α-Pyrone mediates quorum sensing through the conservon system in Nocardiopsis sp.

Actinobacteria produce a plethora of bioactive secondary metabolites that are often regulated by quorum-sensing signaling molecules via specific binding to their cognate TetR-type receptors. Here, we identified monocyclic α-pyrone as a new class of actinobacterial signaling molecules influencing quorum sensing process in Nocardiopsis sp. LDBS0036, primarily evidenced by a significant reduction in the production of phenazines in the pyrone-null mutant compared to the wild-type strain. Exogenous addition of the α-pyrone can partially restore the expression of some pathways to the wild strain level. Moreover, a unique multicomponent system referred to as a conservon, which is widespread in actinobacteria and generally contains four or five functionally conserved proteins, may play an important role in detecting and transmitting α-pyrone signals in LDBS0036. We found the biosynthetic gene clusters of α-pyrone and their associated conservon genes are highly conserved in Nocardiopsis, indicating the widespread prevalence and significant function of this regulate mechanism within Nocardiopsis genus. Furthermore, homologous α-pyrones from different actinobacterial species were also found to mediate interspecies communication. Our results thus provide insights into a novel quorum-sensing signaling system and imply that various modes of bacterial communication remain undiscovered.

Nobiletin Ameliorates Aging of Chicken Ovarian Prehierarchical Follicles by Suppressing Oxidative Stress and Promoting Autophagy.

With the increase in the age of laying chickens, the aging of follicles is accelerated, and the reproductive ability is decreased. Increased oxidative stress and mitochondrial malfunction are indispensable causes of ovarian aging. In this study, the physiological condition of prehierarchical small white follicles (SWFs) was compared between D280 high-producing chickens and D580 aging chickens, and the effect of a plant-derived flavonoid nobiletin (Nob), a natural antioxidant, on senescence of SWFs granulosa cells (SWF-GCs) was investigated. The results showed that Nob treatment activated cell autophagy by activating the AMP-activated protein kinase (AMPK) and Sirtuin-1 (SIRT1) pathways in D-galactose (D-gal)-generated senescent SWF-GCs, restoring the expression of proliferation-related mRNAs and proteins. In addition, the expression of inflammation-related protein NF-κB was significantly enhanced in aging GCs that were induced by D-gal. Nob supplementation significantly increased the antioxidant capacity and decreased the expression of several genes associated with cell apoptosis. Furthermore, Nob promoted activation of PINK1 and Parkin pathways for mitophagy and alleviated mitochondrial edema. Either the AMPK inhibitor dorsomorphin (Compound C) or SIRT1 inhibitor selisistat (EX-527) attenuated the effect of Nob on mitophagy. The protective effect of Nob on natural aging, GC proliferation, and elimination of the beneficial impact on energy regulation of naturally aging ovaries was diminished by inhibition of Nob-mediated autophagy. These data suggest that Nob treatment increases the expression of mitophagy-related proteins (PINK1 and Parkin) via the AMPK/SIRT1 pathways to prevent ovarian aging in the laying chickens.

Bioactive Lignan Honokiol Alleviates Ovarian Oxidative Stress in Aging Laying Chickens by Regulating SIRT3/AMPK Pathway.

Aging is not only a key internal cause of age-related diseases in humans but also poses a threat to the productivity of farm animals with longer breeding cycles, such as laying chickens. Various measures were taken to prolong the laying period by reducing oxidative stress to improve poultry ovarian functions. Within the mitochondria, SIRT3, a member of the Sirtuin family, plays an important role in post-translational modifications and the regulation of protein activities involved in energy metabolism and oxidative response. This study aimed to investigate the alleviating effect of a bioactive lignan Honokiol (HKL) on oxidative stress in aging chicken ovaries in order to retard decline in egg production. The results showed that HKL treatment restored the abnormal balance between cell proliferation and apoptosis, and it enhanced the antioxidant capacity of the H2O2-induced small white follicles (SWFs) by activating the SIRT3/AMPK pathway. Moreover, HKL significantly increased total egg production, the number of yellow follicles, and the mRNA expression of yolk synthesis and deposition-related genes, serum estrogen, and antioxidant levels. These findings suggest that HKL holds promise in enhancing the egg productivity of aging laying chickens by promoting yolk deposition and reducing ovarian oxidative stress.

Protein succinylation: regulating metabolism and beyond.

Modifications of protein post-translation are critical modulatory processes, which alters target protein biological activity，function and/or location, even involved in pathogenesis of some diseases. So far, there are at least 16 types of post-translation modifications identified, particularly through recent mass spectrometry analysis. Among them, succinylation (Ksuc) on protein lysine residues causes a variety of biological changes. Succinylation of proteins contributes to many cellular processes such as proliferation, growth, differentiation, metabolism and even tumorigenesis. Mechanically, Succinylation leads to conformation alteration of chromatin or remodeling. As a result, transcription/expression of target genes is changed accordingly. Recent research indicated that succinylation mainly contributes to metabolism modulations, from gene expression of metabolic enzymes to their activity modulation. In this review, we will conclude roles of succinylation in metabolic regulation of glucose, fat, amino acids and related metabolic disease launched by aberrant succinylation. Our goal is to stimulate extra attention to these still not well researched perhaps important succinylation modification on proteins and cell processes.

Cross-sectional associations between healthy eating index and thyroid function in U.S. male Adults, NHANES 2007-2012.

Little is known about whether diet quality is associated with thyroid function. We aimed to examine the relationship between diet quality and thyroid function. Data were from the National Health and Nutrition Examination Surveys, 2007-2012. A total of 3603 males who were at least 20 years old and had dietary recall data were included in the analysis. Thyroid function was assessed by eight indexes, including total and thyroglobulin antibodies, thyroid peroxidase antibodies, free T4 and T3, total T4 and T3, Tg, and thyroid-stimulating hormone. Multivariable linear regression, subgroup analyses, and interaction terms were employed to test the association between healthy eating index (HEI) and thyroid function. A total of 3603 male participants aged ≥20 years with an average age of 48.17 ± 0.51 years were enrolled. We found a negative association between HEI-2010 and total T3 (ß = -3.41; p = .01) and free T3 (ß = -0.06; p = .01). In subgroup analyses, HEI-2010 was negatively associated with TT3 in male participants aged <65 years old (ß = -4.57; p < .01) and FT3 (ß = -0.09; p < .001). Higher HEI-2010 was inversely associated with lower total T3 and free T3. More well-designed studies are still needed to validate the causal relationship between HEI and thyroid function.

Complete genome sequence of piezotolerant Stutzerimonas kunmingensis 7850S isolated from the sediment of the Mariana Trench.

Stutzerimonas kunmingensis 7850S is a piezotolerant bacterium isolated from the sediment of the Mariana trench. Here, we described the complete genome of strain 7850S, which contains a single circular chromosome of 4,775,870 base pairs with 62.66% G + C content, and harbors 4494 protein-coding genes, 65 transfer RNA genes, and 12 ribosomal RNA genes. The experimental results showed that strain 7850S could grow under hydrostatic pressure of 0.1-70 MPa. Genomic analyses led to identifications of numbers of high hydrostatic pressure-associated genes, such as the ones associated with unsaturated fatty acids, betaine, and ectoine. A complete set of denitrification genes and some heavy metal detoxification genes were also found in this strain. The presence of these genes suggests metabolic characteristics for adaption to hadal environments and provides insights to further understand adaption strategies and ecological roles of Stutzerimonas in hadal environments.

Glutamatergic neurons in paraventricular nucleus of the thalamus regulate the recovery from isoflurane anesthesia.

OBJECTIVES: Previous studies have demonstrated that the paraventricular nucleus of the thalamus (PVT) is a key wakefulness-controlling nucleus in the thalamus. Therefore, PVT may also be involved in the process of general anesthesia. This study intends to explore the role of PVT in isoflurane anesthesia. METHODS: In the present study, we used the expression of c-Fos to observe the neuronal activity of PVT neurons under isoflurane anesthesia. We further recorded the effect of isoflurane anesthesia on the calcium signal of PVT glutamatergic neurons in real time with the help of calcium fiber photometry. We finally used chemogenetic technology to specifically regulate PVT glutamatergic neurons, and observed its effect on isoflurane anesthesia and cortical electroencephalography (EEG) in mice. RESULTS: We found that glutamatergic neurons of PVT exhibited high activity during wakefulness and low activity during isoflurane anesthesia. Activation of PVT glutamatergic neuronal caused an acceleration in emergence from isoflurane anesthesia accompanied with a decrease in EEG delta power (1-4 Hz). Whereas suppression of PVT glutamatergic neurons induced a delay recovery of isoflurane anesthesia, without affecting anesthesia induction. CONCLUSIONS: Assuming a pharmacokinetic explanation for results can be excluded, these results demonstrate that the PVT is involved in regulating anesthesia emergence.

Association between ambient particulate matter exposure and semen quality in fertile men.

BACKGROUND: Several studies have suggested adverse effects of particulate matter (PM) exposure on male reproductive health; few have investigated the association between PM exposure and semen quality in a large population of fertile men. METHODS: We evaluated 14 parameters of semen quality in 1554 fertile men in Nanjing from 2014 to 2016. Individual exposure to particular matter ≤10 µm in diameter (PM10) and ≤ 2.5 µm in diameter (PM2.5) during key periods of sperm development (0-90, 0-9, 10-14, 15-69, and 70-90 days before semen collection) were estimated by inverse distance weighting interpolation. Associations between PM exposure and semen quality were estimated using multivariable linear regression. RESULTS: Higher 90-days average PM2.5 was in association with decreased sperm motility (2.21% for total motility, 1.93% for progressive motility per 10 µg/m3 increase, P <  0.001) and four quantitative aspects of sperm motion (curvilinear velocity (VCL), straight line velocity (VSL), average path velocity (VAP), and amplitude of lateral head displacement (ALH), P <  0.01). The association between PM2.5 exposure and semen quality were generally stronger for the earlier exposure window (70-90 days prior to ejaculation) than for recent exposure (0-9, 10-14, or 15-69 days). In the subgroup of men who had normal sperm parameters (n = 1019), similar results were obtained. Ninety-days PM10 exposure was associated only with decreased VCL and VAP and was not related to sperm concentration. CONCLUSIONS: Exposure to PM2.5 adversely affects semen quality, specifically lower sperm motility, in fertile men.

The Clinical Characteristics and Outcome of Elderly Patients With Acute Pancreatitis.

OBJECTIVES: This study aimed to identify the risk factors for the progression of acute pancreatitis (AP) to severe acute pancreatitis (SAP) and death in elderly patients. METHODS: This was a single-center retrospective study conducted in a tertiary teaching hospital. Data on patient demographics, comorbidities, duration of hospitalization, complications, interventions, and mortality rates were collected. RESULTS: Between January 2010 and January 2021, 2084 elderly patients with AP were included in this study. The mean age of the patients was 70.0 years (standard deviation, 7.1 years). Among them, 324 (15.5%) had SAP and 105 died (5.0%). The 90-day mortality rate in the SAP group was significantly higher than that in the AP group (P < 0.0001). Multivariate regression analysis revealed that trauma, hypertension, and smoking were risk factors for SAP. After multivariate adjustment, acute respiratory distress syndrome, acute kidney injury, sepsis, organ perforation, and abdominal hemorrhage were associated with higher 90-day mortality. CONCLUSIONS: Traumatic pancreatitis, hypertension, and smoking are independent risk factors for SAP in elderly patients. Acute respiratory distress syndrome, acute kidney injury, sepsis, organ perforation, and abdominal hemorrhage are independent risk factors for death in elderly patients with AP.

LINC00665 activates Wnt/ß-catenin signaling pathway to facilitate tumor progression of colorectal cancer via upregulating CTNNB1.

Background LINC00665 is a newly identified oncogene, which has been reported to be oncogene in various cancers. Nevertheless, its role in the progression of colorectal cancer (CRC) remains obscure to the extent. This study aimed at exploring the role and mechanism of LINC00665 in CRC progression. Materials and methods RNA and protein expression were detected via qRT-PCR and western blot. Functional assays were conducted to investigate the role of LINC00665 in the CRC cellular processes. TOP/FOP assay was performed to detect the activity of Wnt/ß-catenin signaling pathway. Mechanism investigations were carried out to explore the regulatory relationship among genes. Results LINC00665 was overtly expressed in CRC cell lines at high levels. Functionally, silencing of LINC00665 could curb in vitro CRC cell growth, migration and invasion, while stimulating cell apoptosis. Mechanically, LINC00665 sponged miR-214-3p to up-regulate CTNNB1 expression, consequently activating Wnt/ß-catenin signaling pathway. Furthermore, LINC00665 could bind to U2AF2 and enhance the association between U2AF2 and CTNNB1, increasing the stability of CTNNB1. CTNNB1 overexpression could reverse the suppressive effects of LINC00665 downregulation. Conclusion LINC00665 stimulates CRC progression through the activation of Wnt/ß-catenin signaling pathway, which hopefully might be a therapeutic target for CRC.

Elevated microRNA-141-3p in placenta of non-diabetic macrosomia regulate trophoblast proliferation.

BACKGROUND: Several studies have reported microRNAs (miRNAs) could regulate the placental development, though the role and mechanism of miRNAs in the development of non-diabetic macrosomia (NDFMS) remains unclear. METHODS: To identify the aberrantly expressed key miRNAs in placenta of NDFMS, we employed a strategy consisting of initial screening with miRNA microarray and further validation with quantitative RT-PCR assay (qRT-PCR). In vitro cellular model and a mouse pregnancy model were used to delineate the functional effects of key miRNA on proliferation, invasion, and migration. FINDINGS: miR-141-3p was identified as the key miRNA with expression level significantly higher in placentas of NDFMS compared with those from normal controls. Overexpressed miR-141-3p in HTR-8/SVneo cells contributed to increased cell proliferation, invasion, and migration. miR-141-3p inhibition in HTR-8/SVneo cells resulted in decreased cell proliferation and invasion. Significantly increased infant birth weight was observed in late pregnancy of C57BL/6J mice treated with miR-141-3p agomir. However, no significant difference was found in early pregnancy of C57BL/6J mice treated with miR-141-3p agomir. INTERPRETATION: miR-141-3p could stimulate placental cell proliferation to participate in the occurrence and development of NDFMS.

Idiopathic male infertility and polymorphisms in the DNA methyltransferase genes involved in epigenetic marking.

The purpose of this study was to investigate the association between male infertility and single-nucleotide polymorphisms (SNPs) of DNA methyltransferases (DNMT) genes (DNMT3B: rs2424909, DNMT1: rs4804490, DNMT3A: rs1550117 and DNMT3L: rs7354779). Eight hundred and thirty three idiopathic infertile males and four hundred and ten fertile controls from the hospitals affiliated to Nanjing Medical University between 2010 and 2012 were recruited in the study. We demonstrated a significantly increased risk of idiopathic infertility with abnormal semen parameters in association with the heterozygous genotype of variant rs4804490. Moreover, the AA genotype of variant rs4804490 was associated with significantly decreased risk for male infertility with abnormal semen parameters. A decreased risk of idiopathic infertility with abnormal semen parameters was associated with the homozygous genotype of variant rs2424909. These results suggested that variants in different DNMT genes have different relationships with idiopathic male infertility, and Chinese men carrying these variants have an increased or decreased risk of abnormal semen parameters.

From the Cover: Metabolomics Reveals a Role of Betaine in Prenatal DBP Exposure-Induced Epigenetic Transgenerational Failure of Spermatogenesis in Rats.

There is increasing concern that early-life exposure to endocrine disruptors affects male offspring reproduction. However, whether di-n-butyl phthalate (DBP), a widely used endocrine disruptor, has transgenerational effects and, if so, the exact underlying molecular mechanisms involved remain unknown. In our study, 5 of time-mated pregnant SD rats were exposed to 0 and 500 mg/kg DBP with corn oil as the vehicle via oral gavage from embryonic days (E8-E14). Epigenetic and metabolomic of testis were analyzed after post-natal 60 days. Sperm and testicular cell functions were examined to confirm the transgenerational effects. DBP exposure significantly decreased the sperm counts in F1 through F3 generation. We found distinct metabolic changes in the testis of both F1 and F3 generation offspring, specifically, a significantly increased level of betaine, which is an important methyl donor. In contrast, the expression of betaine homocysteine S-methyltransferase (BHMT), which catalyzes the transfer of methyl moiety from betaine to homocysteine, significantly decreased. There was accompanying global DNA hypomethylation, along with a reduction in follistatin-like 3 (Fstl3) promoter hypomethylation, which is a known modulator of Sertoli cell number and spermatogenesis. In summary, we conclude that metabolomic and epigenetic changes induced by the aberrant expression of BHMT represent a novel mechanism linking in utero DBP exposure to transgenerational spermatogenesis failure.

Genistein up-regulates miR-20a to disrupt spermatogenesis via targeting Limk1.

Genistein (GEN) is one of the isoflavones that has effect on male reproduction. However, the underlying mechanism remains unknown. miRNAs are a type of small non-coding RNAs that play important roles in spermatogenesis. We measured the GEN levels and miR-17-92 cluster expression in infertile subjects and found that miR-17-92 might be involved in GEN induced abnormal spermatogenesis. To clarify, we fed adult ICR mice with different doses of GEN (0, 0.5, 5, 50 and 250 mg/kg/day) for 35 days to study the underlying mechanism. We found that sperm average path velocity, straight-line velocity and eurvilinear velocity of the mice orally with GEN at 5mg/kg/day were significantly decreased, the expression levels of miR-17 and miR-20a in mice testis were higher in corresponding group. We also found miR-20a was the only miRNA that differentially expressed both in human and mice. By applying bioinformatics methods, Limk1 was predicted to be the target gene of miR-20a that is involved in spermatogenesis. Limk1 were significantly decreased in the corresponding group. Dual-luciferase report assay also proved that miR-20a could directly target Limk1. These results implied that Limk1 might be the target gene of miR-20a that is involved in GEN induced abnormal spermatogenesis.

The impact of BMI on sperm parameters and the metabolite changes of seminal plasma concomitantly.

The development of male infertility increased rapidly worldwide, which coinciding with the epidemic of obesity. However, the impact of weight abnormalities on sperm quality is still contestable. To assess the correlation between BMI and sperm parameters, we searched relevant articles in PubMed, Embase, Web of science, and Wanfang database published until June 2015 without language restriction. Otherwise, we also recruited some participants who attended fertility clinic as well as some general populations in this report. We performed a systematic review and meta-analysis about BMI and sperm parameters containing total sperm count, concentration, semen volume and sperm motility (overall and progressive). Metabolomic analysis of seminal plasma was performed to explore the mechanism from a new perspective. This study found standardized weighted mean differences (SMD) in sperm parameters (total sperm count, sperm concentration, and semen volume) of abnormal weight groups decreased to different degree compared to normal weight. Dose-response analysis found SMD of sperm count, sperm concentration and semen volume respectively fell 2.4%, 1.3% and 2.0% compared with normal weight for every 5-unit increase in BMI. Metabolomic analysis of seminal plasma showed that spermidine and spermine were likely to play a vital role in the spermatogenesis progress. This systematic review with meta-analysis has confirmed there was a relationship between BMI and sperm quality, suggesting obesity may be a detrimental factor of male infertility.