Search

Background. Infertility is a global medical and social problem that affects human health and social development. At present, about 15% of couples of the right age in the world are infertile. As all we know, genetic defects are the most likely underlying cause of the pathology. ATP5D is also known as the delta subunit of mitochondrial ATP synthase. Mitochondria maintain sperm vitality, capacitation, acrosome reaction, and DNA integrity through ATP. Mitochondrial damage can trigger energy synthesis disorders, resulting in decreased sperm quality and function or even disappearance. The specific role of ATP5D in regulation of the male reproductive system remains elusive. Methods. In this study, semen from normal and infertile males were collected and their indicators were examined by analysis of routine sperm parameters; ATP5D protein content in semen was examined by ELISA. Singer sequencing was used to detect whether there was a mutated of ATP5D in semen. Meanwhile, ATP5D knockout (KO) and knockin (KI) male mice were selected at 8-12 weeks of age and mated with adult wild-type (WT) female mice for more than two months to assess their fertility and reproductive ability. Morphological changes in tissues such as testes and epididymis were observed by HE staining; spermatozoa were taken from the epididymis of the mice; sperm counts were performed and morphological changes were observed by Diff-Quik staining. Results. The results showed that the expression of ATP5D in infertile males was significantly lower than that in normal males ( P < 0.001 ) and the normal morphology rate of spermatozoa was much lower than that of normal males, and the sequencing results showed no mutations. The animal reproductive experiments showed no significant changes in the number of fertility in KO/KI mice compared with WT mice, but the duration of fertility was significantly longer ( P = 0.02 ). The testicular cells in KO mice were loosely arranged and disorganized, the lumen was larger, the interstitial cells were atrophied, and the number of spermatozoa was reduced and the malformation rate was higher in WT males. This suggests that ATP5D is an essential protein for sperm formation and fertility in male mice and may be used as a biomarker of male fertility. Conclusion. This study found ATP5D correlated with male infertility and the expression levels were significantly reduced in the seminal plasma of all male infertile patients without gene mutations. KO male significantly prolonged fertility time and impaired testicular histomorphology. This suggests that ATP5D may be associated with spermatogenic function and fertility in male mice and may be used as a biomarker for male fertility. Future studies are required to elucidate the potential mechanisms. The trial registration number is KLL-2021-266.

The intestinal microbiota has an increasingly recognized role in the development of cancer, in which microbial interactions play a more important than expected role. Pancreatic cancer is a highly fatal disease, in which its mortality is closely related to its morbidity. Early detection is the best chance of improving survival. Through an in-depth understanding of the pancreatic cancer microbiota, we could establish screening or early diagnosis methods for pancreatic cancer, implement bacterial treatment, adjust the therapeutic effect, and even reduce adverse reactions. These would lead to new developments and provide hope for patients with pancreatic cancer. Herein, we review the progress in intestinal microbiology research to diagnose and treat pancreatic cancer.

The prognosis of over 90% of infant acute lymphoblastic leukemia (ALL) remains poor because of harboring the mixed-lineage leukemia gene (MLL) fusion. To give insight into the critical coexpressed genes related to the MLL-rearrangement (MLL-R) gene in childhood acute lymphoblastic leukemia, we integrated different bioinformatic methods. First, the gene expression data of MLL-R ALL and normal samples from GSE13159 and GSE13164 were analyzed using “compare” function in the Oncomine database. The top 150 overexpressed and 150 underexpressed genes were identified by the Oncomine website. Then, we employed the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) to define functional genes for the 300 DEGs. The Cytoscape identified two important networks for overexpressed genes, including 35 functional genes, among which PROM1, FLT3, CTGF, LGALS1, IGFBP7, ZNRF1, and RUNX2 were considered as the key genes because of their high expression in MLL-R ALL compared to the expression in other subclassification of leukemia in the MILE dataset. Further analysis of GSE68720, GSE19475, and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) ALL (phase I) database confirmed the robust expression of 7 key genes in MLL-R compared to MLL-germline (MLL-G) childhood ALL. Kaplan-Meier analysis indicated that childhood ALL patients with high PROM1 and CTGF expression had significantly poor overall survival. These findings suggest that PROM1 and CTGF represent two potential therapeutic targets for childhood MLL-R ALL.

There are about 10 million people with epilepsy (PWE) in China. In addition to therapies approved by the National Medical Products Administration, the use of complementary and alternative medicine (CAM) is prevalent in Chines PWE. These CAM therapies mainly comprise traditional Chinese medicine herbs (TCMHs), acupuncture, and music. A retrospective literature search was performed to summarize the updates of CAM in China in the past ten years, and sixty-two papers were finally included. In this following review, we listed the animal and clinical studies to summarize the antiepileptic mechanisms and clinical efficacy of CAM in Chines PWE. The main mechanisms of TCMHs and acupuncture included regulation of neurotransmitters and receptors, voltage-gated ion channels modulation, expression of apoptosis-related genes, antioxidant response, and anti-inflammation. Although there were enormous clinical studies on them, the current available clinical trials were small, short-term, heterogeneous, and had a high risk of bias. With regard to music, a few studies conducted by Chinese scholars suggested that it was beneficial for PWE as an add-on therapy, which was consistent with the results of foreign studies. Further randomized clinical trials in large populations are required to prove the effectiveness and safety of CAM.

Nowadays, human beings are exposed to Cu in varieties of environmental mediums, resulting in health risks needing urgent attention. Our research found that Cu shortened lifespan and induced aging-related phenotypes of Caenorhabditis elegans (C. elegans). Transcriptomics data showed differential expression genes induced by Cu were mainly involved in regulation of metabolism and longevity, especially in fatty acid metabolism. Quantitative detection of free fatty acid by GC/MS further found that Cu upregulated free fatty acids of C. elegans. A mechanism study confirmed that Cu promoted the fat accumulation in nematodes, which was owing to disorder of fatty acid desaturase and CoA synthetase, endoplasmic reticulum unfolded protein response (UPRER), mitochondrial membrane potential, and unfolded protein response (UPRmt). In addition, Cu activated oxidative stress and prevented DAF-16 translocating into nuclear with a concomitant reduction in the expression of environmental stress-related genes. Taken together, the research suggested that Cu promoted aging and induced fat deposition and oxidative damage.

In order to comprehensively explore multitarget mechanism and key active compounds of Artemisia argyi essential oil (AAEO) in the treatment of pressure injuries (PIs), we analyzed the biological functions and pathways involved in the intersection targets of AAEO and PIs based on network pharmacology, and the affinity of AAEO active compounds and core targets was verified by molecular docking finally. In our study, we first screened 54 effective components according to the relative content and biological activity. In total, 103 targets related to active compounds of AAEO and 2760 targets associated with PIs were obtained, respectively, and 50 key targets were overlapped by Venny 2.1.0. The construction of key targets-compounds network was achieved by the STRING database and Cytoscape 3.7.2 software. GO analysis from Matespace shows that GO results are mainly enriched in biological processes, including adrenergic receptor activity, neurotransmitter clearance, and neurotransmitter metabolic process. KEGG analysis by the David and Kobas website shows that the key targets can achieve the treatment on PIs through a pathway in cancer, PI3K-Akt signaling pathway, human immunodeficiency virus 1 infection, MAPK signaling pathway, Wnt signaling pathway, etc. In addition, molecular docking results from the CB-Dock server indicated that active compounds of AAEO had good activity docking with the first 10 key targets. In conclusion, the potential targets and regulatory molecular mechanisms of AAEO in the treatment of PIs were analyzed by network pharmacology and molecular docking. AAEO can cure PIs through the synergistic effect of multicomponent, multitarget, and multipathway, providing a theoretical basis and new direction for further study.

WHAT IS KNOWN AND OBJECTIVES Ciclosporin (CsA), a potent immunosuppressive agent used to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, is characterized by large inter-individual variability and a narrow therapeutic range. The aim of this study was to develop a population pharmacokinetic model for CsA in Chinese allo-HSCT recipients and to identify covariates influencing CsA pharmacokinetics. METHODS A total of 758 retrospective drug monitoring data points were collected after intravenous infusion or oral administration of CsA from 59 patients. Population pharmacokinetic analysis was performed using nonlinear mixed effects modelling expressed by differential equations. Monte Carlo simulation was applied to optimize dosage regimens. The final model was validated using bootstrap and normalized prediction distribution errors. RESULTS AND DISCUSSION The results showed that the daily CsA dose, haematocrit, total bile acid, C-reactive protein (CRP) and co-administration of triazole antifungal agent were identified as significant covariates for clearance (CL) of CsA. The typical value of CL was 19.8 L/h with an inter-individual variability of 13.1%. The volume of distribution was 1340 L. Bioavailability was 67.2% with an inter-individual variability of 8.5%. Dosing simulation based on the developed model indicated that patients with high CRP concentration required a higher daily dose to attain the therapeutic trough concentration. The influence of CRP ultimately on the therapy outcome of CsA is not clear, which needs further study. WHAT IS NEW AND CONCLUSION CRP concentration was identified as a novel marker associated with CsA pharmacokinetics, which should be considered when determining the appropriate dosage of CsA in allo-HSCT recipients.

Gastric cancer is the most common gastrointestinal tumor with an increasing incidence. Furthermore, advanced gastric cancer is more common, but the mechanism underlying the proliferation and metastasis of gastric cancer has not been thoroughly explored. N6-methyladenosine (m6A) methyltransferase 3 (METTL3) may be involved in the proliferation and metastasis of gastric cancer. Therefore, Yes-associated protein 1 (YAP1) in the Hippo pathway was selected as the target, and the relationship between METTL3 and the proliferation and metastasis of gastric cancer was proved through a series of experiments. This research showed that the expression of m6A and METTL3 was upregulated in human gastric cancer tissues and gastric cancer cell lines. After lentiviral transfection, METTL3 silencing in AGS (human gastric adenocarcinoma cell line AGS) and MKN-45 (human gastric cancer cell line MKN-45) gastric cancer cell lines directly inhibited the proliferation, aggressiveness, and migration of gastric cancer cells. Mechanically, the inhibition of the YAP1-TEAD signaling pathway by peptide 17 reduces m6A methylation and the total mRNA level of YAP1. It also eliminates the promoting effect of METTL3 on the proliferation and migration of gastric cancer cells. In turn, the overexpression of YAP1 eliminates the inhibitory effect of METTL3 silencing on the proliferation, migration, and invasion of gastric cancer cells. This article proved that m6A methyltransferase METTL3 promoted the proliferation and migration of gastric cancer cells through the m6A modification of YAP1.

Goose astrovirus (GAstV), an agent of fatal visceral gout in goslings, has been widely circulating in eastern China since 2017, but little is known about its genetic diversity and systematic evolution. In this study, we isolated and sequenced nine nearly full-length GAstV genomes and conducted comprehensive genetic diversity and evolutionary analysis and compared them with other reported GAstV sequences. Our results indicated that two genotypic species of GAstV were circulating in China, and GAstV-2 subgenotype II-c had arisen as the dominant genotype in Shandong province and across the whole country. Multiple alignments of GAstV amino acid sequences revealed several characteristic mutations in GAstV-2 II-c strains, as well as additional residues in the nine new isolates which varied over time. Phylogenetic analysis of three open reading frames demonstrated different evolutionary histories. Evidence of natural recombination was also detected in GAstV, with most of the recombination occurring in the GAstV-2 II-c subgenotype. Molecular adaptation analyses revealed that the evolution of GAstV was shaped by strong negative selection, although a number of amino acids, which potentially affect host infection and cell entry, were subjected to positive pressure. Overall, these findings improve our understanding of the epidemiology and evolution of GAstV and may help in the development of vaccines and diagnostics.

Although, acupoint specificity is regarded as the core of scientific issues in electroacupuncture (EA), the difference of EA on treating functional dyspepsia (FD) at different acupoints is unclear. Therefore, this study aims to investigate the different therapeutic effects of EA at lower extremity or abdominal acupoints on the mucosal integrity and lower-inflammatory response in FD. The intragastric administration of iodoacetamide (IA) was performed in 48 rats to establish the FD model. These rats were randomly divided into the control group, the model group and the six EA groups receiving stimulation at the lower extremity (ST36, ST37, and ST39) or abdominal acupoints (ST25, CV4, and CV12) separately. The open-field test (OFT) was measured after 8 weeks of IA, and gastric emptying was evaluated after 10 days of the EA treatment. The local inflammation markers of CD45, eosinophil major basic protein (EMBP), and the tight junction proteins ZO1 and Claudin3 were assessed by immunofluorescence in all groups. Western blot analysis showed that the EMBP and Occludin1 levels in the duodenal. EA at lower extremity acupoint ST36 could improve the gastric emptying. EA at lower extremity acupoints reduced the immunoreactivity of EMBP, but the CD45 was reregulated by the ST37 and ST39 acupoints. The lower extremity acupoints also ameliorated FD-tight junction protein in the expression of Claudin3 and ZO1. However, only the ST36 suppressed the expression of EMBP and recovered the expression of Occludin1. Similarly, the effect of EA at abdominal acupoints was not obvious either in facilitating gastric motility or in improving inflammatory and mucosal injury. EA at lower extremity and abdominal acupoints with the same stimulation parameters had different therapeutic effects in gastric emptying, intestinal mucosal integrity, and inflammation response, thus proving the specificity of acupoints.

Refrigeration is an important method to extend shelf life of hardy kiwifruit. However, the inappropriate storage temperature can lead to chilling injury in the fruit. We found that firmness, total soluble solids, and total polyphenolic content of the fruit exposed to 0℃ environment were apparently lower, and titratable acidity content, browning rate, weight loss rate, electrolyte leakage, proline content, and malondialdehyde content were higher obviously than 4℃. A total of 244 differentially expressed proteins were found result from differential temperatures, among which 113 were up-regulated and 131 were down-regulated. Subcellular localization results presented that the differentially expressed proteins which were affected by low temperature were located in cytoplasmic, chloroplast, nuclear, mitochondrial, plasma membrane, and extracellular. Kyoto Encyclopedia of Genes and Genomes analysis showed that the differentially expressed proteins were mainly participated in synthesis of citrate cycle, oxidative phosphorylation, fatty acid biosynthesis, and starch and sucrose metabolism. Protein-protein interaction results revealed that central proteins interaction points respectively are 30S ribosomal proteins, 30S ribosomal protein S7, chloroplastic, cell division cycle 5-like protein, 50S ribosomal protein, ribosomal protein, ribosomal protein L6 protein, and SRP54 subunit protein. The quality deviations of all identified peptides were mainly distributed within 10 ppm, and MS2 has an ideal andromeda score, with more than 87.82% peptide scores above 60 points, and the median peptide score of 99.28 points. Therefore, the results of this study provide important information for new gene revelation and gene interaction relationship in hardy kiwifruit of chilling injury. PRACTICAL APPLICATIONS: Inhibition of cold damage in hardy kiwifruit under low temperature is very important work for the development of its storage industry. However, many qualities of fruit will deteriorate after long-term cold storage and those biological activities of the fruits are regulated by proteins. It is, therefore, of great significance to reveal the key proteins caused cold damage in hardy kiwifruit. Moreover, the study results could provide a scientific information for the quality improvement and genetic modification of hardy kiwifruit.