Key role of CYP17A1 in Leydig cell function and testicular development in Qianbei Ma goats.

Reproductive traits are vital economic parameters in goat production, and boosting the reproductive capacity of breeding rams is crucial for enhancing the profitability of goat farming. Currently, research on the reproductive performance of Qianbei Ma goats mainly centers on investigating mechanisms associated with prolificacy and estrous ovulation in ewes, with limited emphasis on ram reproductive aspects. This study used scanning electron microscopy and enzyme-linked immunosorbent assay (ELISA) to profile the morphology of testis and the dynamic changes of Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), and Testosterone (T) in serum at different developmental stages of Qianbei Ma goats. Meanwhile, transcriptome sequencing technology was used to investigate the mRNA expression patterns in testicular tissues at different developmental stages: newborn (0 M), puberty (6 M), sexual maturity (12 M), and physical maturity (18 M). The results showed that the diameter, circumference, and area of the testicular seminiferous tubules gradually increased with age. The levels of T and LH in serum significantly increased from 0 to 6 months after birth (p < 0.05), followed by a stabilization of T levels and a significant decrease in LH levels (p < 0.05). Meanwhile, FSH shows a decreasing trend between 0 and 18 months after birth. A total of 26,437 differentially expressed genes were identified in 6 comparison groups, which involve various biological processes such as immunity, growth, metabolism, development, and reproduction, and are significantly enriched in signaling pathways related to testicular development and spermatogenesis. WGCNA analysis identified 6 regions significantly associated with testicular development and spermatogenesis, and selected 320 genes for constructing a PPI network. Ten candidate genes related to testicular development and spermatogenesis were identified, including TP53, PLK4, RPS9, PFN4, ACTB, CYP17A1, GPX4, CLDN1, AMH and DHH. Of these, the CYP17A1 gene promotes interstitial cell proliferation, and promotes T synthesis. This study provides a theoretical basis and data support for promoting efficient breeding of goats and early breeding of excellent male goats.

Identification of DNA methylation-regulated WEE1 with potential implications in prognosis and immunotherapy for low-grade glioma.

BACKGROUND: WEE1 is a critical kinase in the DNA damage response pathway and has been shown to be effective in treating serous uterine cancer. However, its role in gliomas, specifically low-grade glioma (LGG), remains unclear. The impact of DNA methylation on WEE1 expression and its correlation with the immune landscape in gliomas also need further investigation. METHODS: This study used data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Gene Expression Omnibus (GEO) and utilized various bioinformatics tools to analyze gene expression, survival, gene correlation, immune score, immune infiltration, genomic alterations, tumor mutation burden, microsatellite instability, clinical characteristics of glioma patients, WEE1 DNA methylation, prognostic analysis, single-cell gene expression distribution in glioma tissue samples, and immunotherapy response prediction based on WEE1 expression. RESULTS: WEE1 was upregulated in LGG and glioblastoma (GBM), but it had a more significant prognostic impact in LGG compared to other cancers. High WEE1 expression was associated with poorer prognosis in LGG, particularly when combined with wild-type IDH. The WEE1 inhibitor MK-1775 effectively inhibited the proliferation and migration of LGG cell lines, which were more sensitive to WEE1 inhibition. DNA methylation negatively regulated WEE1, and high DNA hypermethylation of WEE1 was associated with better prognosis in LGG than in GBM. Combining WEE1 inhibition and DNA methyltransferase inhibition showed a synergistic effect. Additionally, downregulation of WEE1 had favorable predictive value in immunotherapy response. Co-expression network analysis identified key genes involved in WEE1-mediated regulation of immune landscape, differentiation, and metastasis in LGG. CONCLUSION: Our study shows that WEE1 is a promising indicator for targeted therapy and prognosis evaluation. Notably, significant differences were observed in the role of WEE1 between LGG and GBM. Further investigation into WEE1 inhibition, either in combination with DNA methyltransferase inhibition or immunotherapy, is warranted in the context of LGG.

Double synergic chitosan-coated poly (lactic-co-glycolic) acid nanospheres loaded with nucleic acids as an intranasally administered vaccine delivery system to control the infection of foot-and-mouth disease virus.

BACKGROUND & AIMS: The spread of foot-and-mouth disease virus (FMDV) through aerosol droplets among cloven-hoofed ungulates in close contact is a major obstacle for successful animal husbandry. Therefore, the development of suitable mucosal vaccines, especially nasal vaccines, to block the virus at the initial site of infection is crucial. PATIENTS AND METHODS: Here, we constructed eukaryotic expression plasmids containing the T and B-cell epitopes (pTB) of FMDV in tandem with the molecular mucosal adjuvant Fms-like tyrosine kinase receptor 3 ligand (Flt3 ligand, FL) (pTB-FL). Then, the constructed plasmid was electrostatically attached to mannose-modified chitosan-coated poly(lactic-co-glycolic) acid (PLGA) nanospheres (MCS-PLGA-NPs) to obtain an active nasal vaccine targeting the mannose-receptor on the surface of antigen-presenting cells (APCs). RESULTS: The MCS-PLGA-NPs loaded with pTB-FL not only induced a local mucosal immune response, but also induced a systemic immune response in mice. More importantly, the nasal vaccine afforded an 80% protection rate against a highly virulent FMDV strain (AF72) when it was subcutaneously injected into the soles of the feet of guinea pigs. CONCLUSIONS: The nasal vaccine prepared in this study can effectively induce a cross-protective immune response against the challenge with FMDV of same serotype in animals and is promising as a potential FMDV vaccine.

Research progress on genetics in cardioembolic stroke.

Cardioembolic stroke, characterized by severe illness, poor prognosis, and high recurrence rate, is one of the important causes of ischemic stroke. In the field of genetic research, numerous genes associated with cardioembolic stroke have been identified, and their potential in predicting disease risk and evaluating risk factors has been progressively explored. Here, we provide an overview of the latest advancements in genetics for cardioembolic stroke, including genome-wide association studies, copy number variation studies, whole-genome sequencing studies. Furthermore, we also summarize the application of genetic datasets in polygenic risk score and Mendelian randomization. The aim of this overview is to provide insights and references from multiple perspectives for future investigations on the genetic information for cardioembolic stroke.

Identifying Qingkailing ingredients-dependent mesenchymal-epithelial transition factor-axiation "π" structuring module with angiogenesis and neurogenesis effects.

OBJECTIVE: To explore the functional role of the drug-dependent mesenchymal-epithelial transition (Met)-axiation "π" structural module of neurogenesis after processing by three components of Qingkailing injection in neurogenesis and angiogenesis in cerebral ischemia. METHODS: We used a Glutathione S-transferase (GST)-pull down assay, isothermal titration calorimetry assay, and other related methods to identify the relationships among Met, inositol polyphosphate phosphatase like 1 (Inppl1), and death associated protein kinase 3 (Dapk3) in this allosteric module. The biological effects of the modules of neurons generation composed of Met, Inppl1, and Dapk3 were measured through Western blot, apoptosis analysis, and double immunofluorescence labeling. RESULTS: The GST-pull down assay revealed that proline-serine-threonine rich domain of Met binds to the Src homology domain of Inppl1 to form a protein-protein complex; Dapk3 with a C-terminal domain interacts weakly with the protein kinase C domain of Met in the intracellular region. Thus, we obtained a "π" structuring module considered a neural regeneration module. The biological effects of angiogenesis and neurogenesis modules composed of Met, Inppl1, and Dapk3 were also verified. CONCLUSION: The study suggested that understanding the functional modules that contribute to pharmaceutics might provide novel signatures that can be used as endpoints to define disease processes under stroke or cerebral ischemia conditions.

Multi-step-ahead and interval carbon price forecasting using transformer-based hybrid model.

Accurate and stable carbon price forecasts serve as a reference for assessing the stability of the carbon market and play a vital role in enhancing investment and operational decisions. However, realizing this goal is still a significant challenge, and researchers usually ignore multi-step-ahead and interval forecasting due to the non-linear and non-stationary characteristics of carbon price series and its complex fluctuation features. In this study, a novel hybrid model for accurately predicting carbon prices is proposed. The proposed model combines multi-step-ahead and interval carbon price forecasting based on the Hampel identifier (HI), time-varying filtering-based empirical mode decomposition (TVFEMD), and transformer model. First, HI identifies and corrects outliers in carbon price. Second, TVFEMD decomposes carbon price into several intrinsic mode functions (imfs) to reduce the non-linear and non-stationarity of carbon price to obtain more regular features in series. Next, these imfs are reconstructed by sample entropy (SE). Subsequently, the orthogonal array tuning method is used to optimize the transformer model's hyperparameters to obtain the optimal model structure. Finally, after hyperparameter optimization and quantile loss function, the transformer is used to perform multi-step-ahead and interval forecasting on each part of the reconstruction, and the final prediction result is obtained by summing them up. Five pilot carbon trading markets in China were selected as experimental objects to verify the proposed model's prediction performance. Various benchmark models and evaluation indicators were selected for comparison and analysis. Experimental results show that the proposed HI-TVFEMD-transformer hybrid model achieves an average MAE of 0.6546, 1.3992, 1.6287, and 2.2601 for one-step, three-step, five-step, and ten-step-ahead forecasting, respectively, which significantly outperforms other models. Furthermore, interval forecasts almost always have a PICI above 0.95 at a confidence interval of 0.1, thereby indicating the effectiveness of the hybrid model in describing the uncertainty in the forecasts. Therefore, the proposed hybrid model is a reliable carbon price forecasting tool that can provide a dependable reference for policymakers and investors.

A new effective method for identifying boletes species based on FT-MIR and three dimensional correlation spectroscopy projected image processing.

This study proposed the necessity of identifying the species for boletes in combination with the medicinal value, nutritional value and the problems existing in the industrial development of boletes. Based on the preprocessing of Fourier transform mid-infrared spectroscopy (FT-MIR) by 1st, 2nd, SNV, 2nd + MSC and 2nd + SG, Multilayer Perceptron (MLP) and CatBoost models were established. To avoid complex preprocessing and feature extraction, we try deep learning modeling methods based on image processing. In this paper, the concept of three-dimensional correlation spectroscopy (3DCOS) projection image was proposed, and 9 datasets of synchronous, asynchronous and integrative images are generated by computer method. In addition, 18 deep learning models were established for 9 image datasets with different sizes. The results showed that the accuracy of the three types of synchronous spectral models reached 100%, while the accuracy of the asynchronous spectral and integrative spectral models of 3DCOS projection images were 96.97% and 97.98% in the case of big datasets, which overcame the defects of poor modeling effect of asynchronous spectral and integrative spectral in previous two-dimensional correlation spectroscopy (2DCOS) studies. In conclusion, the modeling results of 3DCOS projection images are perfect, and we can apply this method to other identification fields in the future.

Effect of Capsaicin Atomization on Cough and Swallowing Function in Patients With Hemorrhagic Stroke: A Randomized Controlled Trial.

BACKGROUND: Patients with hemorrhagic stroke have high mortality and disability rates. Nevertheless, early rehabilitation interventions can improve their outcomes. We aimed to apply capsaicin atomization as early intervention to patients with hemorrhagic stroke and explore improvements in cough and swallowing functions. METHOD: Patients with hemorrhagic stroke were randomly divided into the control group, which received routine care, and the intervention group, which underwent the capsaicin solution nebulization scheme in addition to routine care. Differences in the presence/absence of cough reflex and number of coughs in response to capsaicin, the presence/absence of swallowing reflex in response to water, the presence/absence of postswallow residue, substance P (SP) concentration, and pulmonary inflammation between the two groups were determined before and after the intervention. RESULTS: A total of 53 patients with hemorrhagic stroke were included. Results showed no statistically significant difference in cough reflex in both groups after the intervention (p > .05). The degree of cough in the intervention group was stronger than that in the control group (p = .046). No statistically significant difference was observed in the number of patients with swallowing reflex in response to water between the groups (p > .05). The presence/absence of postswallow residue of the intervention group was stronger than that of the control group (p = .032). No statistically significant difference was observed between the Glasgow Coma Scale scores of the groups after the intervention (p > .05). SP in the intervention group was significantly increased (p = .031). The Clinical Pulmonary Infection Score was significantly lower in the control group, and the difference was statistically significant (p = .028). CONCLUSIONS: Capsaicin nebulization can help enhance the number of coughs in response to capsaicin, reduce postswallow residue, and increase the level of SP in patients with hemorrhagic stroke and has a positive effect on pulmonary inflammation. This study provides intervention points for cough and swallowing rehabilitation after a hemorrhagic stroke. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21956903.

LINC00998-encoded micropeptide SMIM30 promotes the G1/S transition of cell cycle by regulating cytosolic calcium level.

The biological functions of short open reading frame (sORF)-encoded micropeptides remain largely unknown. Here, we report that LINC00998, a previously annotated lncRNA, was upregulated in multiple cancer types and the sORF on LINC00998 encoded a micropeptide named SMIM30. SMIM30 was localized in the membranes of the endoplasmic reticulum (ER) and mitochondria. Silencing SMIM30 inhibited the proliferation of hepatoma cells in vitro and suppressed the growth of tumor xenografts and N-nitrosodiethylamine-induced hepatoma. Overexpression of the 5'UTR-sORF sequence of LINC00998, encoding wild-type SMIM30, enhanced tumor cell growth, but this was abolished when a premature stop codon was introduced into the sORF via single-base deletion. Gain- and loss-of-function studies revealed that SMIM30 peptide but not LINC00998 reduced cytosolic calcium level, increased CDK4, cyclin E2, phosphorylated-Rb and E2F1, and promoted the G1/S phase transition and cell proliferation. The effect of SMIM30 silencing was attenuated by a calcium chelator or the agonist of sarco/endoplasmic reticulum calcium ATPase (SERCA) pump. These findings suggest a novel function of micropeptide SMIM30 in promoting G1/S transition and cell proliferation by enhancing SERCA activity and reducing cytosolic calcium level.

Matrine, a potential c-Myc inhibitor, suppresses ribosome biogenesis and nucleotide metabolism in myeloid leukemia.

Previous studies have shown that matrine, a natural compound extracted from the herb Sophora flavescens, has a good anti-leukemia effect, but its key target and mechanism remains unclear. Here, we found that only c-Myc could respond rapidly to matrine treatment in three myeloid leukemia cell lines, and matrine inhibited both transcription and translation of c-Myc. Ribosome biogenesis and nucleotide metabolism, the key downstream of c-Myc, were significantly suppressed after matrine treatment. Therefore, our results confirmed that matrine is a special c-Myc inhibitor which suppresses ribosome biogenesis and nucleotide metabolism by inhibiting c-Myc in myeloid leukemia. This study provides scientific basis for the development of matrine derivatives to c-Myc-driven cancers.

Litter nitrogen concentration changes mediate effects of drought and plant species richness on litter decomposition.

Biodiversity loss, exotic plant invasion and climatic change are three important global changes that can affect litter decomposition. These effects may be interactive and these global changes thus need to be considered simultaneously. Here, we assembled herbaceous plant communities with five species richness levels (1, 2, 4, 8 or 16) and subjected them to a drought treatment (no, moderate or intensive drought) that was factorially combined with an invasion treatment (presence or absence of the non-native Symphyotrichum subulatum). We collected litter of these plant communities and let it decompose for 9 months in the plant communities from which it originated. Drought decreased litter decomposition, while invasion by S. subulatum had little impact. Increasing species richness decreased litter decomposition except under intensive drought. A structural equation model showed that drought and species richness affected litter decomposition indirectly through changes in litter nitrogen concentration rather than by altering quantity and diversity of soil meso-fauna or soil physico-chemical properties. The slowed litter decomposition under high species diversity originated from a sampling effect, specifically from low litter nitrogen concentrations in the two dominant species. We conclude that effects on litter decomposition rates that are mediated by changing concentrations of the limiting nutrient in litter need to be considered when predicting effects of global changes such as plant diversity loss.

[Epigenetic regulation of microglia-mediated innate immune memory and neurological diseases].

Microglia have the ability to mediate innate immune memory and can be reprogrammed by primary stimuli to enhance or inhibit the immune response of microglia to secondary stimuli. Inflammatory stimulation is an important factor for microglia to mediate innate immune memory. Single or repeated stimulation can induce microglia to form different phenotypes. Microglia-mediated innate immune response is involved in the regulation of immune memory. Enhancer modification is a key pathway of microglia epigenetic regulation, and the H3K27ac enhancer marker is closely related to immune training. TGF-ß1 mediates the interaction between IL-10 and IL-1ß, thereby influencing the microglial phenotype. Microglia glycolysis activity is increased after immune training, and oxidative phosphorylation is associated with immune tolerance. Innate immune memory is closely associated with neurodegenerative diseases, brain tumors, brain damage and psychosis. Further study on the mechanism of microglia-mediated innate immune memory is helpful to understand the occurrence and development of central nervous system diseases and provide new options for the treatment of central nervous system diseases.

Predicting mortality in acute ischaemic stroke treated with mechanical thrombectomy: analysis of a multicentre prospective registry.

OBJECTIVES: We aimed to determine predictors of mortality within 90 days and develop a simple score for patients with mechanical thrombectomy (MT). DESIGN: Analysis of a multicentre prospective registry. SETTING: In six participating centres, patients who had an acute ischaemic stroke (AIS) treated by MT between March 2017 and May 2018 were documented prospectively. PARTICIPANTS: 224 patients with AIS were treated by MT. RESULTS: Of 224 patients, 49 (21.9%) patients died, and 87 (38.8%) were independent. Variables associated with 90-day mortality were age, previous stroke, admission National Institutes of Health Stroke Scale (NIHSS), fasting blood glucose and occlusion site. Logistic regression identified four variables independently associated with 90-day mortality: age ≥80 years (OR 3.26, 95% CI 1.45 to 7.33), previous stroke (OR 2.33, 95% CI 1.04 to 5.21), admission NIHSS ≥18 (OR 2.37, 95% CI 1.13 to 4.99) and internal carotid artery or basilar artery occlusion (OR 2.92, 95% CI 1.34 to 6.40). Using these data, we developed predicting 90-day mortality of AIS with MT (PRACTICE) score ranging from 0 to 6 points. The receiver operator curve analysis found that PRACTICE score (area under the curve (AUC)=0.744, 95% CI 0.669 to 0.820) was numerically better than iScore (AUC=0.661, 95% CI 0.577 to 0.745) and Predicting Early Mortality of Ischemic Stroke score (AUC=0.638, 95% CI 0.551 to 0.725) for predicting 90-day mortality. CONCLUSIONS: We developed a simple score to estimate the 90-day mortality of patients who had an AIS treated with MT. But the score needs to be prospectively validated. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR-OOC-17013052).

Fish consumption, long-chain omega-3 fatty acids intake and risk of stroke: An updated systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Although fish consumption or omega-3 intake is associated with cardio- cerebrovascular disease including stroke, their correlation is still controversial. Therefore, this meta-analysis is to identify the relationship between the risk of stroke and fish consumption or omega-3 intake. METHODS AND STUDY DESIGN: We searched the PubMed, EMBASE and Cochrane Library databases as of May 2019. Multivariateadjusted risk ratios (RRs) with 95% confidence interval (CI) for stroke in different level intake of fish or Longchain omega-3 polyunsaturated fatty acids (LC ω3-PUFAs) were pooled using a random-effects meta-analysis. A dose-response analysis was conducted with the 2-stage generalized least-squares trend program. RESULTS: Our meta-analysis identified a total of 17 prospective cohort studies including 14986 strokes events in 672711 individuals. Meta-analysis revealed that the higher fish consumption was significantly associated with lower risk of stroke (RR=0.871, 95% CI: 0.779-0.975, p=0.016), especially with ischemic stroke (RR=0.808, 95% CI: 0.696- 0.937, p=0.005). Meantime, the combined RR of total stroke was 0.859 (95% CI: 0.769-0.959, p=0.007) for the highest versus lowest intake of LC ω3-PUFAs, and stratification analysis showed that higher LC ω3-PUFAs intake was associated with reduced stroke risk in women (RR=0.793, 95% CI: 0.706-0.891, p=0.000) but not in men. In addition, the dose-response analysis showed fish consumption with 1000g per month and LC ω3-PUFAs intake with 0.5g per month was associated with 17.3% (RR=0.927, 95% CI: 0.83-0.98) and 14% (RR=0.86, 95% CI: 0.78-0.95) lower risk of stroke, respectively. CONCLUSIONS: Both fish consumption and LC ω3-PUFAs intake were negatively associated with the risk of stroke, especially in women, which suggest that increased intake of fishery products and LC ω3-PUFAs may benefit primary prevention of stroke.

Morinda citrifolia (Noni) Juice Suppresses A549 Human Lung Cancer Cells via Inhibiting AKT/Nuclear Factor-κ B Signaling Pathway.

OBJECTIVE: To study the mechanism of the anti-tumor effect of Morinda citrifolia (noni). METHODS: The influences of noni juice on cell proliferation, apoptosis, invasion, migration and the activity of AKT/nuclear factor- κ B (NF- κ B) signaling pathway in A549 human lung cancer cells were detected by MTT, cell counting kit-8, colony formation, Annexin V/PI double labeling, transwell, scratch test and immunoblotting assay, respectively. A549 cells were inoculated into the right axilla of nude mice, followed by noni juice treatment. The body weight of the nude mice was weighed, and the tumor volume and weight were measured. Cell proliferation and expression of apoptosis-related proteins were measured by immunohistochemistry, and the activity of NF- κ B signaling pathway was measured by immunoblotting. RESULTS: The in vitro studies showed that noni juice inhibited the A549 cells proliferation, migration and invasion. Noni juice also promoted cells apoptosis in A549 cells. Immunoblotting assay showed that the phosphorylation level of AKT, p50, and STAT3 proteins was inhibited to different extents after noni juice treatment. The in vivo studies showed that noni juice effectively suppressed tumor formation of A549 cells in nude mice. Noni juice treatment inhibited the expression of Ki67, PCNA, and Bcl-2 protein in the tumor; while promoted the expression of caspase-3 protein. Additionally, we also found that noni juice treatment could restrain the activity of AKT/NF- κ B signaling pathway in the tumor tissue. CONCLUSION: Noni juice inhibited the proliferation of A549 lung cancer cells, induced apoptosis, and inhibited cell invasion and migration via regulating AKT/NF- κ B signaling pathway.

[Effect of butyl alcohol extract of Baitouweng Decoction on epithelial barrier of vaginal mucosa in mice with vulvovaginal candidiasis].

To investigate the effect of butyl alcohol extract of Baitouweng Decoction(BAEB) on the epithelial barrier of vaginal mucosa in mice with vulvovaginal candidiasis(VVC). Seventy-two female SPF Kunming mice were randomly divided into blank group, VVC model group, fluconazole group, and BAEB treatment groups(high, middle and low dose groups). Estradiol benzoate was injected subcutaneously qd alt, and Candida albicans(2×10~6 CFU·mL~(-1)) was inoculated into the vagina of mice during the pseudo estrus period for 7 days to construct a VVC model, followed by drug treatment for 7 days. Gram staining was used to observe the morphology of C. albicans in the vaginal secretions of mice; the amount of fungal load on the vaginal mucosa of mice was detected on agar plate; the pathological status of murine vaginal mucosa was observed by hematoxylin-eosin staining(HE); the integrity of mice vaginal mucosal epithelial barrier was observed by Masson's trichrome staining(MT), HE and periodic acid-schiff staining(PAS). Mucin-1 and mucin-4 protein expression levels of vaginal mucosal epithelial cells in mice were detected by immunohistochemistry; mucin-1 and mucin-4 protein expression levels on mucosal epithelial cells at 0 d, 3 d, and 7 d were determined by Western blot. The results showed that, in VVC model group, there were a large number of C. albicans hyphae and higher fungal load in vagina, within complete mucosal structure, cornified layer shed off, and the protein expression levels of mucin-1 and mucin-4 were significantly increased. After BAEB treatment, the hyphae in the vagina decreased; the fungal load decreased; the vaginal mucosal tissue damages were improved; the epithelial barrier was repaired, and mucin-1 and mucin-4 protein expression levels were down-regulated. The above results indicated that BAEB may play a role in the treatment of VVC by remodeling the integrity of the vaginal mucosal epithelial barrier.

Association of Metformin Use with Asthma Exacerbation in Patients with Concurrent Asthma and Diabetes: A Systematic Review and Meta-Analysis of Observational Studies.

Background: Asthma and diabetes are both diseases that affect a wide range of people worldwide. As a common treatment for diabetes, metformin has also been reported to be effective in improving asthma outcomes. We conducted a combined analysis to examine the efficacy of metformin in reducing asthma exacerbation in patients with concurrent asthma and diabetes. Methods: We searched the PubMed, Embase, and CENTRAL databases for articles published prior to April 2020 to find observational studies of individuals with concurrent asthma and diabetes that compared the risk of asthma exacerbation between metformin users and nonusers. Two researchers separately screened the studies, extracted data, and evaluated the risk of bias. The primary outcome was the adjusted risk of asthma exacerbation. The secondary outcomes were the adjusted risk of asthma-related hospitalization and emergency room visits. Review Manager was used for data analysis and plotting. I 2 and χ 2 tests were used to estimate heterogeneity. A random effects or fixed effects model was used depending on the heterogeneity. Odds ratios were calculated for dichotomous variables. Results: We included two studies with a total of 25252 patients. The pooled effect size showed that metformin was inversely associated with a risk of asthma exacerbation (OR = 0.65, 95% CI 0.28-1.48; χ 2 = 5.42, P=0.02; I 2 = 82%), asthma-related emergency department visits (OR = 0.81, 95% CI 0.74-0.89; χ 2 = 0.36, P=0.55; I 2 = 0%), and hospitalizations (OR = 0.43, 95% CI 0.14-1.29; χ 2 = 4.01, P=0.05; I 2 = 75%). Conclusion: This meta-analysis suggested that metformin decreased the risk of asthma-related emergency room visits for patients with concurrent asthma and diabetes. Metformin reduced the risk of asthma-related hospitalization and exacerbation but was not statistically significant. More randomized trials involving larger samples should be considered, and the mechanisms of these effects need to be fully elucidated.

Programming changes in GLUT1 mediated the accumulation of AGEs and matrix degradation in the articular cartilage of female adult rats after prenatal caffeine exposure.

Osteoarthritis is associated with intrauterine growth retardation (IUGR) and abnormal glucose metabolism. Our laboratory previously reported that prenatal caffeine exposure (PCE) can induce intrauterine maternal glucocorticoid (GC) overexposure in IUGR offspring and increase susceptibility to osteoarthritis after birth. In the present study, we demonstrated the essential role of glucose transporter 1 (GLUT1) programming changes in the increased matrix degradation of articular cartilage and susceptibility to osteoarthritis in female PCE adult offspring. In vivo, we found that PCE decreased the matrix content but did not significantly change the expression of matrix degradation-related genes in the articular cartilage of female fetal rats. The decreased expression of IGF1 and GLUT1 and the content of advanced-glycation-end-products (AGEs) were also detected. At different postnatal stages (2, 6, and 12 weeks), the cartilage matrix content decreased while the degradation-related genes expression increased in the PCE group. Meanwhile, the expression of IGF1 and GLUT1 and AGEs content in the local cartilage increased. In vitro, the expression levels of IGF1 and GLUT1 were inhibited by corticosterone but remained unchanged under caffeine treatment. Exogenous IGF1 can reverse the corticosterone-induced decrease in GLUT1 expression and promote AGEs production, while mifepristone (a glucocorticoid receptor inhibitor) reversed the corticosterone-induced low expression of IGF1 and GLUT1. Exogenous AGEs can increase the expression of inflammatory factors (IL-6 and TNF-α) and degradation-related genes, and decrease the matrix synthesis-related genes expression in chondrocyte. In conclusion, the GC-IGF1-GLUT1 axis mediated intrauterine dysplasia of articular cartilage, increased accumulation of AGEs and matrix degradation after birth in PCE female offspring, thereby increasing their susceptibility to osteoarthritis in adulthood.

A hMTR4-PDIA3P1-miR-125/124-TRAF6 Regulatory Axis and Its Function in NF kappa B Signaling and Chemoresistance.

BACKGROUND AND AIMS: DNA damage-induced NF-κB activation is a major obstacle to effective antitumour chemotherapy. Long noncoding RNAs (lncRNAs) that regulate chemoresistance of cancer cells remain largely unknown. This study aimed to characterize the lncRNAs that may affect chemotherapy sensitivity. APPROACH AND RESULTS: We found that lncRNA PDIA3P1 (protein disulfide isomerase family A member 3 pseudogene 1) was up-regulated in multiple cancer types and following treatment with DNA-damaging chemotherapeutic agents, like doxorubicin (Dox). Higher PDIA3P1 level was associated with poorer recurrence-free survival of human hepatocellular carcinoma (HCC). Both gain-of-function and loss-of-function studies revealed that PDIA3P1 protected cancer cells from Dox-induced apoptosis and allowed tumor xenografts to grow faster and to be more resistant to Dox treatment. Mechanistically, miR-125a/b and miR-124 suppressed the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6), but PDIA3P1 bound to miR-125a/b/miR-124 and relieved their repression on TRAF6, leading to activation of the nuclear factor kappa B (NF-κB) pathway. Consistently, the effect of PDIA3P1 inhibition in promoting Dox-triggered apoptosis was antagonized by silencing the inhibitor of κBα (IκBα) or overexpressing TRAF6. Administration of BAY 11-7085, an NF-κB inhibitor attenuated PDIA3P1-induced resistance to Dox treatment in mouse xenografts. Moreover, up-regulation of PDIA3P1 was significantly correlated with elevation of TRAF6, phosphorylated p65, or NF-κB downstream anti-apoptosis genes in human HCC tissues. These data indicate that enhanced PDIA3P1 expression may confer chemoresistance by acting as a microRNA sponge to increase TRAF6 expression and augment NF-κB signaling. Subsequent investigations into the mechanisms of PDIA3P1 up-regulation revealed that human homologue of mRNA transport mutant 4 (hMTR4), which promotes RNA degradation, could bind to PDIA3P1, and this interaction was disrupted by Dox treatment. Overexpression of hMTR4 attenuated Dox-induced elevation of PDIA3P1, whereas silencing hMTR4 increased PDIA3P1 level, suggesting that Dox may up-regulate PDIA3P1 by abrogating the hMTR4-mediated PDIA3P1 degradation. CONCLUSION: There exists a hMTR4-PDIA3P1-miR-125/124-TRAF6 regulatory axis that regulates NF-κB signaling and chemoresistance, which may be exploited for anticancer therapy.