.001) and hemoglobin levels (P < 0.001) and the appearance of dermatosis (P = 0.03) were observed in parallel with the decrease of CD4(+) T-cell counts whereas viral loads (P < 0.001) and CD8(+) T-cell counts (P = 0.01) were inversely associated with CD4(+) T-cell counts. CONCLUSIONS: Co-infection with HCV but not HBV is highly prevalent among HIV-1-infected FBDs. CD4(+) T-cell counts is a reliable indicator for disease progression among FBDs. Total lymphocyte counts, hemoglobin level and appearance of dermatosis were positively associated with CD8(+) T-cell counts and viral loads were inversely associated with the decreased CD4(+) T-cell counts.

Adult↗

Knowledge discovery in traditional Chinese medicine: state of the art and perspectives.

OBJECTIVE: As a complementary medical system to Western medicine, traditional Chinese medicine (TCM) provides a unique theoretical and practical approach to the treatment of diseases over thousands of years. Confronted with the increasing popularity of TCM and the huge volume of TCM data, historically accumulated and recently obtained, there is an urgent need to explore these resources effectively by the techniques of knowledge discovery in database (KDD). This paper aims at providing an overview of recent KDD studies in TCM field. METHODS: A literature search was conducted in both English and Chinese publications, and major studies of knowledge discovery in TCM (KDTCM) reported in these materials were identified. Based on an introduction to the state of the art of TCM data resources, a review of four subfields of KDTCM research was presented, including KDD for the research of Chinese medical formula, KDD for the research of Chinese herbal medicine, KDD for TCM syndrome research, and KDD for TCM clinical diagnosis. Furthermore, the current state and main problems in each subfield were summarized based on a discussion of existing studies, and future directions for each subfield were also proposed accordingly. RESULTS: A series of KDD methods are used in existing KDTCM researches, ranging from conventional frequent itemset mining to state of the art latent structure model. Considerable interesting discoveries are obtained by these methods, such as novel TCM paired drugs discovered by frequent itemset analysis, functional community of related genes discovered under syndrome perspective by text mining, the high proportion of toxic plants in the botanical family Ranunculaceae disclosed by statistical analysis, the association between M-cholinoceptor blocking drug and Solanaceae revealed by association rule mining, etc. It is particularly inspiring to see some studies connecting TCM with biomedicine, which provide a novel top-down view for functional genomics research. However, further developments of KDD methods are still expected to better adapt to the features of TCM. CONCLUSIONS: Existing studies demonstrate that KDTCM is effective in obtaining medical discoveries. However, much more work needs to be done in order to discover real diamonds from TCM domain. The usage and development of KDTCM in the future will substantially contribute to the TCM community, as well as modern life science.

Databases, Factual↗

Biodegradable cystamine spacer facilitates the clearance of Gd(III) chelates in poly(glutamic acid) Gd-DO3A conjugates for contrast-enhanced MR imaging.

Poly(L-glutamic acid) (PGA)-cystamine-[gadolinium (Gd)-DO3A] was prepared in high yield with a high Gd-DO3A conjugation efficiency. Approximately 55% of the carboxylic groups in PGA were loaded with Gd-DO3A via cystamine as the spacer. Cystamine can be readily cleaved by endogenous thiols to release the Gd(III) chelates from the conjugate facilitating Gd(III) excretion after the magnetic resonance imaging (MRI). The contrast-enhanced MRI with PGA-cystamine-(Gd-DO3A) was investigated in mice bearing MDA-MB-231 breast carcinoma xenografts. PGA-1,6-hexanediamine-(Gd-DO3A), a paramagnetic polymer conjugate of a nondegradable spacer, was used as a control. Both conjugates resulted in similar contrast enhancement in the heart, vasculature, liver and kidneys in the first hour post injection. More substantial signal intensity reduction was observed for PGA-cystamine-(Gd-DO3A) in these organs than PGA-1,6-hexanediamine-(Gd-DO3A) due to release of the Gd chelates from PGA-cystamine-(Gd-DO3A) after the cleavage of the disulfide spacer by the endogenous thiols. Both conjugates resulted in similar tumor enhancement with approximately 70% increased signal intensity in the tumor periphery and 10-40% increased signal intensity in tumor interstitium. No cross-reaction was observed between PGA-cystamine-(Gd-DO3A) and human serum albumin, a plasma protein containing a cysteine residue. PGA-cystamine-(Gd-DO3A) resulted in significantly lower Gd(III) tissue retention than PGA-1,6-hexanediamine-(Gd-DO3A) 10 days after the injection in the mice (P<.05). The conjugation of Gd(III) chelates to biomedical copolymers via the degradable disulfide spacer resulted in significant contrast enhancement in the blood pool and tumor tissue but minimal long-term Gd(III) tissue retention.

Absorbable Implants↗

Release-controlling absorption enhancement of enterally administered Ophiopogon japonicus polysaccharide by sodium caprate in rats.

The aim of this study was to improve the intestinal absorption of Ophiopogon japonicus polysaccharide (OJP) by incorporating it together with sodium caprate (SC) into erodible matrices, designed to release OJP and SC at various rates over different periods of time. OJP, a graminan type fructosan with an average molecular weight in number of 3400 Da has been demonstrated to have anti-myocardial ischemic activity. The determination of OJP blood levels was carried out by the fluorescein isothiocyanate (FITC) prelabeling method. Matrix tablets, possessing different erosion rates, were prepared by changing the amounts of sodium alginate and using the two-layer tableting technique. Formulation effectiveness was evaluated by monitoring OJP plasma levels after intra-intestinal administration of each of the tablets to anesthetized rats. The findings indicate that all the SC containing formulations can significantly improve FITC-OJP bioavailability. Compared with the formulations not containing SC, the increase varied from 5.6- to 20.8-fold for the worst and best SC containing formulations studied, respectively. Moreover, there were no statistically significant differences between the C(max) and AUC(0-4) values obtained for three optimized formulations, which synchronously or nonsynchronously released both FITC-OJP and SC within 1-2 h. Their absorption enhancement effects were 2.1- to 3.6-fold higher than those of faster and slower release formulations studied. Fast delivery of the drug and its absorption adjuvant(s) contributes to their high concentrations at the absorption sites. However, at the same time, it leads to their short residence times and fast dilution by intestinal fluids. The better the balance between the two opposite effects for drug absorption, the more effective absorption enhancement would be obtained.

Animals↗

Pharmacokinetics, biodistribution and contrast enhanced MR blood pool imaging of Gd-DTPA cystine copolymers and Gd-DTPA cystine diethyl ester copolymers in a rat model.

PURPOSE: To investigate plasma pharmacokinetics and biodistribution of biodegradable polydisulfide Gd(III) complexes, Gd-DTPA cystine copolymers (GDCP) and Gd-DTPA cystine diethyl ester copolymers (GDCEP) and their efficacy as blood pool MRI contrast agents in comparison with a nondegradable macromolecular agent, Gd-DTPA 1,6-hexanediamine copolymers (GDHC). METHODS: The pharmacokinetics and biodistribution of GDCP and GDCEP with molecular weight of 35 KDa were investigated in Sprague-Dawley rats after intravenous administration at a dose of 0.1 mmol Gd/kg. GDHC with the same molecular weight was used as a control. The Gd content in the plasma and various tissues and organs were determined by the ICP-OES. Plasma pharmacokinetic parameters were calculated by using a two-compartment model. The contrast enhanced blood pool MR imaging of the agents was evaluated in Sprague-Dawley rats on a Siemens Trio 3T MR scanner. RESULTS: The biodegradable macromolecular agents, GDCP and GDCEP, had faster blood pool clearance than the nondegradable GDHC. The long-term Gd(III) tissue retention of the biodegradable polydisulfide agents was substantially lower than the nondegradable macromolecular agent. Both GDCP and GDCEP resulted in significant blood pool enhancement for the first 2 min post-injection and more rapid disappearance of the enhancement over time than GDHC. The negatively charged GDCP had prolonged enhancement duration as compared to GDCEP. The structure and biodegradability of the macromolecular contrast agents significantly affected their pharmacokinetics and blood pool contrast enhancement. CONCLUSION: Both GDCP and GDCEP provided effective contrast enhancement for MR imaging of the blood pool. The accumulation of toxic Gd(III) ions in the body was greatly reduced with GDCP and GDCEP as compared to the nondegradable control.

Animals↗

Altered RNA editing in mice lacking ADAR2 autoregulation.

ADAR2 is a double-stranded-RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-selective conversion of adenosine to inosine. Previous studies from our laboratory have demonstrated that ADAR2 can modify its own pre-mRNA to create a proximal 3' splice site containing a noncanonical adenosine-inosine dinucleotide. Alternative splicing to this proximal acceptor adds 47 nucleotides to the mature ADAR2 transcript, thereby resulting in the loss of functional ADAR2 protein expression due to premature translation termination in an alternate reading frame. To examine whether the editing of ADAR2 transcripts represents a negative autoregulatory strategy to modulate ADAR2 protein expression, we have generated genetically modified mice in which the ability of ADAR2 to edit its own pre-mRNA has been selectively ablated by deletion of a critical sequence (editing site complementary sequence [ECS]) required for adenosine-to-inosine conversion. Here we demonstrate that ADAR2 autoediting and subsequent alternative splicing are abolished in homozygous deltaECS mice and that ADAR2 protein expression is increased in numerous tissues compared to wild-type animals. The observed increases in ADAR2 protein expression correlate with the extent of ADAR2 autoediting observed with wild-type tissues and correspond to increases in the editing of ADAR2 substrates, indicating that ADAR2 autoediting is a key regulator of ADAR2 protein expression and activity in vivo.

Adenosine Deaminase↗

[Study on index for formulation optimization of sustained or controlled released dosage forms].

Release in vitro is one of the indexes for quality control of solid dosage forms. It is not only the important indexes for evaluation of bioequivalence, also the important parameter of formulation optimization, study of the stability and quality control within producing of sustained or controlled release dosage forms. The review is the study on index for formulation optimization of sustained or controlled released dosege forms in China since 1999, including the application of similarity factor and deviation.

Chemistry, Pharmaceutical↗

Human plasma DNP level after severe brain injury.

OBJECTIVE: To determine the relationship between DNP level after human severe brain injury and hyponatremia as well as isorrhea. METHODS: The peripheral venous plasma as control was collected from 8 volunteers. The peripheral venous plasma from 14 severe brain injury patients were collected in the 1, 3, 7 days after injury. Radioimmunoassay was used to detect the DNP concentration. Meanwhile, daily plasma and urine electrolytes, osmotic pressure as well as 24 h liquid intake and output volume were detected. RESULTS: The normal adult human plasma DNP level was 62.46 pg/ml+/-27.56 pg/ml. In the experimental group, the plasma DNP levels were higher from day 1 to day 3 in 8 of the 14 patients than those in the control group (P(1)=0.05, P(3)=0.03). Negative fluid balance occurred in 8 patients and hyponatremia in 7 patients. The increase of plasma DNP level was significantly correlated with the development of a negative fluid balance (r =-0.69, P<0.01) and hyponatremia (chi(2) =4.38, P<0.05). CONCLUSIONS: The increase of plasma DNP level is accompanied by the enhancement of natriuretic and diuretic responses in severe brain-injured patients, which is associated with the development of a negative fluid balance and hyponatremia after brain injury.

Adult↗

Functional expression of the cotton gibberellic acid oxidase homologous gene GhGA20ox1 in tobacco.

To determine the physiological function of GhGA20ox1, a homologous gene of GA 20-oxidase from elongating cotton fibers, we expressed this gene ectopically in Nicotiana benthamiana. Reverse transcription-PCR analysis showed that the GhGA20ox1 gene was expressed in the transgenic plants at various levels. It was demonstrated that overexpression of GhGA20ox1 enhanced preferentially the GA(4+7) biosynthesis in N. benthamiana and conferred GA-overproduction characters to transformants. The extent of phenotypic alteration in the transgenic plants was found to correlate with the transcriptional levels of GhGA20ox1 and GA contents. Results indicated that the GhGA20ox1 gene promoted the biosynthesis of the active GAs (GA(4+7)) in transgenic tobacco plants therefore represents a useful gene for manipulating GA levels.

Gene Expression Regulation, Enzymologic↗

[Determination of ginsenoside rd in human plasma by LC/MS/MS].

OBJECTIVE: To develop a HPLC/MS/MS method for the determination of ginsenoside Rd in human plasma. METHODS: Plasma samples were pretreated by solid phase extraction (SPE). Ginsenoside Rd (m/z 964.6-->m/z 767.5) and gentiopicrin (m/z 374.1-->195.1) was detected by the positive electrospray ionization (ES+I)-MS method under multiple reaction monitoring (MRM) mode. RESULTS: The calibration curve of ginsenoside Rd in plasma was linear over the range of 3.00-5000.00 ng/ml. The limit of quantitation was 3.00 ng/ml. The relative recovery was 81.01-83.39%. The within-day and between-day RSDs were less than 15%. CONCLUSION This method is accurate, sensitive, and specific. It is suitable for the measurement of plasma ginsenoside Rd concentration.

Area Under Curve↗

[Studies on market of drug delivery system product and drug delivery system of compound Chinese medicine].

Based on the progress in the world market of drug delivery system (DDS) product and the research profile of DDS of compound Chinese Medicine, The article puts forward a new method of studies on DDS of compound Chinese Medicine. It is expected that the theory of compatibility of compound Chinese Medicine can be shown and its role can be exerted to the largest extent with the application of pharmaceutics technology to change the mode of drug delivery of activated components of compound Chinese Medicine.

Drug Combinations↗

Determination of Ophiopogon japonicus polysaccharide in plasma by HPLC with modified postcolumn fluorescence derivatization.

Interest in antimyocardial ischemic activity of a graminan-type fructosan with an average molecular weight of 5,000 Da from Ophiopogon japonicus (FOJ-5) has necessitated the development of a sensitive and specific method to study its pharmacokinetics. An HPLC method with modified postcolumn fluorescence derivatization to determine FOJ-5 in plasma was developed in this study. The Shodex Sugar KS-802 high-performance gel column was chosen for separating FOJ-5 from its degradation products and endogenous carbohydrates. The postcolumn procedure involved acid hydrolysis of the column eluate at 150 degrees C, which decreased the detection limit for FOJ-5 from 1 microg to 25 ng, followed by fluorometric reaction with guanidine in an alkaline medium at 90 degrees C. The clearance of FOJ-5 from the bodies of rats following intravenous injection displayed a complex type of kinetics involving at least two compartments, and the half-life of the elimination of FOJ-5 from plasma administered at 15 mg/kg (18.1 min) was quicker than that administered at 50mg/kg (28.9 min). This modified approach can also be used for microanalysis of both nonreducing oligosaccharides and other neutral polysaccharides.

Animals↗

Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors.

Delivery of small interfering RNAs (siRNAs) into cells is a key obstacle to their therapeutic application. We designed a protamine-antibody fusion protein to deliver siRNA to HIV-infected or envelope-transfected cells. The fusion protein (F105-P) was designed with the protamine coding sequence linked to the C terminus of the heavy chain Fab fragment of an HIV-1 envelope antibody. siRNAs bound to F105-P induced silencing only in cells expressing HIV-1 envelope. Additionally, siRNAs targeted against the HIV-1 capsid gene gag, inhibited HIV replication in hard-to-transfect, HIV-infected primary T cells. Intratumoral or intravenous injection of F105-P-complexed siRNAs into mice targeted HIV envelope-expressing B16 melanoma cells, but not normal tissue or envelope-negative B16 cells; injection of F105-P with siRNAs targeting c-myc, MDM2 and VEGF inhibited envelope-expressing subcutaneous B16 tumors. Furthermore, an ErbB2 single-chain antibody fused with protamine delivered siRNAs specifically into ErbB2-expressing cancer cells. This study demonstrates the potential for systemic, cell-type specific, antibody-mediated siRNA delivery.

Animals↗

Circulating estradiol and hypothalamic corticotrophin releasing hormone enhances along with time after ovariectomy in rats: effects of electroacupuncture.

Repeated electroacupuncture (EA) stimulation is known to enhance the circulating level of estrogen in the ovariectomized rats by stimulating the activity of the hypothalamus-pituitary-adrenal axis. To explore the mechanism of EA in promoting the homeostasis in ovariectomized rats, the hypothalamic CRH content and its mRNA expression as well as the circulating estradiol in the rats along with time after ovariectomy were detected. Female rats were divided into fourteen groups: 1 month after ovariectomy (OVX1M), OVX2M, OVX3M, OVX4M, OVX5M, OVX6M; intact 1 month (INT1M), INT2M, INT3M, INT4M, INT5M, INT6M; OVX1M with EA (OVX1M+EA) and intact 1 month with EA (INT1M+EA). The blood concentrations of estradiol (E2) and total contents of hypothalamic CRH were measured by radioimmunoassay. The expressions of CRHmRNA were semiquantified by RT-PCR. The results showed that the blood E(2) concentrations increased gradually along with time after ovariectomy in the rats. The level was higher in OVX1M+EA than those in OVX1M, 2M, 3M (p < 0.05), which was near to the level in OVX6M. The total content (ng/g tissue) of hypothalamic CRH and the CRHmRNA expressions in the OVX6M rats were higher than other groups (p < 0.05). The CRH content or mRNA expression in the OVX1M+EA increased significantly compared with that in OVX1M (p < 0.05), and it was close to the level in the OVX4M and OVX5M. The results suggested that the circulating E2 and hypothalamic CRH enhances along with time after ovariectomy in rats, and the EA stimulation might speedup the process.

Animals↗