Phylogenetic relationships and genetic differentiation of two Salamandrella species as revealed via COI gene from Northeastern China.

Due to traditional classification methods' limitations, some cryptic species remain undiscovered. To better explore the existence of the Schrenck salamander (Salamandrella tridactyla, a cryptic species of Siberian salamander S. keyserlingii) in China, we conducted a molecular phylogenetic analysis to confirm the taxonomic relationship among Salamandrella species and investigate genetic variation. We used complete sequences of the mitochondrial COI gene from 65 specimens collected across a wide range in Northeastern China. Thirty-five haplotypes were obtained from six populations. They showed medium-high haplotype diversity (Hd) and low nucleotide polymorphism (π). The phylogenetic tree and haplotype network analysis revealed that populations from Greater Khingan Ridge (Huma: HM) and Lesser Khingan Ridge (Tieli: TL) belong to S. keyserlingii, while populations from Changbai Mountain (Shangzhi-zhuziying: SZ, Shangzhi-cuijia: SC, Hailin: HL, and Baishan: BS) belong to S. tridactyla. This indicates the monophyly of Salamandrella and each of the two species. There was a substantial level of genetic differentiation between different species and within populations of the same species. This differentiation was significantly related to geographical distance. At last, the mismatch distribution and neutrality analyses indicated that the TL populations have undergone expansion of history. The study supplements the distributional range of Schrenck salamander. And it provides a theoretical basis for species conservation of Salamandrella species.

Gut microbiota-mediated ursodeoxycholic acids regulate the inflammation of microglia through TGR5 signaling after MCAO.

Ischemic stroke has been demonstrated to cause an imbalance of gut microbiota. However, the change in gut microbiota-mediated bile acids (BAs) metabolites remains unclear. Here, we observed a decrease in gut microbiota-mediated BAs, especially ursodeoxycholic acid (UDCA), in the serum of stroke patients as well as in the intestine, serum and brain of stroke mice. Restoration of UDCA could decrease the area of infarction and improve the neurological function and cognitive function in mice in association with inhibition of NLRP3-related pro-inflammatory cytokines through TGR5/PKA pathway. Furthermore, knocking out TGR5 and inhibiting PKA activity reduce the protective effect of UDCA. Taken together, our results suggest that microbiota-mediated UDCA plays an important role in alleviating inflammatory responses and might be a promising therapeutic target in ischemic stroke.

The association between BMI and serum uric acid is partially mediated by gut microbiota.

Obesity is a risk factor for the development of hyperuricemia, both of which were related to gut microbiota. However, whether alterations in the gut microbiota lie in the pathways mediating obesity's effects on hyperuricemia is less clear. Body mass index (BMI) and serum uric acid (SUA) were separately important indicators of obesity and hyperuricemia. Our study aims to investigate whether BMI-related gut microbiota characteristics would mediate the association between BMI and SUA levels. A total of 6,280 participants from Guangdong Gut Microbiome Project were included in this study. Stool samples were collected for 16S rRNA gene sequencing. The results revealed that BMI was significantly and positively associated with SUA. Meanwhile, BMI was significantly associated with the abundance of 102 gut microbial genera, 16 of which were also significantly associated with SUA. The mediation analysis revealed that the association between BMI and SUA was partially mediated by the abundance of Proteobacteria (proportion mediated: 0.94%, P < 0.05). At the genus level, 25 bacterial genera, including Ralstonia, Oscillospira, Faecalibacterium, etc., could also partially mediate the association of BMI with SUA (the highest proportion is mediated by Ralstonia, proportion mediated: 2.76%, P < 0.05). This study provided evidence for the associations among BMI, gut microbiota, and SUA, and the mediation analysis suggested that the association of BMI with SUA was partially mediated by the gut microbiota. IMPORTANCE Using 16S rRNA sequencing analysis, local interpretable machine learning technique analysis and mediation analysis were used to explore the association between BMI with SUA, and the mediating effects of gut microbial dysbiosis in the association were investigated.

Sex- and Age-Dependent Associations between Parabacteroides and Obesity: Evidence from Two Population Cohort.

Parabacteroides levels are reported to be low in obese individuals, and this genus has shown an anti-obesity capacity in animal studies. Nevertheless, the relationship between Parabacteroides and obesity in different subpopulations, e.g., with respect to age and sex, and its association with subsequent weight change have rarely been explored. The cross-sectional associations of Parabacteroides genus- and species-level OTU abundance with obesity were explored in the Guangdong Gut Microbiome Project (GGMP), which included 5843 adults, and replicated in the Guangzhou Nutrition and Health Study (GNSH), which included 1637 individuals. Furthermore, we assessed the prospective associations of Parabacteroides and its main OTUs' abundance with the subsequent changes in body mass index (BMI) in the GNSH. We found that Parabacteroides was inversely associated with obesity among females and participants aged 40-69 years in the GGMP and the replicated cohort in the GNSH. After a 3-year follow-up, there was no significant correlation between Parabacteroides and the subsequent changes in BMI. However, Seq4172 (P. johnsonii) showed a negative correlation with subsequent BMI changes in the female and middle-aged (40-69 years) subpopulations. Overall, our results indicate that Parabacteroides have an inverse relationship with obesity and that Seq4172 (P. johnsonii) have a negative association with subsequent changes in BMI among females and middle-aged populations in perspective analyses.

Effects of Sheep Bone Collagen Peptide on Liver Lipid Deposition in Ovariectomized Rats.

Liver can be directly involved in the synthesis and decomposition of fatty acids. Liver lipid deposition is one of the most common chronic liver diseases. Estrogen deficiency can cause lipid deposition and energy metabolism disorders in the liver. Sheep bone collagen peptide (SBCP) has been shown to have estrogen-like effects in previous studies. And SBCP has high bioavailability, safety and non-toxic side effects. This study aimed to investigate the effect of SBCP on liver lipid deposition (LLD) caused by estrogen deficiency. Female Wistar rats were treated as follows (n=10): sham group: underwent peri-ovary fat removal operations, ovariectomized rats (model group), ovariectomized rats receiving SBCP treatments: SBCP high dose group (SBCP-H), SBCP medium dose group (SBCP-M) and SBCP low dose group (SBCP-L). After 8 wk, the model group demonstrated severe LLD and liver pathological changes, with increased malondialdehyde (MDA) and free fatty acid (FFA) levels (p<0.05). Additionally, the total superoxide dismutase (T-SOD) activity (p<0.05), serum albumin-to-globulin (A/G) ratio (p<0.05), amount of butyric acid-producing bacteria and short-chain fatty acids (SCFAs) content decreased. SBCP intervention could inhibit the occurrence of LLD and alleviate the liver histopathological damage induced by estrogen deficiency by relieving oxidative stress, preventing the loss of butyric acid-producing bacteria, and decreasing the abundance of Lactobacillus reuteri in the gut. The results suggested that SBCP could improve the LLD indecued by estrogen deficiency.

The novel cereblon modulator CC-885 inhibits mitophagy via selective degradation of BNIP3L.

Mitophagy is a degradative pathway that mediates the degradation of the entire mitochondria, and defects in this process are implicated in many diseases including cancer. In mammals, mitophagy is mediated by BNIP3L (also known as NIX) that is a dual regulator of mitochondrial turnover and programmed cell death pathways. Acute myeloid leukemia (AML) cells with deficiency of BNIP3L are more sensitive to mitochondria-targeting drugs. But small molecular inhibitors for BNIP3L are currently not available. Some immunomodulatory drugs (IMiDs) have been proved by FDA for hematologic malignancies, however, the underlining molecular mechanisms are still elusive, which hindered the applications of BNIP3L inhibition for AML treatment. In this study we carried out MS-based quantitative proteomics analysis to identify the potential neosubstrates of a novel thalidomide derivative CC-885 in A549 cells. In total, we quantified 5029 proteins with 36 downregulated in CRBN+/+ cell after CC-885 administration. Bioinformatic analysis showed that macromitophagy pathway was enriched in the negative pathway after CC-885 treatment. We further found that CC-885 caused both dose- and time-dependent degradation of BNIP3L in CRBN+/+, but not CRBN-/- cell. Thus, our data uncover a novel role of CC-885 in the regulation of mitophagy by targeting BNIP3L for CRL4CRBN E3 ligase-dependent ubiquitination and degradation, suggesting that CC-885 could be used as a selective BNIP3L degradator for the further investigation. Furthermore, we demonstrated that CC-885 could enhance AML cell sensitivity to the mitochondria-targeting drug rotenone, suggesting that combining CC-885 and mitochondria-targeting drugs may be a therapeutic strategy for AML patients.

Studies of acute and subchronic systemic toxicity associated with a copper/low-density polyethylene nanocomposite intrauterine device.

INTRODUCTION: The physiologic safety of devices and materials intended for clinical implantation should be evaluated. This study, a logical extension of our previous work, aimed to investigate the safety of a novel contraceptive device, the copper/low-density polyethylene nanocomposite intrauterine device (nano-Cu/LDPE IUD), through studies of its potential toxicity after acute and subchronic administration in mice and rats. METHODS: For the acute toxicity study, single 50 mL/kg doses of nano-Cu/LDPE IUD extracts were administered to mice via intravenous or intraperitoneal injection. General behavioral adverse effects, mortality, and body weights were evaluated for up to 72 hours. In the 13-week subchronic toxicity study, the nano-Cu/LDPE composite with 10-fold higher than the standard clinical dose was implanted subcutaneously into the dorsal skin of Wistar rats. The control group underwent a sham procedure without material insertion. RESULTS: During all acute study observation times, the biologic reactions of the mice in the nano-Cu/LDPE group did not differ from those observed in the control group. The groups did not differ statistically in terms of body weight gain, and no macroscopic changes were observed in any organs. In the subchronic study, no clinical signs of toxicity or mortality were observed in either the nano-Cu/LDPE or control group during the 13-week period. The nano-Cu/LDPE composite did not cause any alterations in body weight, food consumption, hematologic and biochemical parameters, or organ weight relative to the control for any observed sample group. Histopathologic examinations of the organs revealed normal architecture, indicating that the inserted material did not cause morphologic disturbances in the rats. CONCLUSION: Overall, the results indicate that the nano-Cu/LDPE IUD did not induce systemic toxicity under experimental conditions of the recommended standard practices, suggesting that the novel material IUD is safe and feasible for future contraceptive applications.

FBXW8-dependent degradation of MRFAP1 in anaphase controls mitotic cell death.

Mof4 family associated protein 1 (MRFAP1) is a 14 kDa nuclear protein, which involves in maintaining normal histone modification levels by negatively regulating recruitment of the NuA4 (nucleosome acetyltransferase of H4) histone acetyltransferase complex to chromatin. MRFAP1 has been identified as one of the most up-regulated proteins after NEDD8 (neural precursor cell expressed developmentally down-regulated 8) inhibition in multiple human cell lines. However, the biological function of MRFAP1 and the E3 ligase that targets MRFAP1 for destruction remain mysterious. Here we show, by using an immunoprecipitation-based proteomics screen, that MRFAP1 is an interactor of the F-box protein FBXW8. MRFAP1 is degraded by means of the ubiquitin ligase Cul7/FBXW8 during mitotic anaphase-telophase transition and accumulated in mitotic metaphase. Overexpression of FBXW8 increased the polyubiquitination and decreased the stability of MRFAP1, whereas knockdown of FBXW8 prolonged the half-life of MRFAP1. Moreover, forced expression of MRFAP1 in HeLa cells caused growth retardation and genomic instability, leading to severe mitotic cell death. Thus, Cul7/FBXW8-mediated destruction of MRFAP1 is a regulatory component monitoring the anaphase-telophase transition and preventing genomic instability.

MicroRNA-132 targets PEA-15 and suppresses the progression of astrocytoma in vitro.

Gliomas are highly malignant tumors, the most common of which are astrocytomas. A growing number of studies suggest that dysregulation of miRNAs is a frequent event contributing to the pathogenesis of gliomas. In this study, we found that over-expression of miR-132 inhibited cell proliferation and migration and triggered apoptosis, while knockdown of miR-132 showed opposite effects. PEA-15 was identified as a direct target of miR-132. Reintroduction of PEA-15 without 3'UTR region reversed the inhibitory effects of miR-132 on cell proliferation, migration, and apoptosis. MiR-132 was inversely correlated with the PEA-15 expression. CREB (cAMP response element binding protein) and KLF (Krüppel-like factor 8) were conformed as transcription factors of miR-132, which bidirectionally regulate the expression of miR-132. Our study suggests that miR-132 is an important tumor suppressor of astrocytoma progression by targeting PEA-15, while CREB and KLF can modulate the expression of miR-132, thus providing new insight into the molecular mechanisms underlying astrocytoma progression in vitro.

Biological evaluation of the copper/low-density polyethylene nanocomposite intrauterine device.

Devices and materials intended for clinical applications as medical and implant devices should be evaluated to determine their biocompatibility in physiological systems. This article presents results from cytotoxicity assay of L929 mouse fibroblasts culture, tests for skin irritation, intracutaneous reactivity and sensitization, and material implantation tests for the novel copper/low-density polyethylene nanocomposite intrauterine device (nano-Cu/LDPE IUD) with potential for future clinical utilization. Cytotoxicity test in vitro was conducted to evaluate the change in morphology, growth and proliferation of cultured L929 mouse fibroblasts, which in vivo examination for skin irritation (n = 6) and intracutaneous reactivity (n = 6) were carried out to explore the irritant behavior in New Zealand White rabbits. Skin sensitization was implemented to evaluate the potential skin sensitizing in Hartley guinea pigs (n = 35). The materials were implanted into the spinal muscle of rabbits (n = 9). The cytotoxicity grade of the nano-Cu/LDPE IUD was 0-1, suggested that the composite was nontoxic or mildly cytotoxic; no irritation reaction and skin sensitization were identified in any animals of specific extracts prepared from the material under test; similarly to the control sides, the inflammatory reaction was observed in the rabbits living tissue of the implanted material in intramuscular implantation assay. They indicated that the novel composite intrauterine device presented potential for this type of application because they meet the requirements of the standard practices recommended for evaluating the biological reactivity. The nano-Cu/LDPE IUD has good biocompatibility, which is biologically safe for the clinical research as a novel contraceptive device.

Effect of Xeroderma pigmentosum complementation group F polymorphisms on gastric cancer risk and associations with H.pylori infection.

We conducted a hospital case-control study by genotyping four potential functional single nucleotide polymorphisms (SNPs) to assess the association of Xeroderma pigmentosum complementation group F (XPF) with gastric cancer susceptibility, and role of XPF polymorphisms in combination with H.pylori infection in risk definition. A total of 331 patients with gastric cancer and 355 controls were collected. Four SNPs of XPF, rs180067, rs1799801, rs2276466 and rs744154, were genotyped by Taqman real-time PCR method with a 7900 HT sequence detector system. The gastric cancer patients were more likely to have smoking habit, a family history of cancer and H.pylori infection. We did not find any significant difference in the genotype distributions of XPF rs180067, rs1799801, rs2276466 and rs744154 between cases and controls. However, multivariate logistic analysis showed a non-significant decreased risk in patients carrying rs180067 G allele, rs1799801 T allele or rs2276466 T allele genotypes. A non-significant increased risk of gastric cancer was found in individuals carrying the rs744154 GG genotype. Stratification by H.pylori infection and smoking was not significantly different in polymorphisms of XPF rs180067, rs1799801, rs2276466 and rs744154. The four XPF SNPs did not show significant interaction with H.pylori infection and smoking status (P for interaction was 0.35 and 0.18, respectively). Our study indicated that polymorphisms in rs180067, rs1799801, rs2276466 and rs744154 may affect the risk of gastric cancer but further large sample size studies are needed to validate any association.

[The changes of gastric diseases during the past twenty five years].

OBJECTIVES: To study the changes of duodenal ulcer, gastric ulcer, gastric cancer and Helicobacter pylori (Hp) infectious status, according to the clinical data of endoscopy in our hospital during the past 25 years. METHODS: The patients with duodenal ulcer, gastric ulcer and gastric cancer diagnosed by endoscopy and pathology had been selected, 104 987 general endoscope cases during the period from Jan. 1980 to Dec. 2004. The general cases were divided into 8 age groups as follows: 10-< 20 years old, 20-< 30 years old, 30-< 40 years old, 40-< 50 years old, 50-< 60 years old, 60-< 70 years old, 70-< 80 years old and > or = 80 years old. RESULTS: The average detected rate of duodenal ulcer, gastric ulcer, and gastric cancer are 13.03%, 4.19% and 1.68% respectively. The detected rate of gastric ulcer was decreased after 1996. The detected rate of duodenal ulcer was decreased after 1999. The gastric cancer detected rate fluctuate between 1.02% and 2.36%. The average ages of duodenal ulcer, gastric ulcer and gastric cancer are 41.8, 50.7 and 59.4 respectively. The tendency of average age shows ascendant. In all patients, the detected rate of Hp showed slightly descendent after 1999. CONCLUSIONS: The diagnostic age of duodenal ulcer, gastric ulcer and gastric cancer shows ascendant tendency; The detected rates of duodenal ulcer, gastric ulcer show descendent tendency; There is no apparent change in the detected rate of gastric cancer. The Hp detected rate shows descendent tendency slightly.