Exploring the mediating role of calcium homeostasis in the association between diabetes mellitus, glycemic traits, and vascular and valvular calcifications: a comprehensive Mendelian randomization analysis.

BACKGROUND: The interplay between diabetes mellitus (DM), glycemic traits, and vascular and valvular calcifications is intricate and multifactorial. Exploring potential mediators may illuminate underlying pathways and identify novel therapeutic targets. METHODS: We utilized univariable and multivariable Mendelian randomization (MR) analyses to investigate associations and mediation effects. Additionally, the multivariable MR analyses incorporated cardiometabolic risk factors, allowing us to account for potential confounders. RESULTS: Type 2 diabetes mellitus (T2DM) and glycated hemoglobin (HbA1c) were positively associated with both coronary artery calcification (CAC) and calcific aortic valvular stenosis (CAVS). However, fasting glucose (FG) was only linked to CAVS and showed no association with CAC. Additionally, CAVS demonstrated a causal effect on FG. Calcium levels partially mediated the impact of T2DM on both types of calcifications. Specifically, serum calcium was positively associated with both CAC and CAVS. The mediation effects of calcium levels on the impact of T2DM on CAC and CAVS were 6.063% and 3.939%, respectively. The associations between T2DM and HbA1c with calcifications were influenced by body mass index (BMI) and smoking status. However, these associations were generally reduced after adjusting for hypertension. CONCLUSION: Our findings suggest a genetically supported causal relationship between DM, glycemic traits, and vascular and valvular calcifications, with serum calcium playing a critical mediating role.

Newly recognized orbital malformations in kabuki syndrome: A case report.

Kabuki syndrome (KS) is a rare congenital disorder with distinctive characteristics. Herein, we describe a KS patient carrying a novel mutation in the KMT2D gene, c.11785C > T (p.Gln3929*). The patient presented with typical eyelid deformities, including eversion of the lateral lower eyelids, long palpebral fissures, hypertelorism, and medial epicanthus. Orbital computed tomography revealed orbital bone malformation with temporally and inferiorly displaced zygomatic bone. The bilateral orbits were shallow with an enlarged angle between the lateral walls. Zygomatic and maxillary bone dysplasia were also observed. Orbital bone anomalies are thought to be one of the characteristics of KS.

Characterization of Volatile Compounds in Donkey Meat by Gas Chromatography-Ion Mobility Spectrometry (GC-IMS) Combined with Chemometrics.

Volatile compounds (VOCs) are an important factor affecting meat quality. However, the characteristic VOCs in different parts of donkey meat remain unknown. Accordingly, this study represents a preliminary investigation of VOCs to differentiate between different cuts of donkey meat by using headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) combined with chemometrics analysis. The results showed that the 31 VOCs identified in donkey meat, ketones, alcohols, aldehydes, and esters were the predominant categories. A total of 10 VOCs with relative odor activity values ≥1 were found to be characteristic of donkey meat, including pentanone, hexanal, nonanal, octanal, and 3-methylbutanal. The VOC profiles in different parts of donkey meat were well differentiated using three- and two-dimensional fingerprint maps. Nine differential VOCs that represent potential markers to discriminate different parts of donkey meat were identified by chemometrics analysis. These include 2-butanone, 2-pentanone, and 2-heptanone. Thus, the VOC profiles in donkey meat and specific VOCs in different parts of donkey meat were revealed by HS-GC-IMS combined with chemometrics, whcih provided a basis and method of investigating the characteristic VOCs and quality control of donkey meat.

Investigation of clear cell renal cell carcinoma grades using diffusion-relaxation correlation spectroscopic imaging with optimized spatial-spectrum analysis.

OBJECTIVES: To differentiate high-grade from low-grade clear cell renal cell carcinoma (ccRCC) using diffusion-relaxation correlation spectroscopic imaging (DR-CSI) spectra in an equal separating analysis. METHODS: Eighty patients with 86 pathologically confirmed ccRCCs who underwent DR-CSI were enrolled. Two radiologists delineated the region of interest. The spectrum was derived based on DR-CSI and was further segmented into multiple equal subregions from 2*2 to 9*9. The agreement between the 2 radiologists was assessed by the intraclass correlation coefficient (ICC). Logistic regression was used to establish the regression model for differentiation, and 5-fold cross-validation was used to evaluate its accuracy. McNemar's test was used to compare the diagnostic performance between equipartition models and the traditional parameters, including the apparent diffusion coefficient (ADC) and T2 value. RESULTS: The inter-reader agreement decreased as the divisions in the equipartition model increased (overall ICC ranged from 0.859 to 0.920). The accuracy increased from the 2*2 to 9*9 equipartition model (0.68 for 2*2, 0.69 for 3*3 and 4*4, 0.70 for 5*5, 0.71 for 6*6, 0.78 for 7*7, and 0.75 for 8*8 and 9*9). The equipartition models with divisions >7*7 were significantly better than ADC and T2 (vs ADC: P = .002-.008; vs T2: P = .001-.004). CONCLUSIONS: The equipartition method has the potential to analyse the DR-CSI spectrum and discriminate between low-grade and high-grade ccRCC. ADVANCES IN KNOWLEDGE: The evaluation of DR-CSI relies on prior knowledge, and how to assess the spectrum derived from DR-CSI without prior knowledge has not been well studied.

Diagnosis and treatment of transnasal endoscopic optic canal decompression for traumatic optic neuropathy.

Objective: To investigate the clinical efficacy and prognostic factors of transnasal endoscopic optic decompression in the treatment of traumatic optic neuropathy (TON). Methods: A retrospective analysis was performed on 13 TON patients in The Seventh Affiliated Hospital of Sun Yat-sen University and Shenzhen Eye Hospital in Shenzhen City (China) from June 2020 to April 2022. These patients had received transnasal endoscopic optic decompression, and hormonal and neurotrophic drugs were given after surgery. Visual acuity (VA) improvement was used as the criterion to judge clinical efficacy. Results: In a total of 13 patients, 13 injured eyes (12 men and 1 woman; mean age, 28.0 ± 11.8 years) received transnasal endoscopic optic decompression. After surgery, nine patients had improved VA, whereas four patients failed to show any improvement, resulting in a total effective rate of 69.2%. Of the six patients with no light perception preoperatively, three had effective results after the operation, giving an effective rate of 50.0%. Of the seven patients with residual light sensation preoperatively, six had effective results after the operation, giving an effective rate of 85.7%. Of the 10 patients operated on within 7 days after injury, seven had effective results, giving an effective rate of 70%. Of the three patients injured and operated on after 7 days, two had effective results, giving an effective rate of 66.7%. Conclusion: Transnasal endoscopic optic nerve decompression is an effective treatment method for TON. The presence of residual light perception and the timing of surgery within 7 days are crucial to the prognosis.

Donkey Oil-Based Ketogenic Diet Prevents Tumor Progression by Regulating Intratumor Inflammation, Metastasis and Angiogenesis in CT26 Tumor-Bearing Mice.

Colon cancer is one of the typical malignant tumors, and its prevalence has increased yearly. The ketogenic diet (KD) is a low-carbohydrate and high-fat dietary regimen that inhibits tumor growth. Donkey oil (DO) is a product with a high nutrient content and a high bioavailability of unsaturated fatty acids. Current research investigated the impact of the DO-based KD (DOKD) on CT26 colon cancer in vivo. Our findings revealed that DOKD administration significantly lowered CT26+ tumor cell growth in mice, and the blood ß-hydroxybutyrate levels in the DOKD group was significantly higher than those in the natural diet group. Western blot results showed that DOKD significantly down-regulated Src, hypoxia inducible factor-1α (HIF-1α), extracellular signal-related kinases 1 and 2 (Erk1/2), snail, neural cadherin (N-cadherin), vimentin, matrix metallopeptidase 9 (MMP9), signal transducer and activator of transcription 3 (STAT3), and vascular endothelial growth factor A (VEGFA), and it significantly up-regulated the expressions of Sirt3, S100a9, interleukin (IL)-17, nuclear factor-kappaB (NF-κB) p65, Toll-like receptor 4 (TLR4), MyD88, and tumor necrosis factor-α. Meanwhile, in vitro validation results showed that LW6 (a HIF-1α inhibitor) significantly down-regulated the expressions of HIF-1α, N-cadherin, vimentin, MMP9, and VEGFA, which supported those of the in vivo findings. Furthermore, we found that DOKD inhibited CT26+ tumor cell growth by regulating inflammation, metastasis, and angiogenesis by activating the IL-17/TLR4/NF-κB p65 pathway and inhibiting the activation of the Src/HIF-1α/Erk1/2/Snail/N-cadherin/Vimentin/MMP9 and Erk1/2/HIF-1α/STAT3/VEGFA pathways. Our findings suggest that DOKD may suppress colon cancer progression and help prevent colon cancer cachexia.

The added value of AI-based computer-aided diagnosis in classification of cancer at prostate MRI.

OBJECTIVES: To develop an artificial intelligence (AI) model for prostate segmentation and prostate cancer (PCa) detection, and explore the added value of AI-based computer-aided diagnosis (CAD) compared to conventional PI-RADS assessment. METHODS: A retrospective study was performed on multi-centers and included patients who underwent prostate biopsies and multiparametric MRI. A convolutional-neural-network-based AI model was trained and validated; the reliability of different CAD methods (concurrent read and AI-first read) were tested in an internal/external cohort. The diagnostic performance, consistency and efficiency of radiologists and AI-based CAD were compared. RESULTS: The training/validation/internal test sets included 650 (400/100/150) cases from one center; the external test included 100 cases (25/25/50) from three centers. For diagnosis accuracy, AI-based CAD methods showed no significant differences and were equivalent to the radiologists in the internal test (127/150 vs. 130/150 vs. 125/150 for reader 1; 127/150 vs.132/150 vs. 131/150 for reader 2; all p > 0.05), whereas in the external test, concurrent-read methods were superior/equal to AI-first read (87/100 vs. 71/100, p < 0.001, for reader 2; 79/100 vs. 69/100, p = 0.076, for reader 1) and better than/equal to radiologists (79/100 vs. 72/100, p = 0.039, for reader 1; 87/100 vs. 86/100, p = 1.000, for reader 2). Moreover, AI-first read/concurrent read improved consistency in both internal test (κ = 1.000, 0.830) and external test (κ = 0.958, 0.713) compared to radiologists (κ = 0.747, 0.600); AI-first read method (8.54 s/7.66 s) was faster than readers (92.72 s/89.54 s) and concurrent-read method (29.15 s/28.92 s), respectively. CONCLUSION: AI-based CAD could improve the consistency and efficiency for accurate diagnosis; the concurrent-read method could enhance the diagnostic capabilities of an inexperienced radiologist in unfamiliar situations. KEY POINTS: • For prostate cancer segmentation, the performance of multi-small Vnet displays optimal compared to small Vnet and Vnet (DSCmsvnet vs. DSCsvnet, p = 0.021; DSCmsvnet vs. DSCvnet, p < 0.001). • For prostate gland segmentation, the mean/median DSCs for fine and coarse segmentation were 0.91/0.91 and 0.88/0.89, respectively. Fine segmentation displays superior performance compared to coarse (DSCcoarse vs. DSCfine, p < 0.001). • For PCa diagnosis, AI-based CAD methods improve consistency in internal (κ = 1.000; 0.830) and external (κ = 0.958; 0.713) tests compared to radiologists (κ = 0.747; 0.600); the AI-first read (8.54 s/7.66 s) was faster than the readers (92.72 s/89.54 s) and the concurrent-read method (29.15 s/28.92 s).

Detection of prostate cancer using diffusion-relaxation correlation spectrum imaging with support vector machine model - a feasibility study.

BACKGROUND: To evaluate the performance of diffusion-relaxation correlation spectrum imaging (DR-CSI) with support vector machine (SVM) in detecting prostate cancer (PCa). METHODS: In total, 114 patients (mean age, 66 years, range, 48-87 years) who received a prostate MRI and underwent biopsy were enrolled in three stages. Thirty-nine were assigned for the exploration stage to establish the model, 18 for the validation stage to choose the appropriate scale for mapping and 57 for the test stage to compare the diagnostic performance of the DR-CSI and PI-RADS. RESULTS: In the exploration stage, the DR-CSI model was established and performed better than the ADC and T2 values (both P < 0.001). The validation result shows that at least 2 pixels were required for both the long-axis and short-axis in the mapping procedure. In the test stage, DR-CSI had higher accuracy than PI-RADS ≥ 3 as a positive finding based on patient (84.2% vs. 63.2%, P = 0.004) and lesion (78.8% vs. 57.6%, P = 0.001) as well as PI-RADS ≥ 4 on lesion (76.5% vs. 64.7%, P = 0.029), while there was no significant difference between DR-CSI and PI-RADS ≥ 4 based on patient (P = 0.508). For clinically significant PCa, DR-CSI had higher accuracy than PI-RADS ≥ 3 based on patients (84.2% vs. 63.2%, P = 0.004) and lesions (62.4% vs. 48.2%, P = 0.036). There was no significant difference between DR-CSI and PI-RADS ≥ 4 (P = 1.000 and 0.845 for the patient and lesion levels, respectively). CONCLUSIONS: DR-CSI combined with the SVM model may improve the diagnostic accuracy of PCa. TRIAL REGISTRATION: This study was approved by the Ethics Committee of our institute (Approval No. KY2018-213). Written informed consent was obtained from all participants.

Comparative Transcriptome Analysis of Slow-Twitch and Fast-Twitch Muscles in Dezhou Donkeys.

The skeletal muscle fiber profile is closely related to livestock meat quality. However, the molecular mechanisms determining muscle fiber types in donkeys are not completely understood. In this study, we selected the psoas major muscle (PM; mainly composed of oxidative-type muscle fibers) and biceps femoris muscle (BF; mainly composed of glycolytic-type muscle fibers) and systematically compared their mRNA and microRNA transcriptomes via RNA-seq. We identified a total of 2881 differentially expressed genes (DEGs) and 21 known differentially expressed miRNAs (DEmiRs). Furthermore, functional enrichment analysis showed that the DEGs were mainly involved in energy metabolism and actin cytoskeleton regulation. The glycolysis/gluconeogenesis pathway (including up-regulated genes such as PKM, LDHA, PGK1 and ALDOA) was more highly enriched in BF, whereas the oxidative phosphorylation pathway and cardiac muscle contraction (including down-regulated genes such as LDHB, ATP2A2, myosin-7 (MYH7), TNNC1, TPM3 and TNNI1) was more enriched in PM. Additionally, we identified several candidate miRNA-mRNA pairs that might regulate muscle fiber types using the integrated miRNA-mRNA analysis. Combined with the results of protein-protein interaction (PPI) analysis, some interesting DEGs (including ACTN3, TNNT3, TPM2, TNNC2, PKM, TNNC1 and TNNI1) might be potential candidate target genes involved in the miRNA-mediated regulation of the myofibril composition. This study is the first to indicate that DEmiRs, especially eca-miR-193a-5p and eca-miR-370, and potential candidate target genes that are mainly involved in actin binding (e.g., ACTN3, TNNT3 and TNNC1) and the glycolysis/gluconeogenesis pathways (e.g., PKM) might coregulate the myofibril composition in donkeys. This study may provide useful information for improving meat quality traits in Dezhou donkeys.

MR Spectroscopy for Detecting Fumarate Hydratase Deficiency in Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome.

Background Noninvasive in vivo detection of fumarate accumulation may help identify fumarate hydratase deficiency in renal cancer related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Purpose To investigate the feasibility of MR spectroscopy (MRS) in detecting elevated fumarate levels in HLRCC-associated renal cancers. Materials and Methods This study included an experimental xenograft mouse model and prospective clinical cohort. First, MRS was performed on patient-derived tumor xenograft models and control models to detect fumarate. Then, consecutive participants with clinical suspicion of HLRCC-associated renal tumors were enrolled. For the detection of fumarate, MRS results were classified as detected, borderline, undetected, or technical failure. The sensitivity, specificity, and accuracy of MRS for diagnosing HLRCC-associated renal cancer were assessed. The signal-to-noise ratio (SNR) of the fumarate peak was calculated and evaluated with receiver operating characteristic curve analysis. Results Fumarate peaks were detected at 6.54 parts per million in all three patient-derived xenograft models. A total of 38 participants (21 men; mean age, 47 years [range, 18-71 years]) with 46 lesions were analyzed. All primary HLRCC-associated renal cancers showed a fumarate peak; among the seven metastatic HLRCC-associated lesions, a fumarate peak was detected in three lesions and borderline in two. When only detected peaks were regarded as positive findings, the sensitivity, specificity, and accuracy of MRS at the lesion level were 69% (nine of 13 lesions), 100% (33 of 33 lesions), and 91% (42 of 46 lesions), respectively. When borderline peaks were also included as a positive finding, the sensitivity, specificity, and accuracy reached 85% (11 of 13 lesions), 88% (29 of 33 lesions), and 87% (40 of 46 lesions), respectively. The SNR of fumarate showed an area under the receiver operating characteristic curve of 0.87 for classifying HLRCC-associated tumors. Conclusion MR spectroscopy of fumarate was sensitive and specific for hereditary leiomyomatosis and renal cell carcinoma-associated tumors. © RSNA, 2022 Online supplemental material is available for this article.

A transcriptional regulatory network of HNF4α and HNF1α involved in human diseases and drug metabolism.

HNF4α and HNF1α are core transcription factors involved in the development and progression of a variety of human diseases and drug metabolism. They play critical roles in maintaining the normal growth and function of multiple organs, mainly the liver, and in the metabolism of endogenous and exogenous substances. The twelve isoforms of HNF4α may exhibit different physiological functions, and HNF4α and HNF1α show varying or even opposing effects in different types of diseases, particularly cancer. Additionally, the regulation of CYP450, phase II drug-metabolizing enzymes, and drug transporters is affected by several factors. This article aims to review the role of HNF4α and HNF1α in human diseases and drug metabolism, including their structures and physiological functions, affected diseases, regulated drug metabolism genes, influencing factors, and related mechanisms. We also propose a transcriptional regulatory network of HNF4α and HNF1α that regulates the expression of target genes related to disease and drug metabolism.

Metabolic Alternations During Gestation in Dezhou Donkeys and the Link to the Gut Microbiota.

The maternal intestinal microbial community changes dramatically during pregnancy and plays an important role in animal growth, metabolism, immunity and reproduction. However, our understanding of microbiota compositional dynamics during the whole pregnancy period in donkey is incomplete. This study was carried out to evaluate gut microbiota alterations as well as the correlation with serum biochemical indices, comparing pregnant donkeys to non-pregnant donkeys. A total of 18 pregnant (including EP, early-stage pregnancy; MP, middle-stage pregnancy and LP, late-stage pregnancy) and six non-pregnant (C as a control) donkey blood samples and rectum contents were collected. The results showed that pregnant donkeys had higher microbial richness than non-pregnant donkeys and that the lowest microbial diversity occurred at the EP period. Moreover, the relative abundances of the families Clostridiaceae and Streptococcaceae were significantly higher in the EP group (p < 0.05) than that in the C and MP groups, while the relative abundances of the families Lachnospiraceae and Rikenellaceae were significantly lower in the EP group (p < 0.05) than that in the C group. The predicted microbial gene functions related to the inflammatory response and apoptosis, such as Staphylococcus aureus infection, the RIG-1-like receptor signaling pathway and apoptosis, were mainly enriched in EP. Furthermore, pregnant donkeys had higher glucose levels than non-pregnant donkeys, especially at EP period. EP donkeys had lower triglyceride, total protein and albumin levels but higher malondialdehyde, interleukin 1ß, interleukin 6 and tumor necrosis factor-α levels than those in the C and MP groups. Additionally, there were strong correlations between inflammatory cytokine levels and the relative abundances of genera belonging to the Clostridiaceae and Streptococcaceae families. This is the first comparative study performed in donkeys that indicates that pregnancy status (especially in the early pregnancy period) alters the gut microbiota composition, which was correlated with serum biochemical parameters. These results could provide useful information for improving the reproductive management in Dezhou donkeys.

microRNA-181a-5p impedes the proliferation, migration, and invasion of retinoblastoma cells by targeting the NRAS proto-oncogene.

OBJECTIVES: Accumulating research have reported that microRNAs (miRNAs) play important roles in Retinoblastoma (RB). Nonetheless, the function and underlying mechanism of miR-181a-5p in RB remain ambiguous. METHODS: The relative expression levels of miR-181a-5p and NRAS mRNA were detected by quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR). RB cell proliferation was measured using the Cell Counting Kit-8 (CCK-8) and 5'-Bromo-2'-deoxyuridine (BrdU) assays. Transwell assays and flow cytometry were performed to detect the migration, invasion, and apoptosis of RB cells. The interaction between miR-181a-5p and NRAS was explored using luciferase experiments, western blotting, and qRT-PCR. RESULTS: miR-181a-5p expression was found to be decreased in RB tissues and cell lines, and its expression was correlated with unfavorable pathological features of the patients. In vitro experiments revealed that miR-181a-5p reduced RB cell proliferation, migration, and invasion while enhancing apoptosis. Further research confirmed that NRAS is a direct target of miR-181a-5p. miR-181a-5p inhibited NRAS expression at both the mRNA and protein levels. Co-transfection of pcDNA-NRAS or NRAS small interfering RNA (siRNA) reversed the effects of miR-181a-5p mimics or miR-181a-5p inhibitors on RB cells. CONCLUSION: miR-181a-5p was significantly downregulated during the development of RB, and it suppressed the malignant behaviors of RB cells by targeting NRAS.

Exposure to High-Altitude Environment Is Associated with Drug Transporters Change: microRNA-873-5p-Mediated Alteration of Function and Expression Levels of Drug Transporters under Hypoxia.

Hypoxia is the main characteristic of a high-altitude environment, affecting drug metabolism. However, so far, the mechanism of microRNA (miRNA) involved in the regulation of drug metabolism and transporters under high-altitude hypoxia is still unclear. This study aims to investigate the functions and expression levels of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), breast cancer resistance protein (BCRP), peptide transport 1 (PEPT1), and organic anion-transporting polypeptides 2B1 (OATP2B1) in rats and colon cancer (Caco-2) cells after exposure to high-altitude hypoxia. The protein and mRNA expression of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were determined by Western blot and qPCR. The functions of MDR1, MRP2, BCRP, PEPT1, and OATP2B1 were evaluated by determining the effective intestinal permeability and absorption rate constants of their specific substrates in rats under high-altitude hypoxia, and uptake and transport studies were performed on Caco-2 cells. To screen the miRNA associated with hypoxia, Caco-2 cells were examined by high throughput sequencing. We observed that the miR-873-5p was significantly decreased under hypoxia and might target MDR1 and pregnane X receptor (PXR). To clarify whether miR-873-5p regulates MDR1 and PXR under hypoxia, Caco-2 cells were transfected with mimics or inhibitors of miR-873-5p and negative control (NC). The function and expression of drug transporters were found to be significantly increased in rats and Caco-2 cells under hypoxia. We found that miR-873-5p regulated MDR1 and PXR expression. Herein, it is shown that miRNA may affect the expression of drug transporter and nuclear receptor under hypoxia. SIGNIFICANCE STATEMENT: This study explores if alterations to the microRNAs (miRNAs), induced by high-altitude hypoxia, can be translated to altered drug transporters. Among miRNAs, which show a significant change in a hypoxic environment, miR-873-5p can act on the multidrug resistance protein 1 (MDR1) gene; however, there are multiple miRNAs that can act on the pregnane X receptor (PXR). This study speculates that the miRNA-PXR-drug transporter axis is important in the physiological disposition of drugs.

Effects of donkey milk on oxidative stress and inflammatory response.

Donkey milk is gaining interest as a natural nutritional and medicinal product, mainly because its composition is similar to that of human milk, and it has some potential biological properties, such as antioxidant, anti-inflammatory, antiaging, antimicrobial, and anticancer properties. Considering the increasing prevalence of several chronic diseases related to oxidative stress and inflammation and the multiple beneficial properties and nutritional value of donkey milk, an up-to-date review of the current studies related to the antioxidative and anti-inflammatory abilities of donkey milk is necessary. Therefore, this review aims to discuss the relationship between inflammation and oxidative stress; and to further systematically review the progress of recent research on donkey milk, mainly including its nutritional value and functional properties. Particularly, we highlighted the anti-inflammatory and antioxidative properties of donkey milk using in vitro model, animal model, and the potential role of donkey milk in alleviating some chronic diseases related to inflammation. PRACTICAL APPLICATIONS: This paper was conducted on anti-inflammation and antioxidant activities of donkey milk and its related products, in addition to a summary of the relationship between oxidative stress and inflammation and the value of donkey milk. Donkey milk and its related products have been shown to scavenge reactive oxygen species, activate the antioxidant system, enhance immune function, and maintain the balance of intestinal flora in in vitro and in vivo models. This paper should provide a better understanding of the influences of oxidative stress and inflammation on host health and the biological functions and application of donkey milk, and will provide a certain basis for the nutritional regulation of several chronic diseases related to oxidative stress and inflammation. However, the underlying mechanism is poorly understood. In addition, few clinical studies have been performed to establish its multiple benefits in humans. Further research is warranted to evaluate its impacts on health at molecular levels.

Deoxynivalenol and zearalenone: Different mycotoxins with different toxic effects in donkey (Equus asinus) endometrial epithelial cells.

Deoxynivalenol (DON) and zearalenone (ZEA), which are commonly found in feed products, exhibit serious negative effects on the reproductive systems of domestic animals. However, the toxicity of mycotoxins on the uterine function of donkey (Equus asinus) remains unclear. This study investigated the biological effects of DON and ZEA exposure on donkey endometrial epithelial cells (EECs). It was administered 10 µM and 30 µM DON and ZEA to cells cultured in vitro. The results showed that 10 µM DON exposure markedly changed the expression levels of pyroptosis-associated genes and that 30 µM ZEA exposure changed the expression levels of inflammation-associated genes in EECs. The mRNA expression of cancer-promoting genes was markedly upregulated in cells exposed to DON and 30 µM ZEA; in particular, 10 µM and 30 µM DON and ZEA markedly disturbed the expression of androgen and estrogen secretion-related genes. Furthermore, Q-PCR, Western blot, and immunofluorescence analyses verified the different expression patterns of related genes in DON- and ZEA-exposed EECs. Collectively, these results illustrated the impact of exposure to different toxins and concrete toxicity on the mRNA expression of EECs from donkey in vitro.

microRNA-181a-5p impedes the proliferation, migration, and invasion of retinoblastoma cells by targeting the NRAS proto-oncogene

Abstract Objectives Accumulating research have reported that microRNAs (miRNAs) play important roles in Retinoblastoma (RB). Nonetheless, the function and underlying mechanism of miR-181a-5p in RB remain ambiguous. Methods The relative expression levels of miR-181a-5p and NRAS mRNA were detected by quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR). RB cell proliferation was measured using the Cell Counting Kit-8 (CCK-8) and 5′-Bromo-2′-deoxyuridine (BrdU) assays. Transwell assays and flow cytometry were performed to detect the migration, invasion, and apoptosis of RB cells. The interaction between miR-181a-5p and NRAS was explored using luciferase experiments, western blotting, and qRT-PCR. Results miR-181a-5p expression was found to be decreased in RB tissues and cell lines, and its expression was correlated with unfavorable pathological features of the patients. In vitro experiments revealed that miR-181a-5p reduced RB cell proliferation, migration, and invasion while enhancing apoptosis. Further research confirmed that NRAS is a direct target of miR-181a-5p. miR-181a-5p inhibited NRAS expression at both the mRNA and protein levels. Co-transfection of pcDNA-NRAS or NRAS small interfering RNA (siRNA) reversed the effects of miR-181a-5p mimics or miR-181a-5p inhibitors on RB cells. Conclusion miR-181a-5p was significantly downregulated during the development of RB, and it suppressed the malignant behaviors of RB cells by targeting NRAS.

A Decade's Review of miRNA: A Center of Transcriptional Regulation of Drugmetabolizing Enzymes and Transporters under Hypoxia.

BACKGROUND: Hypoxia has a negative effect on the cardiovascular system, nervous system, and metabolism, which contributes to potential changes in drug absorption, distribution, metabolism, and excretion (ADME). However, hypoxia can also alter the expression of microRNA (miRNA), thereby regulating drug-metabolizing enzymes, transporters, and ADME genes, such as hypoxia-inducible factor, inflammatory cytokine, nuclear receptor, etc. Therefore, it is crucial to study the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. METHODS: A systematic review of published studies was carried out to investigate the role of miRNA in the regulation of drug-metabolizing enzymes and transporters under hypoxia. Data and information on expression changes in miRNA, drug-metabolizing enzymes, and transporters under hypoxia were analyzed and summarized. RESULTS: Hypoxia can up or down-regulate the expression of miRNA. The effect of hypoxia on Cytochrome P450 (CYP450) is still a subject of debate. The widespread belief is that hypoxia decreased the activity and expression of CYP1A1, CYP1A2, CYP2E1, and CYP3A1 and increased those of CYP3A6 and CYP2D1 in rats. Hypoxia increased the expression of a multidrug resistance-associated protein, breast cancer resistance protein, peptide transporter, organic cation transporter, and organic anion transporter. miRNA negatively regulated the expression of drugmetabolizing enzymes and transporters. CONCLUSION: The findings of this review indicated that miRNA plays a key role in the expression changes of drugmetabolizing enzymes and transporters under hypoxia.

MicroRNA-137 targets EZH2 to exert suppressive functions in uveal melanoma via regulation of Wnt/ß-catenin signaling and epithelial-to-mesenchymal transition.

PURPOSE: Uveal melanoma (UM) is one of the primary intraocular malignancies. Emerging studies have confirmed dysregulation of microRNA (miRNA/miR) in UM. The present study focused on the biofunctions of miR-137 in UM. METHODS: MiR-137 expressions in tissue samples were analyzed by qRT-PCR. MTT and transwell assays were applied to investigate the impacts of miR-137 on UM cell proliferation, invasion and migration. Luciferase assay was carried out to explore the downstream target of miR-137. Western blot was used to analyze the roles of miR-137 in UM cells, Wnt/ß-catenin pathway and epithelial-mesenchymal transition (EMT). RESULTS: qRT-PCR showed that miR-137 expressions were lower in UM tissue samples than para-carcinoma tissues, whereas EZH2 was simultaneously upregulated. MiR-137 overexpression evidently suppressed UM cell proliferation, invasion and migration. The findings also indicated that miR-137 restoration could block Wnt/ß-catenin pathway and EMT in UM cells thus resulting in downregulation of malignant behaviors. EZH2 was a downstream target of miR-137 as demonstrated by luciferase assay. CONCLUSION: The present study indicated that EZH2 participated in the anti-UM functions of miR-137. Taken together, the data in our study established miR-137/EZH2 axis in regulating UM progression, suggesting that miR-137 may function as a novel therapeutic biomarker for UM patients.

Validation of CT radiomics for prediction of distant metastasis after surgical resection in patients with clear cell renal cell carcinoma: exploring the underlying signaling pathways.

OBJECTIVES: To develop a radiomics model using preoperative multiphasic CT for predicting distant metastasis after surgical resection in patients with localized clear cell renal cell carcinoma (ccRCC) and to identify key biological pathways underlying the predictive radiomics features using RNA sequencing data. METHODS: In this multi-institutional retrospective study, a CT radiomics metastasis score (RMS) was developed from a radiomics analysis cohort (n = 184) for distant metastasis prediction. Using a gene expression analysis cohort (n = 326), radiomics-associated gene modules were identified. Based on a radiogenomics discovery cohort (n = 42), key biological pathways were enriched from the gene modules. Furthermore, a multigene signature associated with RMS was constructed and validated on an independent radiogenomics validation cohort (n = 37). RESULTS: The 9-feature-based RMS predicted distant metastasis with an AUC of 0.861 in validation set and was independent with clinical factors (p < 0.001). A gene module comprising 114 genes was identified to be associated with all nine radiomics features (p < 0.05). Four enriched pathways were identified, including ECM-receptor interaction, focal adhesion, protein digestion and absorption, and PI3K-Akt pathways. Most of them play important roles in tumor progression and metastasis. A 19-gene signature was constructed from the radiomics-associated gene module and predicted metastasis with an AUC of 0.843 in the radiogenomics validation cohort. CONCLUSIONS: CT radiomics features can predict distant metastasis after surgical resection of localized ccRCC while the predictive radiomics phenotypes may be driven by key biological pathways related to cancer progression and metastasis. KEY POINTS: • Radiomics features from primary tumor in preoperative CT predicted distant metastasis after surgical resection in patients with localized ccRCC. • CT radiomics features predictive of distant metastasis were associated with key signaling pathways related to tumor progression and metastasis. • Gene signature associated with radiomics metastasis score predicted distant metastasis in localized ccRCC.