Cyclophilin A regulates the apoptosis of A549 cells by stabilizing Twist1 protein.

Cyclophilin A (CypA, also known as PPIA) is an essential member of the immunophilin family. As an intracellular target of the immunosuppressive drug cyclosporin A (CsA) or a peptidyl-prolyl cis/trans isomerase (PPIase), it catalyzes the cis-trans isomerization of proline amidic peptide bonds, through which it regulates a variety of biological processes, such as intracellular signaling, transcription and apoptosis. In this study, we found that intracellular CypA enhanced Twist1 phosphorylation at Ser68 and inhibited apoptosis in A549 cells. Mechanistically, CypA could mediate the phosphorylation of Twist1 at Ser68 via p38 mitogen-activated protein kinase (also known as MAPK14), which inhibited its ubiquitylation-mediated degradation. In addition, CypA increased interaction between Twist1 and p65 (also known as RELA), as well as nuclear accumulation of the Twist1-p65 complex, which regulated Twist1-dependent expression of CDH1 and CDH2. Our findings collectively indicate the role of CypA in Twist1-mediated apoptosis of A549 cells through stabilizing Twist1 protein.

CPK10 protein kinase regulates Arabidopsis tolerance to boron deficiency through phosphorylation and activation of BOR1 transporter.

Boron (B) is crucial for plant growth and development. B deficiency can impair numerous physiological and metabolic processes, particularly in root development and pollen germination, seriously impeding crop growth and yield. However, the molecular mechanism underlying boron signal perception and signal transduction is rather limited. In this study, we discovered that CPK10, a calcium-dependent protein kinase in the CPK family, has the strongest interaction with the boron transporter BOR1. Mutations in CPK10 led to growth and root development defects under B-deficiency conditions, while constitutively active CPK10 enhanced plant tolerance to B deficiency. Furthermore, we found that CPK10 interacted with and phosphorylated BOR1 at the Ser689 residue. Through various biochemical analyses and complementation of B transport in yeast and plants, we revealed that Ser689 of BOR1 is important for its transport activity. In summary, these findings highlight the significance of the CPK10-BOR1 signaling pathway in maintaining B homeostasis in plants and provide targets for the genetic improvement of crop tolerance to B-deficiency stress.

MST4 negatively regulates type I interferons production via targeting MAVS-mediated pathway.

BACKGROUND: Cytosolic RNA sensing can elicit immune responses against viral pathogens. However, antiviral responses must be tightly regulated to avoid the uncontrolled production of type I interferons (IFN) that might have deleterious effects on the host. Upon bacterial infection, the germinal center kinase MST4 can directly phosphorylate the adaptor TRAF6 to limit the inflammatory responses, thereby avoiding the damage caused by excessive immune activation. However, the molecular mechanism of how MST4 regulates virus-mediated type I IFN production remains unknown. METHODS: The expression levels of IFN-ß, IFIT1, and IFIT2 mRNA were determined by RT-PCR. The expression levels of p-IRF3, IRF3, RIG-I, MAVS, and MST4 proteins were determined by Western blot. The effect of secreted level of IFN-ß was measured by ELISA. The relationship between MST4 and MAVS was investigated by immunofluorescence staining and coimmunoprecipitation. RESULTS: In this study, we reported that MST4 can act as a negative regulator of type I IFN production. Ectopic expression of MST4 suppressed the Poly (I:C) (polyino-sinic-polycytidylic acid)- and Sendai virus (SeV)-triggered production of type I IFN, while the knockdown of MST4 enhanced the production of type I IFN. Mechanistically, upon SeV infection, the MST4 competed with TRAF3 to bind to the 360-540 domain of MAVS, thereby inhibiting the TRAF3/MAVS association. Additionally, MST4 facilitated the interaction between the E3 ubiquitin ligase Smurf1 and MAVS. This promoted the K48-linked ubiquitination of MAVS, thereby accelerating the ubiquitin-mediated proteasome degradation of MAVS. CONCLUSIONS: Our findings showed that MST4 acted as a crucial negative regulator of RLR-mediated type I IFN production. Video Abstract.

SARS-CoV-2 3C-like protease antagonizes interferon-beta production by facilitating the degradation of IRF3.

The prevalence of SARS-CoV-2 is a great threat to global public health. However, the relationship between the viral pathogen SARS-CoV-2 and host innate immunity has not yet been well studied. The genome of SARS-CoV-2 encodes a viral protease called 3C-like protease. This protease is responsible for cleaving viral polyproteins during replication. In this investigation, 293T cells were transfected with SARS-CoV-2 3CL and then infected with Sendai virus (SeV) to induce the RIG-I like receptor (RLR)-based immune pathway. q-PCR, luciferase reporter assays, and western blotting were used for experimental analyses. We found that SARS-CoV-2 3CL significantly downregulated IFN-ß mRNA levels. Upon SeV infection, SARS-CoV-2 3CL inhibited the nuclear translocation of IRF3 and p65 and promoted the degradation of IRF3. This effect of SARS-CoV-2 3CL on type I IFN in the RLR immune pathway opens up novel ideas for future research on SARS-CoV-2.

Diallyl disulfide improves lipid metabolism by inhibiting PCSK9 expression and increasing LDL uptake via PI3K/Akt-SREBP2 pathway in HepG2 cells.

BACKGROUND AND AIM: Diallyl disulfide (DADS), a volatile sulfide extracted from garlic, has been suggested as a chemical of anti-atherosclerotic drugs, while its molecular mechanism for this benefit has not fully been understood. The aim of the present study was to investigate the effects of DADS on lipid metabolism and its potential mechanisms in HepG2 cells induced by lipopolysaccharides (LPS). METHODS AND RESULTS: HepG2 cells were treated with LPS with or without different concentrations of DADS (0, 20, 40, 80, 160 µg/ml) for 24 h. The cell activity was detected by CCK8, and Dil-LDL uptake assay was used to examine the LDL uptake. Real-time PCR and Western blot were used to detect the expression of LDLR, PCSK9 SREBP2 and HMGCR. In addition, we examined the effect of the combination of DADS with atorvastatin on PCSK9 expression. The results showed that LPS significantly increased PCSK9 and SREBP2 expressions in a dose-dependent manner in HepG2 cells. DADS attenuated PCSK9, SREBP2 and HMGCR expressions and up-regulated the expression of LDLR. Moreover, DADS reversed the expressions of PCSK9, SREBP2, HMGCR and LDLR induced by LPS and DADS could promote the LDL uptake in HepG2 cells. Furthermore, DADS decreased the expression of PCSK9 by activating the PI3K/Akt-SREBP2 signal pathway. Notably, DADS could reduce PCSK9 expression induced by atorvastatin in HepG2 cells. CONCLUSION: DADS could significantly attenuated PCSK9 expression in a dose-dependent manner induced by LPS and increased the LDLR expression in HepG2 cells, which was associated with the activation of PI3K/Akt-SREBP2 signaling pathway.

The Structural Characterization of a Novel Water-Soluble Polysaccharide from Edible Mushroom Leucopaxillus giganteus and Its Antitumor Activity on H22 Tumor-Bearing Mice.

In the present study, a novel cold water-soluble polysaccharide fraction (LGP) with the average molecular weight of 1.78×106  Da was extracted and purified from Leucopaxillus giganteus and its primary structure as well as in vivo antitumor activity was evaluated. The monosaccharide composition of LGP was determined by ion chromatography to be galactose, xylose, glucose and fucose in a molar ratio of 2.568 : 1.209 : 1 : 0.853. Its backbone was composed of α-D-Glu, α-D-Xyl, α-D-Gal and α-L-Fuc. The results of in vivo antitumor experiment demonstrated that LGP could effectively protect immune organs, has excellent antitumor activity, and inhibit the proliferation of H22 solid tumors in a dose-dependent manner. By analyzing Annexin V-FITC/PI staining, cell cycle and mitochondrial membrane potential detection assay, we concluded that LGP induced apoptosis of H22 cells via S phase arrest and mitochondria-mediated apoptotic pathway. Our results could provide valuable information for the potential application of LGP as an anti-hepatoma agent.

Interaction of Soy Protein Isolate Hydrolysates with Cyanidin-3-O-Glucoside and Its Effect on the In Vitro Antioxidant Capacity of the Complexes under Neutral Condition.

The interaction of soy protein isolate (SPI) and its hydrolysates (SPIHs) with cyanidin-3-O-glucoside (C3G) at pH 7.0 were investigated to clarify the changes in the antioxidant capacity of their complexes. The results of intrinsic fluorescence revealed that C3G binds to SPI/SPIHs mainly through hydrophobic interaction, and the binding affinity of SPI was stronger than that of SPIHs. Circular dichroism and Fourier-transform infrared spectroscopy analyses revealed that the interaction with C3G did not significantly change the secondary structures of SPI/SPIHs, while the surface hydrophobicity and average particle size of proteins decreased. Furthermore, the SPI/SPIHs-C3G interaction induced an antagonistic effect on the antioxidant capacity (ABTS and DPPH) of the complex system, with the masking effect on the ABTS scavenging capacity of the SPIHs-C3G complexes being lower than that of the SPI-C3G complexes. This study contributes to the design and development of functional beverages that are rich in hydrolysates and anthocyanins.

Efficacy evaluation of Lattice Carbon Dioxide Laser Therapy in the treatment of postmenopausal patients with mild to moderate stress urinary incontinence.

OBJECTIVES: To investigate the efficacy and postoperative complications of lattice carbon dioxide laser in the treatment of postmenopausal patients with mild to moderate stress urinary incontinence. METHODS: A total of 30 postmenopausal female patients with mild to moderate stress urinary incontinence, recruited from the Affiliated Hospital of Hebei University from September to November 2019, were selected as the study subjects and treated with lattice carbon dioxide laser therapy. Treatment was given at intervals of one month. The degree of urinary incontinence, the urinary incontinence questionnaire (ICI-Q-SF) score, and the urinary incontinence quality of life scale (I-QOL)) Score, surgical satisfaction, one hour pad test and postoperative complications before treatment and after each treatment of all patients were respectively recorded and compared. RESULTS: Compared with those before treatment, the grade of urinary incontinence and ICI-Q-SF scores of these 30 patients after each treatment were lower, and their I-QOL scores were higher. The difference of one hour urine pad test was statistically significant (P<0.05), but the follow-up data of three months after the third treatment was close to that of one month after the first treatment. The satisfaction rate of these 30 patients was 76.67% (23/30). After treatment, only one patient presented vaginal itching discomfort on the first day after surgery and the symptoms disappeared three days later. No obvious complications occurred in the other 29 patients. CONCLUSION: The treatment of mild and moderate postmenopausal patients with stress urinary incontinence with lattice carbon dioxide laser can effectively reduce the incidence of incontinence and improve the quality of life.

Meis2 represses the osteoblastic transdifferentiation of aortic valve interstitial cells through the Notch1/Twist1 pathway.

AIM: Calcific aortic valve disease (CAVD) is the most common valvular disease worldwide. The osteoblastic transdifferentiation of aortic valve interstitial cells (VICs) is the essential process of CAVD, but the underlying mechanisms are poorly understood. Aortic VICs are generated from epithelial-to-mesenchymal transition (EMT) and migration of neural crest cells (NCCs).Meis2 has been associated with EMT and NCCs migration during development, but its role in CAVD is unknown. This study aims to elucidate the specific functions of Meis2 and its downstream targets in aortic valve calcification. MATERIAL AND METHODS: Levels of Meis2 were examined in calcified (n = 30) and normal (n = 30) human aortic valve tissues, respectively. Meis2 was inhibited in porcine aortic VICs in vitro, and the effect on osteoblastic transdifferentiation and its downstream pathway were studied. RESULTS: Meis2 gene and protein expression decreased significantly in calcified human aortic valve tissue compared with the normal ones. Inhibiting Meis2 by siRNAs reduced the gene and protein expression of Notch1 and Twist1, and induced the osteoblastic transdifferentiation of the porcine aortic VICs in vitro. CONCLUSIONS: The present study indicated that Meis2 repress the osteoblastic transdifferentiation of aortic VICs through the Notch1/Twist1 signaling pathway. The Results identify Meis2 as a potential intervention target for the prevention of CAVD.

Liraglutide improves lipid metabolism by enhancing cholesterol efflux associated with ABCA1 and ERK1/2 pathway.

BACKGROUND: Reverse cholesterol transport (RCT) is an important cardioprotective mechanism and the decrease in cholesterol efflux can result in the dyslipidemia. Although liraglutide, a glucagon like peptide-1 analogue, has mainly impacted blood glucose, recent data has also suggested a beneficial effect on blood lipid. However, the exact mechanism by which liraglutide modulates lipid metabolism, especially its effect on RCT, remain undetermined. Hence, the aim of the present study was to investigate the potential impacts and potential underlying mechanisms of liraglutide on the cholesterol efflux in both db/db mice and HepG2 cells. METHODS: Six-week old db/db mice with high fat diet (HFD) and wild type mice were administered either liraglutide (200 µg/kg) or equivoluminal saline subcutaneously, twice daily for 8 weeks and body weight was measured every week. After the 8-week treatment, the blood was collected for lipid evaluation and liver was obtained from the mice for hematoxylin-eosin (HE) staining, red O staining and Western blotting. Cholesterol efflux was assessed by measuring the radioactivity in the plasma and feces after intraperitoneal injection of 3H-labeled cholesterol. HepG2 Cells were treated with different concentrations of glucose (0, 5, 25, and 50 mmol/L) with or without liraglutide (1000 nmol/L) for 24 h. The intracellular cholesterol efflux was detected by BODIPY-cholesterol fluorescence labeling. Real-time PCR or Western blotting was used to examine the expression levels of ABCA1, ABCG1 and SR-B1. RESULTS: Liraglutide significantly decreased blood glucose, serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). It also reduced liver lipid deposition in db/db mice fed with HFD. Moreover, the movement of 3H-cholesterol from macrophages to plasma and feces was significantly enhanced in db/db mice fed with HFD after liraglutide adminstration. In vitro study, liraglutide could promote the cholesterol efflux of HepG2 cells under high glucose, and also increase the expression of ABCA1 by activating the ERK1/2 pathway. CONCLUSIONS: Liraglutide could improve lipid metabolism and hepatic lipid accumulation in db/db mice fed with HFD by promoting reversal of cholesterol transport, which was associated with the up-regulation of ABCA1 mediated by the ERK1/2 phosphorylation.

Selective overexpression of Toll-like receptor-4 in skeletal muscle impairs metabolic adaptation to high-fat feeding.

Toll-like receptor-4 (TLR-4) is elevated in skeletal muscle of obese humans, and data from our laboratory have shown that activation of TLR-4 in skeletal muscle via LPS results in decreased fatty acid oxidation (FAO). The purpose of this study was to determine whether overexpression of TLR-4 in skeletal muscle alters mitochondrial function and whole body metabolism in the context of a chow and high-fat diet. C57BL/6J mice (males, 6-8 mo of age) with skeletal muscle-specific overexpression of the TLR-4 (mTLR-4) gene were created and used for this study. Isolated mitochondria and whole muscle homogenates from rodent skeletal muscle (gastrocnemius and quadriceps) were investigated. TLR-4 overexpression resulted in a significant reduction in FAO in muscle homogenates; however, mitochondrial respiration and reactive oxygen species (ROS) production did not appear to be affected on a standard chow diet. To determine the role of TLR-4 overexpression in skeletal muscle in response to high-fat feeding, mTLR-4 mice and WT control mice were fed low- and high-fat diets for 16 wk. The high-fat diet significantly decreased FAO in mTLR-4 mice, which was observed in concert with elevated body weight and fat, greater glucose intolerance, and increase in production of ROS and cellular oxidative damage compared with WT littermates. These findings suggest that TLR-4 plays an important role in the metabolic response in skeletal muscle to high-fat feeding.

Intravenous tranexamic acid for intracerebral meningioma resections: A randomized, parallel-group, non-inferiority trial.

STUDY OBJECTIVES: Tranexamic acid (TXA) is an antifibrinolytic that is widely used to reduce surgical bleeding. However, TXA occasionally causes seizures and the risk might be especially great after neurosurgery. We therefore tested the hypothesis that TXA does not meaningfully increase the risk of postoperative seizures within 7 days after intracranial tumor resections. DESIGN: Randomized, double-blind, placebo-controlled, non-inferiority trial. SETTING: Beijing Tiantan Hospital, Capital Medical University. PATIENTS: 600 patients undergoing supratentorial meningioma resection were included from October 2020 to August 2022. INTERVENTIONS: Patients were randomly assigned to a single dose of 20 mg/kg of TXA after induction (n = 300) or to the same volume of normal saline (n = 300). MEASUREMENT: The primary outcome was postoperative seizures occurring within 7 days after surgery, analyzed in both the intention-to-treat and per-protocol populations. Non-inferiority was defined by an upper limit of the 95% confidence interval for the absolute difference being <5.5%. Secondary outcomes included incidence of non-epileptic complication within 7 days, changes in hemoglobin concentration, estimated intraoperative blood loss. Post hoc analyses included the types and timing of seizures, oozing assessment, and a sensitivity analysis for the primary outcome in patients with pathologic diagnosis of meningioma. MAIN RESULTS: All 600 enrolled patients adhered to the protocol and completed the follow-up for the primary outcome. Postoperative seizures occurred in 11 of 300 (3.7%) of patients randomized to normal saline and 13 of 300 (4.3%) patients assigned to tranexamic acid (mean risk difference, 0.7%; 1-sided 97.5% CI, -∞ to 4.3%; P = 0.001 for noninferiority). No significant differences were observed in any secondary outcome. Post hoc analysis indicated similar amounts of oozing, calculated blood loss, recurrent seizures, and timing of seizures. CONCLUSION: Among patients having supratentorial meningioma resection, a single intraoperative dose of TXA did not significantly reduce bleeding and was non-inferior with respect to postoperative seizures after surgery. REGISTRY INFORMATION: This trial was registered at clinicaltrials.gov (NCT04595786) on October 22, 2020, by Dr.Yuming Peng.

Cloning and Functional Identification of Gibberellin Receptor SvGID1s Gene of Salix viminalis.

Gibberellins (GAs) play a key role in the transition from vegetative growth to flowering and the GA receptor GID1 (GIBBERELLIN INSENSITIVE DWARF1) is the central part of GA-signaling. The differential expression of SvGID1 was found in the transcriptome sequencing in our previous study, which was further verified at different stages of flowering of Salix viminalis. In order to reveal the function GID1 of S. viminalis, two genes of SvGID1b and SvGID1c were cloned and transformed into Arabidopsis thaliana, respectively. The results showed that the full ORF length of SvGID1b and SvGID1c genes were both 1035 bp, encoding 344 amino acids, which were typical globular proteins. The peptide chain contained more α-helix structure, and had 99% similarity with GID1b and GID1c amino acid sequences of Salix suchowensis. Phylogenetic analysis showed that SvGID1s had close genetic relationship with woody plants such as Populus alba and Populus tomentosa, and had far genetic relationship with rice. After overexpression in A. thaliana, the total gibberellin, active gibberellin content and the expression level of GA3ox1, the key gene for GA4 synthesis, were not significantly different from those in the wild-type, while the expression levels of FUL, SOC1 and FT, the key genes for flowering in plants, were increased, and the expression levels of FLC and GAI were decreased. The ectopic expression of SvGID1s increased the sensitivity of plants to gibberellin and enhanced gibberellin effect, caused early bolting, budding and flowering, led to higher plant, longer hypocotyl and other phenomena. The results provide a theoretical basis for clarifying the regulation of gibberellin on flower bud differentiation of flowering plants.

Entrapment of cyanidin-3-O-glucoside in ß-conglycinin: From interaction to bioaccessibility and antioxidant activity under thermal treatment.

The thermal-induced interaction between ß-conglycinin (7S) and cyanidin-3-O-glucoside (C3G) on the bioaccessibility and antioxidant capacity of C3G was investigated. High ratio of 7S to C3G (1:100) led to a more ordered secondary structure of 7S. Thermal treatment promoted the formation of 7S-C3G complexes via hydrophobic and hydrogen bonds but did not induce the formation of 7S-C3G covalent products. Thermal treatment at 65 °C and 121 °C enhanced the binding affinity of 7S-C3G complexes by 46.19 % and 1203 % compared with 25 °C. The 7S-C3G interaction decreased C3G bioaccessibility by 4.37 %, 8.74 %, and 46.37 % at 25 °C, 65 °C, and 121 °C. Diphenylpicrylhydrazyl (DPPH) and ABTS antioxidant capacity assay indicated an antagonistic effect between 7S and C3G. The increased binding affinity of C3G to 7S limited the bioaccessibility of C3G and promoted the antagonism of antioxidant capacity between 7S and C3G. 7S addition was detrimental to the antioxidant capacity and bioaccessibility of C3G in vitro after thermal processing.

Arsenic exposure caused male infertility indicated by testis and sperm metabolic dysfunction in SD rats.

Arsenic containment is one of the most severe environmental problems. It has been reported that arsenic exposure could cause male reproductive damage. However, the evidence chain from sodium arsenite (NaAsO2) exposure to adverse male fertility outcomes has not been completed by molecular events. In this study, adult male rats were exposed to NaAsO2 for eight weeks via drinking water for verifying their reproductive capacity by checking the phenotypes of testis damage, sperm quality, and female pregnancy rate. H&E staining indicated testicular cells had atrophied, and necrosis was observed under transmission electron microscopy. Sperm viability tended to decrease, and sperm malformation increased. Notably, metabolites in the testes and sperm showed substantial disruption, especially sperm metabolites. The pregnancy rate tests showed that arsenic decreased male rats' reproduction, with some adverse outcomes of the increased numbers of unpregnant females. However, the fetal crown-rump length remained unaltered, indicating that the pregnancy rate was impacted by arsenic exposure but not fetal growth. On arsenic toxicometabolomics analysis, docosahexaenoic acid (DHA) in sperm was the clearest metabolic sign to correlate with the unpregnant rate. In summary, arsenic exposure can cause male infertility via the injured sperm, which results in decreased female pregnancy. The DHA information may imply the dietary intervention for improving sperm quality. Although the fetal growth of the successful pregnancy has not been affected, the changes in epigenetic phenotypes carried by sperms still need to be verified.

The role of cell death in SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), showing high infectiousness, resulted in an ongoing pandemic termed coronavirus disease 2019 (COVID-19). COVID-19 cases often experience acute respiratory distress syndrome, which has caused millions of deaths. Apart from triggering inflammatory and immune responses, many viral infections can cause programmed cell death in infected cells. Cell death mechanisms have a vital role in maintaining a suitable environment to achieve normal cell functionality. Nonetheless, these processes are dysregulated, potentially contributing to disease pathogenesis. Over the past decades, multiple cell death pathways are becoming better understood. Growing evidence suggests that the induction of cell death by the coronavirus may significantly contributes to viral infection and pathogenicity. However, the interaction of SARS-CoV-2 with cell death, together with its associated mechanisms, is yet to be elucidated. In this review, we summarize the existing evidence concerning the molecular modulation of cell death in SARS-CoV-2 infection as well as viral-host interactions, which may shed new light on antiviral therapy against SARS-CoV-2.

The effect of tranexamic acid on intraoperative blood loss in patients undergoing brain meningioma resections: Study protocol for a randomized controlled trial.

INTRODUCTION: Tranexamic acid (TXA) has been proven to prevent thrombolysis and reduce bleeding and blood transfusion requirements in various surgical settings. However, the optimal dose of TXA that effectively reduce intraoperative bleeding and blood product infusion in patients undergoing neurosurgical resection of meningioma with a diameter ≥ 5 cm remains unclear. METHODS: This is a single-center, randomized, double-blinded, paralleled-group controlled trial. Patients scheduled to receive elective tumor resection with meningioma diameter ≥ 5 cm will be randomly assigned the high-dose TXA group, the low-dose group, and the placebo. Patients in the high-dose TXA group will be administered with a loading dose of 20 mg/kg TXA followed by continuous infusion TXA at a rate of 5 mg/kg/h. In the low-dose group, patients will receive the same loading dose of TXA followed by a continuous infusion of normal saline. In the control group, patients will receive an identical volume of normal saline. The primary outcome is the estimated intraoperative blood loss calculated using the following formula: collected blood volume in the suction canister (mL)-the volume of flushing (mL) + the volume from the gauze tampon (mL). Secondary outcomes include calculated intraoperative blood loss, intraoperative coagulation function assessed using thromboelastogram (TEG), intraoperative cell salvage use, blood product infusion, and other safety outcomes. DISCUSSION: Preclinical studies suggest that TXA could reduce intraoperative blood loss, yet the optimal dose was controversial. This study is one of the early studies to evaluate the impact of intraoperative different doses infusion of TXA on reducing blood loss in neurological meningioma patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05230381. Registered on February 8, 2022.

Ozone exposure associates with sperm quality indicators: Sperm telomere length as a potential mediating factor.

Evidence linking O3 exposure and human semen quality is limited and conflicting and the mechanism underlying the association remains unclear. Therefore, we investigated the associations between ambient O3 exposure and sperm quality parameters and explored the mediating role of sperm mitochondrial DNA copy number (mtDNAcn) and sperm telomere length (STL) among 1068 potential sperm donors who provided 5002 repeated semen samples over approximately 90 days. We found that every 10 µg/m3 increase in O3 exposure was associated with a decrease in STL, sperm concentration, total count, total motile sperm number, and semen volume. However, O3 exposure was associated with increased total motility and progressive motility. The association for sperm quality parameters was stronger when exposure was measured at spermatogenesis stages I and II. For STL, the strongest association was observed when exposure was measured at spermatogenesis stage II. Additionally, we found that approximately 9% and 8% of the association between O3 exposure and sperm concentration and count was mediated by STL, respectively. In summary, our findings suggest that O3 pollution may affect sperm telomere length, eventually leading to reduced semen quality.

Environmental metal exposure, seminal plasma metabolome and semen quality: Evidence from Chinese reproductive-aged men.

Environmental metal exposure has been associated with decreasing semen quality, but the effects of multiple metal exposure on seminal plasma metabolome remain obscure. In this study, semen and repeated urine samples from 551 volunteers were collected in Wuhan City. Heavy metals and trace elements were measured using inductively coupled plasma mass spectrometer, and seminal plasma metabolomes were acquired using liquid chromatography coupled with high-resolution mass spectrometry. Weighted gene co-expression network analysis showed more than half of the seminal plasma metals were associated with specific metabolite modules, whereas only a few urine metals presented weak associations, indicating that seminal plasma may be an ideal biological sample for male reproductive biomarker discovery and exposure risk assessment. Seminal plasma zinc (Zn) and selenium (Se) concentrations were significantly associated with 22 metabolites (e.g., glycerophospholipids, acyl-carnitines and amino acid derivatives). Among these metabolites, acyl-carnitines were positively associated with semen quality and sperm concentration. Moreover, acyl-carnitines were associated with both Zn and Se exposure, indicating the potential role of carnitine pathway in their toxicity mechanism. Our findings suggest that seminal plasma metabolome connects Zn and Se exposure and sperm concentrations in Chinese men of reproductive age.

Identification of core genes associated with type 2 diabetes mellitus and gastric cancer by bioinformatics analysis.

Background: Gastric cancer (GC) is the most common type of malignant neoplasm of the digestive system. Diabetes mellitus (DM) or hyperglycemia may increase the incidence or mortality of GC. We aimed to investigate the possible genetic relationship between GC, DM, and type 2 diabetes mellitus (T2DM), and to identify core genes that are associated with T2DM and GC. Methods: The GeneCards database was used to screen DM-, T2DM-, and GC-related genes, and a protein-protein interaction (PPI) network of the genes/proteins associated with overlapping genes between DM, T2DM, and GC was constructed. Molecular Complex Detection (MCODE) was used to identify the significant module. CytoHubba (U.S. National Institute of General Medical Sciences) was utilized to detect hub genes in the PPI. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) resources were used to analyze selected module genes, as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment of PPI networks. The Kaplan-Meier plotter database, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN and western blot were used to identify the prognostic value of hub genes and their expression in GC and normal tissue. Results: One thousand one hundred and fifty-two DM-related genes, 466 GC-related genes, and 531 T2DM-related genes were obtained. Subsequently, 401 genes/proteins associated with 59 overlapping genes were screened. Two significant modules, which had higher scores, and 10 hub genes were chosen. Finally, caspase 3 (CASP3), and tumor protein P53 (TP53) were identified as core genes. Conclusions: We identified two genes that may play key roles in T2DM and GC: CASP3, TP53. Our study will contribute to further understanding the possible mechanism of diabetes progression to GC and provide useful information to identify new biomarkers for GC, and provided theoretical basis for the prevention of the occurrence and development of GC.