Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.

A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer's disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-ß and tau pathologies, and improved the animals' memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational-experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.

Effects of high serum uric acid levels on oxidative stress levels and semen parameters in male infertile patients.

ABSTRACT: This study is to investigate the effect of high serum uric acid (UA) level on oxidative stress and semen quality of male infertility patients.A cohort of 654 male individuals aged between 20 and 45 years old were included in this study, and their semen and venous blood samples were collected. The serum UA, blood glucose, blood lipids, and hormone levels were determined by chemiluminescence method. The changes in inflammatory factors, oxidative stress, adipokines, and biochemical indices in seminal plasma were determined by ELISA. Organic acids in seminal plasma were detected with reversed-phase ultra high performance liquid chromatography.Compared with the control group, the amount of semen and the total number of sperm in the hyperuricemia group significantly reduced (P < .05). Semen volume decreased with the increase of serum UA level, and the total number of sperm also decreased. The level of luteinizing hormone increased and the level of testosterone decreased in the hyperuricemia group. The concentration of superoxide dismutase decreased and the concentration of endothelin increased in the hyperuricemia group (P < .05). The concentration of seminal plasma α-glucosidase and alkaline phosphatase in the hyperuricemia group decreased significantly (P < .05). Compared with the control group, the contents of ascorbic acid, tartaric acid, lactic acid, and UA in the seminal plasma were significantly reduced in the hyperuricemia group (P < .05).Blood UA level may become a new risk predictor of semen quality in infertile men.

[Establishment of a method for detection of thiols in seminal plasma and its application in patients with hyperuricemia].

OBJECTIVE: To establish a method of reversed-phase ultra-performance liquid chromatography with fluorescence (UPLC-FL) detection for simultaneous determination of homocysteine (Hcy), cysteine (Cys), cysteine glycine (CysGly) and glutathione (GSH) and analysis of the contents of the four thiols in the seminal plasma of normal men and patients with hyperuricemia (HUA). METHODS: Seminal plasma samples were collected from 30 normal sperm donors and 30 HUA patients and reduced with tris (2-carboxyethyl) phosphine hydrochloride. Then, the samples were subjected to protein precipitation with trichloroacetic acid solution, derivative reaction with 7-fluorobenzofuran-4-sulfate and isolation with a C18 column, with 0.025 mol/L KH2PO4 (pH 3.0) for mobile phase A and pure methanol for B, followed by equal gradient elution with an excitation wavelength of 380 nm and an emission wavelength of 510 nm. RESULTS: The correlation coefficients (R2) of the four thiols all exceeded 0.999, with an average recovery rate of 94.23－107.87%. Compared with the normal sperm donors, the HUA patients showed significantly increased contents of Cys (ï¼»108.01 ± 48.03ï¼½ vs ï¼»250.10 ± 55.87ï¼½ µmol/L, P < 0.05), Hcy (ï¼»113.97 ± 6.32ï¼½ vs ï¼»48.35 ± 15.07ï¼½ µmol/L, P < 0.05), and GSH (ï¼»3.15 ± 1.48ï¼½ vs ï¼»4.63 ± 1.17ï¼½ µmol/L, P < 0.05), but a decreased level of CysGly (ï¼»12.79 ± 3.18ï¼½ vs ï¼»5.94 ± 0.99ï¼½ µmol/L, P < 0.05). CONCLUSIONS: The method of reversed-phase UPLC-FL detection established in this study has made it possible simultaneous detection of Hcy, Cys, CysGly and GSH in the seminal plasma, which is applicable to laboratory research and clinical routine examination. Patients with hyperuricemia may incur oxidative damage to the reproductive system.

[Ultra-performance liquid chromatography for determination of the contents of biogenic amines in the seminal plasma].

OBJECTIVE: To establish an ultra-performance liquid chromatography (UPLC) method for determination of the contents of the three biogenic amines putacine, spermidine and spermine in human seminal plasma. METHODS: Seminal plasma samples were extracted with 5% trichloroacetic acid and processed by pre-column derivatization with dansyl chloride. Chromatographic separation was performed with a C18 (2.1×50 mm,1.7 µm) chromatographic column using water and acetonitrile for mobile-phase gradient elution at a flow rate of 0.3 ml/min, a detection wavelength of 245 nm, a column temperature of 35℃ and an injection volume was 3.0 µl. The contents of putacine, spermidine and spermine in the seminal plasma of 52 healthy sperm donors (the normal group) and 23 azoospermia patients (the AS group) were measured, and their correlation with routine semen parameters were analyzed. RESULTS: The three biogenic amines showed a good linearity (r ≥ 0.999), with a lower detection limit of 0.03－0.08 µg/ml. The relative standard deviation (RSD) of precision was ≤ 0.72% and the average recovery rate was 79.74%－108.87%. The normal group, compared with the AS patients, showed significantly higher contents of putrescine (ï¼»8.19 ± 7.85ï¼½ vs ï¼»2.43 ± 1.38ï¼½ mg/ml, P < 0.05), spermidine (ï¼»77.30 ± 32.58ï¼½ vs ï¼»31.99 ± 16.21ï¼½ mg/ml, P < 0.05) and spermine (ï¼»246.44 ± 83.99ï¼½ vs ï¼»166.15 ± 79.28ï¼½ mg/ml, P < 0.05). However, the contents of the three biogenic amines in the seminal plasma exhibited no significant correlation with the routine semen parameters in the normal group. CONCLUSIONS: The ultra-performance liquid chromatography method we established, with the advantages of high sensitivity and reproducibility and short peak-time, can quickly and accurately determine the contents of biogenic amines in the seminal plasma.

[Correlation of seminal plasma biochemical indexes with routine semen parameters in sperm donors].

OBJECTIVE: To investigate the relationship of seminal plasma biochemical indexes with routine semen parameters and that between seminal plasma biochemical indexes. METHODS: Using the automatic biochemical analyzer, we measured the contents of neutral α-glucosidase (NAG), fructose hexokinase (Fru) , citric acid (CA), acid phosphatase (ACP), (zinc) Zn, uric acid (UA), lactase dehydrogenase (LDH) and α-hydroxybutyrate dehydrogenase (α-HBDH) in the seminal plasma of 84 sperm donors in the Human Sperm Bank of Hebei Province. We analyzed the correlation between these indexes and that between routine semen parameters and these indexes. RESULTS: Sperm concentration and total sperm count were correlated positively with the contents of seminal plasma NAG, ACP, Zn, CA, LDH and α-HBDH (P<0.05) but negatively with Fru (P<0.05), the percentage of progressively motile sperm positively with seminal plasma Zn (P<0.05), and CA positively with NAG, Zn, LDH, α-HBDH and ACP (P<0.01) but negatively with Fru (P<0.01), NAG positively with Zn, LDH, α-HBDH and ACP (P<0.05) but Fru negatively with ACP (P<0.01), Zn positively with LDH, α-HBDH and ACP (P<0.01), and LDH positively with α-HBDH and ACP (P<0.01) but UA negatively with ACP (P<0.05). CONCLUSIONS: Biochemical indexes in the seminal plasma of healthy men are not only closely related to each other, but also to some routine semen parameters.

NAD+ in Alzheimer's Disease: Molecular Mechanisms and Systematic Therapeutic Evidence Obtained in vivo.

Mitochondria in neurons generate adenosine triphosphate (ATP) to provide the necessary energy required for constant activity. Nicotinamide adenine dinucleotide (NAD+) is a vital intermediate metabolite involved in cellular bioenergetics, ATP production, mitochondrial homeostasis, and adaptive stress responses. Exploration of the biological functions of NAD+ has been gaining momentum, providing many crucial insights into the pathophysiology of age-associated functional decline and diseases, such as Alzheimer's disease (AD). Here, we systematically review the key roles of NAD+ precursors and related metabolites in AD models and show how NAD+ affects the pathological hallmarks of AD and the potential mechanisms of action. Advances in understanding the molecular roles of NAD+-based neuronal resilience will result in novel approaches for the treatment of AD and set the stage for determining whether the results of exciting preclinical trials can be translated into the clinic to improve AD patients' phenotypes.

Defective Autophagy and Mitophagy in Alzheimer's Disease: Mechanisms and Translational Implications.

The main histopathology of Alzheimer's disease (AD) is featured by the extracellular accumulation of amyloid-ß (Aß) plaques and intracellular tau neurofibrillary tangles (NFT) in the brain, which is likely to result from co-pathogenic interactions among multiple factors, e.g., aging or genes. The link between defective autophagy/mitophagy and AD pathologies is still under investigation and not fully established. In this review, we consider how AD is associated with impaired autophagy and mitophagy, and how these impact pathological hallmarks as well as the potential mechanisms. This complicated interplay between autophagy or mitophagy and histopathology in AD suggests that targeting autophagy or mitophagy probably is a promising anti-AD drug candidate. Finally, we review the implications of some new insights for induction of autophagy or mitophagy as the new therapeutic way that targets processes upstream of both NFT and Aß plaques, and hence stops the neurodegenerative course in AD.

Differentially expressed microRNA in testicular tissues of hyperuricaemia rats.

This study is to identify the differentially expressed miRNAs in testicular tissues of rats with hyperuricaemia-induced male infertility. We found that the hyperuricaemia model group had significantly increased serum uric acid, while significantly decreased sperm concentration and motile sperm percentage than normal group (p < .05). A total of 39 differentially expressed miRNAs were identified in the testicular tissues of hyperuricaemia rats compared with the control rats, ten of which were validated by real-time PCR. The target mRNAs of 7 differentially expressed miRNAs (miR-10b-5p, miR-26a-5p, miR-136-5p, miR-151-3p, miR-183-5p, miR-362-3p and miR-509-5p) from 3'-untranslated region binding perspective were enriched in signalling pathways of Wnt, Jak-STAT, mTOR and MAPK. The target mRNAs of 6 differentially expressed miRNAs (miR-136-5p, miR-144-3p, miR-99a-5p, miR-509-5p, miR-451-5p and miR-362-3p) from coding sequence binding perspective were enriched in signalling pathways of Calcium, Notch and MAPK. The functions of miRNAs in testicular tissues of rats with hyperuricaemia were revealed by the differentially expressed miRNAs (miR-183-5p, miR-99a-5p, miR-10b-5p, miR-151-3p, miR-26a-5p, miR-451-5p, miR-362-3p, miR-136-5p, miR-144-3p and miR-509-5p)-mRNAs interaction network. The differentially expressed miRNAs in the testicular tissues of hyperuricaemia rats might shed light on the mechanism of hyperuricaemia-induced male infertility.

Delineating the Role of Mitophagy Inducers for Alzheimer Disease Patients.

Alzheimer's disease (AD) is the most common cause of dementia in elderly that serves to be a formidable socio-economic and healthcare challenge in the 21st century. Mitochondrial dysfunction and impairment of mitochondrial-specific autophagy, namely mitophagy, have emerged as important components of the cellular processes contributing to the development of AD pathologies, namely amyloid-ß plaques (Aß) and neurofibrillary tangles (NFT). Here, we highlight the recent advances in the association between impaired mitophagy and AD, as well as delineate the potential underlying mechanisms. Furthermore, we conduct a systematic review the current status of mitophagy modulators and analyzed their relevant mechanisms, evaluating on their advantages, limitations and current applications in clinical trials for AD patients. Finally, we describe how deep learning may be a promising method to rapid and efficient discovery of mitophagy inducers as well as general guidance for the workflow of the process.

Administration of quercetin improves mitochondria quality control and protects the neurons in 6-OHDA-lesioned Parkinson's disease models.

Mounting evidence suggests that mitochondrial dysfunction and impaired mitophagy lead to Parkinson's disease (PD). Quercetin, one of the most abundant polyphenolic flavonoids, displays many health-promoting biological effects in many diseases. We explored the neuroprotective effect of quercetin in vivo in the 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD and in vitro in 6-OHDA-treated PC12 cells. In vitro, we found that quercetin (20 µM) treatment improved mitochondrial quality control, reduced oxidative stress, increased the levels of the mitophagy markers PINK1 and Parkin and decreased α-synuclein protein expression in 6-OHDA-treated PC12 cells. Moreover, our in vivo findings demonstrated that administration of quercetin also relieved 6-OHDA-induced progressive PD-like motor behaviors, mitigated neuronal death and reduced mitochondrial damage and α-synuclein accumulation in PD rats. Furthermore, the neuroprotective effect of quercetin was suppressed by knockdown of either Pink1 or Parkin.

The Mechanism of Zinc Sulfate in Improving Fertility in Obese Rats Analyzed by Sperm Proteomic Analysis.

This study investigates the mechanism underlying the improving effect of zinc on fertility in obese rats using proteomics. The effects of three different doses of ZnSO4 on spermatogenesis and hormone levels were studied. Testicular spermatogenesis was observed by HE staining. Serum estrogen and testosterone levels were measured by chemiluminescent microparticle immunoassay. Sperm proteomic analysis was performed by liquid chromatography-mass spectrometry. The DAVID database was used to perform the GO enrichment analysis and KEGG pathway analysis of the differentially expressed genes, and the STRING online database was used to construct a PPI network. The sperm count, sperm motility, and testosterone hormones of the ZnSO4-treated rats group were increased. ZnSO4 improved testicular structure and spermatogenesis abnormalities caused by obesity. Proteomic analysis showed that there were 401 differentially expressed proteins in a total of 6 sperm samples from the ZnSO4-treated group and the obesity groups. Differential proteins were input into the DAVID website. The 341 identified proteins were then classified according to their biological functions. The KEGG analysis showed that the enriched signal pathways included glycolysis/gluconeogenesis, carbon metabolism, citrate cycle, fatty acid metabolism, and pyruvate metabolism. Some proteins were shown to be associated with valine, leucine, and isoleucine degradation pathways. STRING analysis obtained 36 node proteins. Cytoscape analysis showed that these proteins mainly participated in nine networks including metabolic process, oxidation-reduction, aerobic respiration, RNA splicing, and glutathione conjugation. ZnSO4 may improve the fertility of obese male rats by regulating protein expression related to metabolism, inflammation, and sperm maturation.

[Correlation of insulin resistance with male reproductive hormone levels and semen parameters].

OBJECTIVE: To investigate the influence of insulin resistance on male reproductive hormones and semen quality. METHODS: Using the electrochemiluminescence method, we measured the levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), estradiol (E2) and testosterone (T) in the serum of 83 infertile males. We detected the levels of fasting plasma glucose (FPG) and fasting insulin (FINS) and calculated the insulin resistance index presented as homeostasis model assessment of insulin resistance (HOMA-IR). Based on HOMA-IR, we divided the patients into three tertile groups, T1 (HOMA-IR 0.36－0.55, n = 27), T2 (HOMA-IR 0.56－0.80, n = 28) and T3 (HOMA-IR 0.81－1.97, n = 28), obtained their semen parameters by computer-assisted semen analysis (CASA) and analyzed the correlation of HOMA-IR with male reproductive hormone levels and semen parameters. RESULTS: With the elevation of HOMA-IR, the patients of the T1, T2 and T3 groups showed significant decreases in the serum T level (ï¼»14,26 ± 4.27ï¼½ vs ï¼»14.75 ± 5.00ï¼½ vs ï¼»11.62 ± 3.68ï¼½ nmol/L, P <0.05) and the percentage of progressively motile sperm (PMS) (ï¼»51.04 ± 15.10ï¼½% vs ï¼»48.04 ± 16.24ï¼½% vs ï¼»37.84 ± 18.23ï¼½%, P <0.05). HOMA-IR was correlated negatively with the serum T level (r = －0.333, P = 0.002), semen volume (r = －0.23, P = 0.029) and PMS (r = －0.27, P = 0.015), and so was FINS with the serum T level (r = －0.327, P = 0.003) and PMS (r = －0.315, P = 0.004), while the semen volume was correlated positively with the levels of serum T (r = 0.221, P = 0.048) and FSH (r = 0.222, P = 0.047). Multivariate linear regression analysis showed that HOMA-IR was an independent influencing factor for PMS and the body mass index (BMI) was that for the semen volume and total sperm count. CONCLUSIONS: Insulin resistance may reduce semen quality by changing the levels of male reproductive hormones.

[Correlation of reproductive hormone levels and seminal plasma oxidative stress with semen quality in obese males].

OBJECTIVE: To investigate the correlation of the levels of reproductive hormones and oxidative stress in the seminal plasma with semen parameters in obese males. METHODS: Based on the body mass index (BMI), we divided 138 infertile men into three groups: normal (BMI <24 kg/m2, n = 48), overweight (24 kg/m2≤BMI<28 kg/m2, n = 47), and obesity (BMI ≥28 kg/m2, n = 43). We determined the concentrations of follicle-stimulating hormone (FSH), luteotropic hormone (LH), prolactin (PRL), testosterone (T) and estradiol (E2) in the serum by electrochemiluminescence and measured the levels of superoxide dismutase (SOD), glutathione-S-transferases (GSTs), reactive oxygen species (ROS) and malondialdehyde (MDA) in the seminal plasma by ELISA, compared the above indexes among the three groups, and analyzed their correlation with the semen volume, sperm concentration, total sperm count, and percentage of progressively motile sperm (PMS). RESULTS: The semen volume was significantly lower in the obesity than in the normal group (ï¼»2.63 ± 0.74ï¼½ vs ï¼»3.37 ± 1.00ï¼½ ml, P < 0.05), and so was the percentage of PMS in the overweight and even lower in the obesity than in the normal group (ï¼»47.91 ± 12.89ï¼½ and ï¼»41.27 ± 15.77ï¼½ vs ï¼»54.04 ± 13.29ï¼½%, P < 0.05). Compared with the normal group, both the overweight and obesity groups showed markedly decreased levels of serum T (ï¼»4.83 ± 1.42ï¼½ vs ï¼»3.71 ± 1.22ï¼½ and ï¼»3.49 ± 1.12ï¼½ ng/ml, P<0.05), T/LH ratio (1.53 ± 0.57 vs 1.19 ± 0.54 and 0.97 ± 0.51, P<0.05), SOD (ï¼»112.05 ± 10.54ï¼½ vs ï¼»105.85 ± 6.93ï¼½ and ï¼»99.33 ± 8.39ï¼½ U/ml, P<0.05), and GSTs (ï¼»31.75±6.03ï¼½ vs ï¼»29.54±5.78ï¼½ and ï¼»29.02±4.52ï¼½ U/L, P<0.05), but remarkably increased seminal plasma ROS (ï¼»549.93±82.41ï¼½ vs ï¼»620.61±96.13ï¼½ and ï¼»701.47±110.60ï¼½ IU/ml, P<0.05) and MDA (ï¼»7.46 ± 2.13ï¼½ vs ï¼»8.72 ± 1.89ï¼½ and ï¼»10.47 ± 2.10ï¼½ nmol/L, P<0.05). BMI was correlated positively with ROS and MDA, but negatively with the semen volume, PMS, T, T/LH, SOD and GSTs (P<0.05); LH negatively with sperm concentration, total sperm count and GSTs (P<0.05); PRL negatively GSTs (P<0.05); E2 positively with SOD (P<0.05); T positively with SOD (P<0.05) but negatively with MDA (P<0.05); T/LH positively with PMS and SOD (P<0.05) but negatively with ROS and MDA (P<0.05); SOD positively with semen volume, PMS and GSTs (P<0.05) but negatively with ROS and MDA (P<0.05); GSTs negatively with sperm concentration; total sperm count and MDA (P<0.05); ROS positively with MDA (P<0.01) but negatively with PMS (P<0.05); and MDA negatively with semen volume (P<0.05). Multivariate logistic regression analysis showed that the independent factors influencing the semen volume were BMI and GSTs, those influencing the total sperm count were BMI and T, and those influencing PMS were BMI and MDA. CONCLUSIONS: Increased BMI induces changes in the levels of male reproductive hormones and seminal plasma oxidative stress and affects semen quality, which may be associated with male infertility.

[Correlation of seminal plasma zinc alpha-2 glycoprotein with semen quality in obese males].

OBJECTIVE: To investigate the relationship between seminal plasma zinc alpha-2 glycoprotein (ZAG) and semen quality in obese males. METHODS: This study included 130 obese male patients with idiopathic infertility Based on the concentration of seminal plasma ZAG, we divided the patients into three tertile groups: tertile 1 (T1, 73.45－97.15 µg/ml, n = 43), T2 (97.16－115.46 µg/ml, n = 44), and T3 (115.47－220.11 µg/ml, n = 43). We measured the concentrations of seminal plasma zinc (SPZ) and ZAG of the patients by ELISA, obtained the semen parameters, and analyzed the correlation of semen quality with the levels of SPZ and ZAG and the influence of obesity on SPZ, ZAG and semen quality. RESULTS: The mean level of seminal plasma ZAG in the 130 obese male patients was (111.29 ± 26.50) µg/ml. There were statistically significant differences in sperm concentration and total sperm count among the three tertile groups (P < 0.05). The level of seminal plasma ZAG was correlated negatively with the body mass index (BMI), waist circumference (WC), sperm concentration and sperm count (P < 0.01), that of SPZ positively with BMI and WC (P < 0.05) but negatively with semen volume and the percentage of progressively motile sperm (P < 0.05). The level of serum ZAG, however, exhibited no correlation with SPZ, seminal plasma ZAG or semen quality. Obesity was found to be associated with significantly decreased concentration of seminal plasma ZAG and percentage of progressively motile sperm but remarkably increased level of SPZ (P < 0.05). CONCLUSIONS: Obesity may induce the metabolic disorder of SPZ and ZAG, change the microenvironment of seminal plasma, and consequently affect semen quality.

[Correlation of the levels of seminal plasma homocysteine, folate and cobalamin with semen parameters in obese men].

OBJECTIVE: To investigate the correlation of seminal plasma homocysteine (Hcy) and its metabolic factors folate (FA) and cobalamin (VB12) with semen quality in obese men. METHODS: We randomly selected 83 male patients with idiopathic infertility for this study and, according to the body mass index (BMI), divided them into a normal BMI (n = 28), an overweight (n = 28) and an obesity group (n = 27). We determined the levels of Hcy, FA and VB12 in the seminal plasma by ELISA and analyzed their correlation with the semen parameters of the patients in different groups. RESULTS: Compared with the normal BMI group, the obese males showed significant decreases in the semen volume (ï¼»3.23 ± 0.86ï¼½ vs ï¼»2.58 ± 0.77ï¼½ ml, P < 0.05), total sperm count (ï¼»191.35 ± 103.00ï¼½ vs ï¼»121.55 ± 88.08ï¼½ ×106, P < 0.05), percentage of progressively motile sperm (ï¼»52.88 ± 15.58ï¼½ % vs ï¼»38.97 ± 16.52ï¼½ %, P < 0.05), seminal plasma Hcy (ï¼»7.41 ± 1.29ï¼½ vs ï¼»6.62 ± 0.85ï¼½ µmol/L, P < 0.05), and VB12 (ï¼»282.41 ± 30.38ï¼½ vs ï¼»230.07 ± 37.75ï¼½ pmol/L, P < 0.05). There were no statistically significant differences in the semen parameters between the overweight group and the normal BMI or the obese group (P > 0.05), or in sperm concentration or the FA level among the three groups of patients (P > 0.05). The levels of seminal plasma Hcy and VB12 were correlated positively with the semen volume (r = 0.281 and 0.242, P < 0.05) and total sperm count (r = 0.229 and 0.258, P < 0.05) but negatively with BMI (r = －0.293 and －0.238, P < 0.05). No correlation, however, was found either between sperm concentration and the percentage of progressively motile sperm (P > 0.05) or between the FA level and BMI or semen parameters (P > 0.05). CONCLUSIONS: The levels of seminal plasma Hcy and VB12 are correlated with BMI, semen volume and total sperm count, which suggests that the concentrations of seminal plasma Hcy and VB12 may be associated with the fertility of obese men.

[Hyperuricemia reduces semen parameters in infertile men].

OBJECTIVE: To explore the impact of hyperuricemia (HUA) on semen quality in infertile men. METHODS: Based on the level of fasting serum uric acid (SUA ≥420 µmol/L), 402 infertile men were divided into a normal SUA group (n = 304) and an HUA group (n = 98), and also into four age groups: 20－24, 25－29, 30－34, and 35－44 years old. Semen parameters were obtained from the patients by computer-assisted semen analysis and the levels of SUA determined by chemical colorimetry. RESULTS: The mean semen volume was significantly lower in the HUA than in the normal SUA group (2.40 vs 2.80 ml, P < 0.05), and so was the total sperm count (120.51 vs 187.21 ×106, P < 0.05). The mean semen volume was remarkably lower in the 25－29 and 30－34 years old patients with HUA than in those with normal SUA (2.40 and 2.55 ml vs 2.85 and 2.90 ml, P < 0.05), and so was the total sperm count in the 30－34 years old patients with HUA than in those with normal SUA (109.69 vs 192.91 ×106, P < 0.05). Correlation analysis showed that the level of SUA was negatively correlated with the semen volume (r = －0.193, P < 0.05) and total sperm count of the patients (r = －0.163, P < 0.05). CONCLUSIONS: Hyperuricemia significantly reduces the semen volume and total sperm count of infertile men, and the level of serum uric acid is closely related with semen quality.

[Mutation analysis and treatment of a case with globozoospermia].

OBJECTIVE: To explore genetic mutation and clinical treatment for a patient with globozoospermia. METHODS: Histomorphology of the sperms was studied by Wright-Giemsa staining and transmission electron microscopy. Potential mutation of the DPY19L2 gene was detected by PCR amplification and Sanger sequencing. RESULTS: Wright-Giemsa staining showed that all spermatozoa from the patient were round-headed and lacked the acrosome, with the nuclei of sperm head stained in dark and full. Transmission electron microscopy revealed large round sperm heads, with an even layer of unit membrane surrounding the nuclei and dispersed cytoplasmic vacuoles but no acrosomal structure. The patient has harbored a homozygous deletion of the DPY19L2 gene. With intracytoplasmic sperm injection (ICSI) treatment, fertilization rate of the oocytes has reached 28.6%, which resulted in a successful pregnancy. A healthy male was born. CONCLUSION: The homozygous deletion of DPY19L2 probably underlies the globozoospermia in this case, for which ICSI has provided an effective treatment. However, there is still a risk of low oocyte fertilization rate or fertilization failure. Further studies are required.

Positive regulation of placentation by L-amino acid transporter-1 (lat1) in pregnant mice.

Placenta plays multi-functions in embryo-uterine dialogue through facilitating gas and nutrient exchange, providing an immunological barrier between the fetus and mother and secreting hormones and growth factors to regulate pregnancy. The successful formation and development of placenta requires invasion and differentiation of trophoblast cells, and any defects would result pregnancy related diseases such as intrauterine growth retardation (IUGR), preeclampsia (PE). Lat1 (L-type amino acids transporter 1) is a major Na+ independent transporter of large neutral amino acids, including several essential amino acids. It has been showed that amino acid was fundamental regulator on cell function and energy metabolism in early embryonic development. It has been reported that Lat1 mRNA expressed in zygote, blastocyst during the pre-implantation stages and trophoblast giant cells (TGCs) in post-implantation placenta in mouse. Little is known the role of lat1 on placentation. Our research was to explore the effects of lat1 on the placentation in mouse. The expression of lat1 was detected from day 9 to 18 of pregnancy in placenta. The effects of lat1 on placentation were assessed with inhibitor of leucine transport 2-aminobicyclo-(2, 2, 1)-haptane-2-carboxylic acid (BCH) treatment by uterine horns injection on day 8 (D8) of pregnancy. The protein of lat1 was mainly localized in the cytoplasm of maternal decidual cell, spongiotro-phoblast cell (Sp) and labyrinth (Lab). Inhibition of lat1 transportation activity by uterine horns injection with BCH in vivo results in disorder of placental anatomical structure in mid-late pregnancy. These results suggest that lat1 might play an important role in mouse placentation progress.

[Metabonomics in the diagnosis and treatment of male infertility].

Metabonomics is an emerging branch of science for the study of endogenous small molecule metabolites in organisms, which plays an important role in evaluatingthediagnosis and treatment of male infertility by exploring the metabolites of body fluids, cells and tissues. With its advantages ofmass information, noninvasiveness, and celerity, metabonomics will be widely applied to clinical researches in the future. This review introducesmetabonomics and its analytical techniques and data processing procedures,its latest application in the studies of the etiology, diagnosis and the treatment of male infertility, and the prospect of its future application in the researches of male reproduction.

[Correlation of semen parameters with inflammatory factors in the seminal plasma of obese males].

OBJECTIVE: To investigate the influence of inflammatory factors on semen parameters in the seminal plasma of obese men. METHODS: Based on the body mass index (BMI), 171 males were divided into a normal group (BMI < 24 kg/m2, n = 59), an overweight group (24 ≤ BMI < 28 kg/m2, n = 54), and an obesity group (BMI =≥ 28 kg/m2, n = 58). The routine semen parameters of the subjects were obtained by computer-assisted semen analysis, the levels of TNF-α, IL-6 and VEGF in the seminal plasma were measured by ELISA, and the correlation of BMI with the above indexes was analyzed. RESULTS: Sperm concentration was significantly decreased in the obesity group in comparison with the normal and overweight groups (ï¼»40.19 ± 24.05ï¼½ vs ï¼»66.54 ± 34.81ï¼½ and ï¼»57.73 ± 24.61ï¼½ ×106/ml, P <0.01), and so was the total number of sperm (ï¼»110.22 ± 75.44ï¼½ vs ï¼»200.75 ± 102.66ï¼½ and ï¼»157.46 ± 112.89ï¼½ ×106, P <0.01) and the percentage of progressively motile sperm (PMS) (ï¼»30.80 ± 15.56ï¼½ vs ï¼»50.75 ± 10.17ï¼½ and ï¼»39.71 ± 9.73ï¼½%, P <0.01). The levels of TNF-α and IL-6 in the seminal plasma were markedly elevated in the obesity group as compared with the normal and overweight groups (ï¼»76.90 ± 14.64ï¼½ vs ï¼»64.47 ± 11.92ï¼½ and ï¼»69.74 ± 12.32ï¼½ pg/ml, P <0.05; ï¼»54.17 ± 17.81ï¼½ vs ï¼»39.26 ± 9.09ï¼½ and ï¼»46.25 ± 13.66ï¼½ pg/ml, P <0.01), while that of VEGF remarkably reduced in the former group in comparison with the latter two (ï¼»154.24 ± 30.23ï¼½ vs ï¼»199.23 ± 36.28ï¼½ and ï¼»181.57 ± 34.41ï¼½ pg/ml, P <0.01). The levels of TNF-α, IL-6, and VEGF were significantly correlated with BMI (r = 0.254, 0.321 and －0.407, P <0.01), those of TNF-α and IL-6 negatively with the percentage of PMS (r =－0.163, P <0.05; r = －0.333, P <0.01). There was a positive correlation between TNF-α and IL-6 (r = 0.468, P <0.01), a negative correlation between IL-6 and VEGF (r = 0.177, P <0.05), but no correlation between TNF-α and VEGF (r = 0.058, P >0.05). CONCLUSIONS: The levels of TNF-α and IL-6 are increased and that of VEGF decreased in the seminal plasma of obese males, which may affect the semen quality.