Eightly-four novel thioheterocyclic nucleoside derivatives were designed, synthesized, and evaluated for antitumor activity in vitro and in vivo. Most of the compounds inhibited the growth of HCT116 and HeLa cancer cells in vitro, among them 33a and 36b exhibited potent activity against HCT116 cells (IC₅₀ = 0.27 and 0.49 μmol/L, respectively). Both compounds 33a and 36b inhibited cell metastasis, arrested the cell cycle in the G₂/M phase, and induced apoptosis in vitro. Mechanistic studies revealed that 33a and 36b increased ROS levels, led to DNA damage, ER stress, and mitochondrial dysfunction, and inhibited autophagy in HCT116 cells. Biological information analysis, RNA-sequencing, Gene Set Enrichment Analysis (GSEA), drug affinity responsive target stability (DARTS) assay, cellular thermal shift assay (CETSA), and SPR experiments identified that compounds 33a and 36b showed antitumor activity by suppressing the c-MYC pathway. c-MYC silencing assays indicated that c-MYC proteins participated in 33a-mediated anticancer activities in HCT116 cells. More importantly, compound 33a presented favorable pharmacokinetic properties in mice (T _1/2 = 6.8 h) and showed significant antitumor efficacy in vivo without obvious toxicity, showing promising potential for further clinical development.

To summarize the clinical diagnosis and treatment process and genetic test results and characteristics of one child with Angelman syndrome (AS) complicated with oculocutaneous albinism type 2 (OCA2), and to review the literature. "Angelman syndrome" "P gene" and "Oculocutaneous albinism type 2" were used as keywords to search at CNKI, Wanfang, and PubMed databases (from creation to December 2019). Then all the patients were analyzed. The patient in this study was a girl aged 1 year. After birth, she was found to present as white body, yellow hair, and nystagmus. She could raise her head at the age of 2 months and turn over at the age of 7 months. The head circumference was 42 cm and she could not sit alone or speak at present. Trio-based exome sequencing revealed that the patient carried a homozygous mutation of c.168del (p.Gln58ArgfsTer44) in the P gene, and her father was heterozygous and her mother was wild-type. The detection of copy number variation showed deletion on the maternal chromosome at 15q11.2-13.1 region (P gene located in this region) in the patient. Until December 2019, a total of 4 cases in the 4 literature had been reported. Adding our case here, the 5 cases were summarized and found that all the cases showed white skin, golden hair, and shallow iris after birth. Comprehensive developmental delay was found around 6 months of age after birth, and the language remained undeveloped in 2 cases till follow-up into childhood. Seizures occurred in 4 patients. Two cases had ataxia. All the 5 cases had acquired microcephaly. Two cases had a family history of albinism. Electroencephalogram monitoring was completed in 3 cases and the results were abnormal. Genetic tests showed that all the 5 cases had deletion on maternal chromosome at 15q11-13 region. Four cases carried mutation of P gene on paternal chromosome. And 1 case was clinically diagnosed as OCA2 without P gene test. AS combined with OCA2 is relatively rare. OCA2 is easily diagnosed based on the obvious clinical manifestations after birth. When combined with clinical manifestations such as neurodevelopmental delay, it might indicate the possibility of AS that is hardly diagnosed clinically at an early stage. Genetic tests can reveal the cross-genetic phenomenon of AS and OCA2 and the complex of them can be eventually diagnosed.
Female ; Humans ; Albinism, Oculocutaneous/genetics* ; DNA Copy Number Variations ; Membrane Transport Proteins/genetics* ; Molecular Biology ; Mutation ; Infant

Idiopathic asthenozoospermia, a common factor in male infertility, is characterized by altered sperm motility function in fresh ejaculate. Although the β-defensin 126 (DEFB126) protein is associated with asthenozoospermia, DEFB126 gene polymorphisms have not been extensively studied. Therefore, the association between DEFB126 gene polymorphisms and asthenozoospermia requires further investigation. Screening was performed by semen analysis, karyotype analysis, and Y microdeletion detection, and 102 fertile men and 106 men with asthenozoospermia in Chengdu, China, were selected for DEFB126 gene sequence analyses. Seven nucleotide mutations and two nucleotide deletions in the DEFB126 gene were detected. rs11467417 (317-318 del/del), rs11467497 (163-166 wt/del), c.152T>C, and c.227A>G were significantly different between the control and asthenozoospermia groups, likely representing high-risk genetic factors for asthenozoospermia among males. DEFB126 expression was not observed in sperm with rs11467497 homozygous deletion and was unstable in sperm with rs11467417 homozygous deletion. The rs11467497 four-nucleotide deletion leads to truncation of DEFB126 at the carboxy-terminus, and the rs11467417 binucleotide deletion produces a non-stop messenger RNA (mRNA). The above deletions may be responsible for male hypofertility and infertility by reducing DEFB126 affinity to sperm surfaces. Based on in silico analysis, the amino acids 51M and 76K are located in the highly conserved domain; c.152T>C (M51T) and c.227A>G (K76R) are predicted to be damaging and capable of changing alternative splice, structural and posttranslational modification sites of the RNA, as well as the secondary structure, structural stability, and hydrophobicity of the protein, suggesting that these mutations are associated with asthenozoospermia.
Male ; Humans ; Asthenozoospermia/metabolism* ; Sperm Motility/genetics* ; Homozygote ; Polymorphism, Single Nucleotide ; Semen ; Sequence Deletion/genetics* ; Spermatozoa/metabolism* ; Nucleotides/metabolism* ; beta-Defensins/metabolism*

Humans ; Nasopharyngeal Carcinoma/pathology* ; Osteoradionecrosis/pathology* ; Skull Base/surgery* ; Nasopharyngeal Neoplasms/pathology* ; Head

A large number and wide varieties of microorganisms colonize in the human gastrointestinal tract. They construct an intestinal microecological system in the intestinal environment. The intestinal symbiotic flora regulates a series of life actions, including digestion and absorption of nutrient, immune response, biological antagonism, and is closely associated with the occurrence and development of many diseases. Therefore, it is greatly essential for the host's health status to maintain the equilibrium of intestinal microecological environment. After effective compositions of traditional Chinese medicines are metabolized or biotransformed by human intestinal bacteria, their metabolites can be absorbed more easily, and can even decrease or increase toxicity and then exhibit significant different biological effects. Meanwhile, traditional Chinese medicines can also regulate the composition of the intestinal flora and protect the function of intestinal mucosal barrier to restore the homeostasis of intestinal microecology. The relevant literatures in recent 15 years about the interactive relationship between traditional Chinese medicines and gut microbiota have been collected in this review, in order to study the classification of gut microflora, the relationship between intestinal dysbacteriosis and diseases, the important roles of gut microflora in intestinal bacterial metabolism in effective ingredients of traditional Chinese medicines and bioactivities, as well as the modulation effects of Chinese medicine on intestinal dysbacteriosis. In addition, it also makes a future prospect for the research strategies to study the mechanism of action of traditional Chinese medicines based on multi-omics techniques.

Weaning rabbits under the age of 3 months are most susceptible to coccidiosis, which is caused by the infection of 11 Eimeria species.However, no data is available about the susceptibility of rabbits under the age of 3 months.In this study, groups of rabbits at different ages (30 d, 50 d and 70 d) were infected with same dose of sporulated oocysts of Eimeria media or E.irresidua.Oocysts shed in feces during day 1 and day 5 after the infection were counted daily.The total number of oocysts production of 70 d old rabbits infected with E.media only was 3.7 ×107, obviously less than 30 d old rabbits (1.03 ×108) and 50 d rabbits (6.5 ×107).The same phenomenon was seen in rabbits infected with E.irresidua. At the same time, the clinical symptoms of the younger rabbits were obvious, reflecting depression, constipation and diarrhea.These results indicated that weaning rabbits at the age of 30 days are the most susceptible and thus provides clues to the control of coccidiosis in young rabbits.

Eimeria intestinalis is one relatively high pathogenic specie of rabbit coccidia.Fully understanding of its biological characteristics makes great contribution to the control of rabbit coccidiosis.In this study, the pathogenicity and immunogenicity of E.intestinalis ZJK strain was studied on weaning rabbits by investigating clinical syndrome, body weight loss and oocyst output.Four groups of rabbits were inoculated with sporulated oocysts in the dose of 0, 1 ×104 , 1 ×105 and 1 ×106, respectively.Then these rabbits were challenged with 1 ×106 oocysts 21 days post inoculation.The results show that the infection with 1 ×104 oocysts was sufficient to cause clinical syndrome and body weight loss, compared with the control group.And the groups given more oocysts show worse symptom.After challenge, no difference of the body weight gain was seen between non-infected control group and immunized groups; meanwhile, the oocyst output of the immunized rabbits was much lower than that of the non-immunized but challenged control group.These results suggest that E. intestinalis ZJK strain is of mediate pathogenicity and excellent immunogenicity. Therefore, a precocious line of E. intestinalis based on this strain can be a suitable candidate for the development of a live attenuated vaccine for rabbit coccidiosis.

Eimeria spp.of rabbits which cause great economic losses in rabbit industry belong to Phylum Apicomplexa. Since rabbit coccidia contain 11species, which have different pathogenicity between each other, it is necessary to identify the exact species in the feild samples to control rabbit coccidiosis.In order to improve the sensitivity and expand the application of PCR detection, we introduced the Whole Genome Amplification technique to preamplify the DNA template extracted from oocysts, then WGA product were used to amplify the ITS-1 sequence to identify species.The results showed that the optimized method guaranteed higher sensitivity which can identify the species based on single oocyst.Detection of 10 filed samples showed excellent specificity and consistency with morphological identification.By this method, the species that hard to discriminate under microscope can be accurately identified.Application of this method which provides higher sensitivity and specificity could make great effort to the rabbit coccidiosis investigation in practice.

Asian Continental Ancestry Group ; Bartter Syndrome ; genetics ; Child ; Chloride Channels ; genetics ; Humans ; Male ; Mutation