Causal inference between pernicious anemia and cancers: a bidirectional two-sample mendelian randomization analysis.

BACKGROUND: Observational study investigated the association between pernicious anemia (PA) and cancers. However, with the exception of gastric cancer, the results are mostly contradictory. The purpose of this study was to investigate the potential causal relationship between PA and cancers through bidirectional two-sample Mendelian randomized (MR) analysis. METHODS: The European sample FinnGen project provided the genetic summary data for PA and 20 site-specific cancers. This bidirectional two-sample MR design mainly used the inverse variance weighting (IVW) method to evaluate the causal relationship between PA and cancer risk. Benjamini-Hochberg correction was performed to reduce the bias caused by multiple tests. RESULTS: Our study shows that there was a causal relationship between PA and gastric cancer, prostate cancer, testicular cancer and malignant melanoma of skin, and there was a reverse causal relationship between prostate cancer or gastric cancer and PA (P < 0.05). After Benjamini-Hochberg correction test, there was still a causal correlation between PA and gastric or prostate cancer (P' < 0.05), while there was only an implied causal association between PA and testicular cancer and malignant melanoma of skin (P'> 0.05). There was still a reverse causal relationship between gastric cancer and PA (P'< 0.05), while prostate cancer shows an implied reverse causal relationship(P'> 0.05). In addition, MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy. CONCLUSIONS: PA may be genetically associated with testicular cancer, prostate cancer, gastric cancer, and malignant melanoma of skin.

Adipose Derived Mesenchymal Stem Cells-Derived Mitochondria Transplantation Ameliorated Erectile Dysfunction Induced by Cavernous Nerve Injury.

PURPOSE: Erectile dysfunction (ED) is a common postoperative complication of pelvic surgery for which there is currently no effective treatment. This study investigated the therapeutic effects and potential mechanisms of adipose derived mesenchymal stem cells-derived mitochondria (ADSCs-mito) transplantation in a rat model of bilateral cavernous nerve injury (CNI) ED. MATERIALS AND METHODS: We isolated mitochondria from ADSCs and tested their quality. In vivo, twenty male Sprague Dawley rats were randomly divided into four groups: sham operation group and CNI groups that received intracavernous injection of either phosphate buffer solution, ADSCs-mito or ADSCs. Two weeks after therapy, the erectile function of the rats was evaluated and the penile tissues were harvested for histologic analysis and western blotting. In vitro, the apoptosis rate, reactive oxygen species (ROS), mitochondria derived active oxygen (mtROS) and adenosine triphosphate (ATP) levels were detected in corpus cavernosum smooth muscle cells (CCSMCs) after the incubation with ADSCs-mito. In addition, intercellular mitochondrial transfer was visualized by co-culture of ADSCs and CCSMCs. RESULTS: The ADSCs, ADSCs-mito and CCSMCs were isolated and identified successfully. ADSCs-mito transplantation notably restored the erectile function and smooth muscle content of CNI ED rats. Moreover, the levels of ROS, mtROS and cleaved-caspase 3 were reduced and the levels of superoxide dismutase and ATP were increased after ADSCs-mito transplantation. In CNI ED rats, the mitochondrial structure of cells in penile tissues was destroyed. ADSCs could transfer its own mitochondria to CCSMCs. Pre-treatment with ADSCs-mito could significantly decrease apoptosis rate, ROS levels and mtROS levels as well as restore the ATP level in CCSMCs. CONCLUSIONS: ADSCs-mito transplantation significantly ameliorated ED induced by CNI, with similar potency to ADSCs treatment. The ADSCs-mito might exert their effects via anti-oxidative stress, anti-apoptosis and modulating energy metabolism of CCSMCs. Mitochondrial transplantation should be a promising therapeutic method for treating CNI ED in the future.

Ultrasound-targeted microbubble destruction mediates PDE5i/NO integration for cavernosum remodeling and penile rehabilitation.

Erectile dysfunction (ED) caused by cavernous nerve injury (CNI) is refractory to heal mainly ascribed to the adverse remodeling of the penis induced by ineffectual microvascular perfusion, fibrosis, and neurotrophins scarcity in cavernosum. Phosphodiesterase type V inhibitors (PDE5i) have been regarded as an alternative candidate drug for avoiding penile neuropathy. However, the therapeutic efficacy is severely limited due to poor accumulation under systemic medication and endogenous nitric oxide (NO) deficiency in cavernosum. Herein, an innovative liposomal microbubble (MB) loaded with both Sildenafil (one of PDE5i) and NO was designed. Ultrasound-targeted MB destruction (UTMD)-mediated efficient release and integration erectogenic agents into corpus cavernosum with high biosafety. On a bilateral CNI rat model, the multifunctional MB-cooperated UTMD improved microvascular perfusion in penis, simultaneously, alleviated hypoxia and oxidative stress, indicating successful activation of NO-cyclic guanosine monophosphate pathway. Also, evaluation of the endothelial/muscular composition, intracavernosal pressure, and neural integrity in the penis proved that coordinated intervention reversed the abnormal structural remodeling and promoted the recovery of functional erection. Our work demonstrates that MB loading Sildenafil and NO combined with UTMD hold great promise to "awaken" the efficacy of PDE5i in neurogenic ED, which provided a superior option for ensuring penile rehabilitation.

Bibliometric Analysis of Global Trends in Research on Seasonal Variations in Gut Microbiota from 2012 to 2022.

Seasons are the important influencing factor for gut microbiota, which in turn affects the ecology and evolution of the host. The seasonal variation in gut microbiota has increasingly attracted the attention of researchers and professionals worldwide. However, studies of seasonal variations in gut microbiota have not been systematically analyzed by bibliometrics or visual analysis. This study is based on 271 publications from 2012 to 2022 in the Web of Science Core Collection database (WOSCC) to analyze hot spots and trends in this field. The collaborations between different countries, institutions, authors, journals, and keywords were bibliometrically analyzed using Excel, CiteSpace (Version 6.2. R4), and VOSviewer (version 1.6.19) software. The number of publications has been increasing rapidly and shows a general upward trend. China and the Chinese Academy of Sciences are the country and institution contributing the most, respectively. The research hotspots and trends mainly include the diversity of gut microbiota communities in different seasons, the relationship between diet and gut microbiota in seasonal changes, and the relationship between gut microbiota and evolutionary adaptation in seasonal changes. This is the first bibliometric and visualization analysis of seasonal variations in gut microbiota, which may advance this field and lay the foundation for future research.

Overexpression of PRDX2 in Adipose-Derived Mesenchymal Stem Cells Enhances the Therapeutic Effect in a Neurogenic Erectile Dysfunction Rat Model by Inhibiting Ferroptosis.

Neurogenic erectile dysfunction (NED) is a common and serious complication after pelvic surgery. The clinical translation of adipose-derived mesenchymal stem cell (ADSC) therapies in NED remains a major challenge due to their low survival rate and limited therapeutic effect. Peroxiredoxin 2 (PRDX2) is a member of the peroxidase family that exerts its therapeutic effects by inhibiting oxidative stress (OS) and ferroptosis, and PRDX2 is expected to enhance the therapeutic effect of ADSCs in treating NED. The purpose of this study was to investigate whether PRDX2 could improve the survival of ADSCs and determine whether overexpression of PRDX2 in ADSCs (PRDX2-ADSCs) could enhance the therapeutic effect of NED. This study investigated the potential role of PRDX2-ADSCs through a NED model induced by bilateral cavernous nerve injury (BCNI) and three in vitro models established by H2O2-stimulated ADSCs, H2O2-stimulated corpus cavernosum smooth muscle cells (CCSMCs), and RSL3-stimulated CCSMCs. We found that PRDX2 could significantly improve the viability of ADSCs by suppressing apoptosis and OS in H2O2-stimulated ADSCs. We also found that BCNI triggered ferroptosis of the corpus cavernosum, which was manifested by increased reactive oxygen species (ROS), total iron content, and MDA as well as decreased SOD and GSH. Our results further demonstrated changes in the expression of key proteins (GPX4 and ACSL4) in the ferroptosis pathway, whereas PRDX2-ADSCs ameliorated BCNI-induced erectile dysfunction and ferroptosis of the corpus cavernosum in NED rats. Consistently, PRDX2-ADSCs attenuated OS in H2O2-stimulated CCSMCs and inhibited ferroptosis in RSL3-stimulated CCSMCs, as evidenced by the decrease in ROS, total iron content, and MDA and the increase in SOD and GSH together with changes in ferroptosis-related protein (GPX4 and ACSL4) expression. In conclusion, overexpression of PRDX2 in ADSCs enhanced the therapeutic effect in a rat model of neurogenic erectile dysfunction by inhibiting ferroptosis via regulation of the GPX4/ACSL4 axis.

Melatonin-Primed Mesenchymal Stem Cells-Derived Small Extracellular Vesicles Alleviated Neurogenic Erectile Dysfunction by Reversing Phenotypic Modulation.

Erectile dysfunction (ED) is an adverse side effect of pelvic surgery with no effective treatment. In this study, it is explored whether melatonin could improve the therapeutic effects of small extracellular vesicles (sEVs), derived from mesenchymal stem cells (MSCs), on cavernous nerve injury (CNI) ED, and the underlying mechanisms are investigated. The sEVs from melatonin-pretreated MSCs (MT-EVs) and MSCs (NC-EVs) are isolated and applied to CNI ED. Transplantation of MT-EVs remarkably increases erectile function and reduces phenotypic modulation in CNI ED rats. The therapeutic effects of MT-EVs are superior to those of NC-EVs. Sequencing implies that miR-10a-3p is enriched in MT-EVs, and directly targets the protein kinase inhibitor α (PKIA). After the suppression of miR-10a-3p, the therapeutic actions of MT-EVs are abolished, but are rescued by PKIA. Similarly, RhoA/ROCK is inhibited by MT-EVs, but this action is reversed by suppressing miR-10a-3p, accompanied by corresponding changes in PKIA. In conclusion, transplantation of MT-EVs could significantly alleviate CNI ED. MT-EVs may relieve the phenotypic modulation of the corpora cavernosum smooth muscle cells via the miR-10a-3p/PKIA/RhoA/ROCK signaling axis. These nanovesicles should be potential therapeutic vectors or bioactive materials for CNI ED.

A novel nomogram for anastomotic leakage after surgery for rectal cancer: a retrospective study.

Background: Anastomotic leakage remains one of the most common serious complications after rectal cancer surgery. How to predict its occurrence and prevent it remains largely elusive. Objective: This study aimed to identify the risk factors of anastomotic leakage and construct a nomogram for predicting postoperative anastomotic leakage in patients with rectal cancer. Methods: The data of 406 patients with rectal cancer after gastrointestinal surgery in the Third Affiliated Hospital of Sun Yat-sen University from January 2011 to May 2020 were collected (243 in the training set and 163 in the testing set). Logistic regression was applied to determine the risk factors of postoperative anastomotic leakage of rectal cancer, and a nomogram prediction model was thus established. Predictive performance of the nomogram was evaluated by C-index and area under the receiver-operating characteristic (ROC) curve. Results: Logistic regression analysis showed that preoperative bowel obstruction (odds ratio [OR] = 12.846, 95% confidence interval CI [1.441-114.54], p = 0.022) and early first defecation after surgery (OR = 0.501, 95% CI [0.31-0.812], p = 0.005) were independent risk factors, which could be used to develop a nomogram to predict the occurrence of anastomotic leakage accurately. The evaluation of the prediction model shows that the C-index value of the model was 0.955, the area under the ROC curve (AUC) of the training set was 0.820, and the testing set was 0.747, whereas the optimal cut-off point based on the nomogram score was 174.6. Conclusion: This nomogram had a good prediction ability for postoperative anastomotic leakage in patients with rectal cancer. It can provide a reference for perioperative treatment and the selection of surgical methods to promote individualized and accurate treatment.

Analysis of genetic information from the antlers of Rangifer tarandus (reindeer) at the rapid growth stage.

Reindeer is the only deer species in which both males and females regularly grow antlers, providing an excellent model for studying the rapid growth and annual regeneration of antlers. The study of genetic information from reindeer is the basis for revealing the unique mechanism of antler growth. In the present study, we obtained 18.86 GB of clean reads, which were assembled to obtain 94,575 unigenes (average length: 704.69). Among these reads, 30,980 sequences were identified by searching a database of known proteins and then annotated with Gene Ontology (GO) terms, Clusters of Orthologous Groups (COG) classifications and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. All 7,480 simple sequence repeats (SSRs) were detected. A total of 84,435 and 82,226 high-quality single-nucleotide polymorphisms (SNPs) were identified in male and female reindeer, respectively. We identified 31 genes that were highly expressed in reindeer antlers. These genes regulate cell activities that are closely associated with the process of rapid tissue growth. Our results provide a basis for studying reindeer antlers and for further studying the molecular genetics, population genetics, and functional genomics of reindeer.

Significance of neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio and prognostic nutritional index for predicting clinical outcomes in T1-2 rectal cancer.

BACKGROUND: Inflammation-related parameters have been revealed to have prognostic value in multiple caners. However, the significance of some inflammation-related parameters, including the peripheral blood neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) and prognostic nutritional index (PNI), remains controversial in T1-2 rectal cancer (RC). METHODS: Clinical data of 154 T1-2 RC patients were retrospectively reviewed. The cut-off values for NLR, PLR, LMR, and PNI were determined by receiver operating characteristic curves. The relationships of these parameters with postoperative morbidities and prognosis were statistically analysed. RESULTS: The optimal cut-off values for preoperative NLR, PLR, LMR and PNI were 2.8, 140.0, 3.9, and 47.1, respectively. Significant but heterogeneous associations were found between NLR, PLR, LMR and PNI and clinicopathological factors. In addition, high NLR, high PLR, and low PNI were correlated with an increased postoperative morbidity rate. Patients with high NLR/PLR or low LMR/PNI had lower OS and DFS rates. On multivariate analysis, only high NLR was identified as an independent risk factor for poor DFS. CONCLUSIONS: NLR, PLR, and PNI are valuable factors for predicting postoperative complications in T1-2 RC patients. A preoperative NLR of more than 2.8 is an independent prognostic factor for poor DFS in T1-2 RC patients.

Origins of Chinese reindeer (Rangifer tarandus) based on mitochondrial DNA analyses.

The most southern population of reindeer (Rangifer tarandus) inhabits northeastern China, but the migration route and origin of this population have not been confirmed. The sequences of mitochondrial DNA control regions from domestic and wild herds from Eurasia and China were analysed. The results showed that the Chinese reindeer population originated independently from north-central Russian domestic herds, belonging to a large reindeer population that was present across Beringia during the last glacial period. Some studies have reported that the Chinese reindeer population is closely related to wild forest reindeer herds in Russia. Our results, however, indicate that wild forest reindeer herds of southeastern Russia contributed little or nothing to the Chinese reindeer herd gene pool. Chinese reindeer herds have a much greater genetic similarity to more northerly distributed tundra-type herds that inhabit open areas. The present findings will be essential for future conservation planning for Chinese reindeer.

DNA methylation and mRNA expression of COL6A3 in antler mesenchyme of female and male reindeer.

BACKGROUD: Reindeer is the only deer species that both male and female produce antlers, which provides a particularly interesting case in studying the differences between antlers of the two sexes. Alpha 3(VI) Collagen Gene (COL6A3), forms a microfibrillar network associated with the structural integrity and biomechanical properties, has been found to be one of the differentially expressed genes in antler mesenchyme of female and male reindeer. OBJECTIVE AND METHODS: The promoter sequence of reindeer COL6A3 gene was obtained using the cloning technology and analyzed by the bioinformatics methods. Bisulfite sequencing PCR (BSP) was used to detect the methylation status of the COL6A3 promoter in reindeer antler mesenchyme. Real-time quantitative PCR was used to detect COL6A3 expression in the antler mesenchyme of female and male reindeer. RESULTS: Sequence analysis revealed that the reindeer COL6A3 partial promoter sequence was 983 bp including the possible promoter region at + 105 bp to + 155 bp. Homology and phylogenetic analysis indicated that the COL6A3 promoter of reindeer had the closest genetic distance with Bos taurus, Capra hircus and Ovis aries. BSP results indicated that the methylation level of COL6A3 promoter in the female reindeer antler mesenchyme was significantly higher than in the male. Correlating with increased methylation status, we also found that COL6A3 mRNA expression in female reindeer antler mesenchyme was significantly lower than in the male. CONCLUSION: The higher methylation level of the COL6A3 gene in female reindeer antler mesenchyme coincides with decreased COL6A3 mRNA expression, thereby affecting the transposon silencing mechanism and possibly contributing to apparent differences of antlers in female and male reindeer.

Metagenomic analysis of captive Amur tiger faecal microbiome.

BACKGROUND: The gastrointestinal tracts of animals are home to large, complex communities of microbes. The compositions of these communities ultimately reflect the coevolution of microorganisms with their animal host and are influenced by the living environment, diet and immune status of the host. Gut microbes have been shown to be important for human disease and health, but little research exists in the gut microbiome of the Amur tiger, which is one of the most endangered species in the world. RESULTS: In this study, we present the use of whole-metagenome shotgun sequencing to analyze the composition and functional structures of the gut microbiota in captive Amur tigers. Our results showed a high abundance of four major phyla in captive Amur tigers, including Proteobacteria, Firmicutes, Actinobacteria and Fusobacteria. Moreover, at the genus level, Escherichia, Collinsella and Fusobacterium were most abundant in the captive Amur tiger fecal metagenome. At the species level, Escherichia coli, Fusobacterium ulcerans and Fusobacterium varium were the species with highest abundances in the captive Amur tiger gut microbiota. The primary functional categories of the Amur tiger faecal metagenome were associated mainly with Carbohydrate metabolism, Membrane transport and Amino acid metabolism based on the KEGG pathway database. The comparative metagenomic analyses showed that the captive Amur tiger fecal metagenome had a lower abundance of Spirochaetes, Cyanobacteria and Ascomycota than other animals, and the primary functional categories were primarily associated with carbohydrate metabolism subsystems, clustering-based subsystems and protein metabolism. CONCLUSIONS: We presented here for the first time the use of the shotgun metagenomic sequencing approach to study the composition and functional structures of the gut microbiota in captive Amur tiger.

Metagenomic analysis revealed the effects of goat milk feeding and breast feeding on the gut microbiome of Amur tiger cubs.

BACKGROUND: Ingredients in breast milk can help establish a healthy community of microorganisms in the infant gut, but no research exists regarding the effects of goat milk feeding and breast feeding on the gut microbiome of the Amur tiger, which is one of the most endangered species in the world. METHODS: In this study, we used whole-metagenome shotgun sequencing to analyze the effects of two different feeding patterns, goat milk feeding and breast feeding, on the composition and functional structures of gut microbiota in Amur tiger cubs. RESULTS: Goat milk-fed cubs have fewer beneficial bacteria and more pathogenic bacteria and a higher microbial diversity in their gut than breastfed cubs. A total of 15 genera showed statistically significant differences; the relative abundances of Streptomyces scabiei, Streptomyces avermitilis and Streptomyces davawensis were significantly decreased, whereas those of Niabella soli, Aeromonas media and Brochothrix thermosphacta were significantly increased in the goat milk-fed group compared with those in the breastfed group. At the functional level, carbohydrate metabolism, translation and replication and repair decreased, and amino acid metabolism, membrane transport and metabolism of cofactors and vitamins increased in the gut microbiota of goat milk-fed cubs compared with breastfed cubs. CONCLUSION: Our results indicate for the first time that the different milk feeding patterns of goat milk feeding and breast feeding can change the composition and functional structures of gut microbiota in Amur tiger cubs and that breastfed tiger cubs and goat milk-fed tiger cubs have distinct microbiotas in their guts.

Variations in gut microbiota and fecal metabolic phenotype associated with Fenbendazole and Ivermectin Tablets by 16S rRNA gene sequencing and LC/MS-based metabolomics in Amur tiger.

BACKGROUND: The Amur tiger is one of the most endangered species in the world, and the healthy population of captive Amur tigers assists the recovery of the wild population. Gut microbes have been shown to be important for human disease and health, but little research exists regarding the microbiome of Amur tigers in captivity. METHODS: In this study, we used an integrated approach of 16S rRNA gene sequencing combined with ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS)-based metabolomics to analyze the effects of Fenbendazole and Ivermectin Tablets on the gut microbiota and fecal metabolic phenotype of the Amur tiger. RESULTS: The relative abundances of the bacterial genera Collinsella, Clostridium XI and Megamonas were decreased, whereas those of Escherichia and Clostridium sensu stricto were increased in experimental Amur tigers compared with those in normal controls. Meanwhile, distinct changes in the fecal metabolic phenotype of the experimental Amur tigers were also found, including lower levels of acrylic acid, acetoacetate and catechol and higher amounts of 5,6-dihydrouracil, adenine hydrochloride hydrate and galactitol. Moreover, the differentially abundant gut microbes were substantially associated with the altered fecal metabolites, especially the bacteria in the Firmicutes and Actinomycetes, which were involved in the metabolism of 5,6-dihydrouracil, 6-phospho-d-gluconate and 1-methylnicotinamide. CONCLUSION: Our results indicate for the first time that Fenbendazole and Ivermectin Tablets not only disturb the gut microbiota at the abundance level but also alter the metabolic homeostasis of the Amur tiger.

Analysis on Genetic Diversity of Reindeer (Rangifer tarandus) in the Greater Khingan Mountains Using Microsatellite Markers.

Jian-Cheng Zhai, Wei-Shi Liu, Ya-Jie Yin, Yan-Ling Xia, and He-Ping Li (2017) The only population of reindeer (Rangifer tarandus) in China, herded extensively by the Ewenki people, is the most southern population in the world. Genetic diversity plays a key role in the survival of endangered reindeer. To systematically understand the genetic variability of reindeer in China, 163 individuals from 8 populations were analyzed using 11 microsatellite loci. A total of 85 alleles were detected and the average number of alleles per locus was 7.7. The observed heterozygosity and expected heterozygosity ranged from 0.3736 to 0.5299 and from 0.6491 to 0.7608. Hardy-Weinberg equilibrium analysis indicated that a de ciency of heterozygotes existed in all eight populations. Both the FST and AMOVA analyses showed a low level of genetic di erentiation among populations. UPGMA dendrogram revealed that population SYL formed one cluster, separating from the other populations. Then the GWQ and YSH populations formed another cluster and clustered with the BDX, BLJY, DML, DW and MLYS populations. Increasing the current exchange rate of reindeer among different populations and establishing natural reserve may be the e ective approaches to conserve the fragile reindeer populations in China.