Carnosine ameliorates postoperative cognitive dysfunction of aged rats by limiting astrocytes pyroptosis.

Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly patients, and neuroinflammation is a key hallmark. Recent studies suggest that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-mediated astrocytes pyroptosis is involved in the regulation of neuroinflammation in many neurocognitive diseases, while its role in POCD remains obscure. Carnosine is a natural endogenous dipeptide with anti-inflammatory and neuroprotective effects. To explore the effect of carnosine on POCD and its mechanism, we established a POCD model by exploratory laparotomy in 24-month-old male Sprague-Dawley rats. We found that the administrated of carnosine notably attenuated surgery-induced NLRP3 inflammasome activation and pyroptosis in astrocytes, central inflammation, and neuronal damage in the hippocampus of aged rats. In addition, carnosine dramatically ameliorated the learning and memory deficits of surgery-induced aged rats. Then in the in vitro experiments, we stimulated primary astrocytes with lipopolysaccharide (LPS) after carnosine pretreatment. The results also showed that the application of carnosine alleviated the activation of the NLRP3 inflammasome, pyroptosis, and inflammatory response in astrocytes stimulated by LPS. Taken together, these findings suggest that carnosine improves POCD in aged rats via inhibiting NLRP3-mediated astrocytes pyroptosis and neuroinflammation.

A meta-analysis of UCA1 accuracy in the detection of bladder cancer.

INTRODUCTION: Bladder cancer (BCa) exhibits a relatively high prevalence, yet convenient tools for its early detection are lacking. Our study aims to assess the diagnostic value of Urothelial Carcinoma-Associated 1 (UCA1) in the early detection of BCa. METHODS: Systematic searches were performed in electronic databases (PubMed, Web of Science, Science Direct, CNKI, Wanfang, and VIP) until 20 July 2023. QUADAS-2 was used for quality assessment, while Meta-DiSc 1.4 and STATA 14.0 were employed for statistical analysis. RESULTS: A total of 1252 BCa patients and 779 controls, from 12 identified articles, were included. UCA1 showed strong discriminatory ability in BCa detection, with an overall sensitivity of 0.84 specificity of 0.91, and a 0.91 area under the curve (AUC). Strikingly, UCA1 expressed in urine and tissue exhibited higher diagnostic value (0.92 AUC) compared to that in blood (0.86 AUC). Furthermore, urine UCA1 demonstrated remarkable diagnostic performance with 91% sensitivity and 98% specificity. Deeks' funnel plot detected no substantial publication bias. CONCLUSION: UCA1 could serve as a potential biomarker for BCa detection with good diagnostic performance. Besides, compared to UCA1 in blood, urine and tissue UCA1 exhibited higher diagnostic value. Further prospective clinical research is needed to corroborate the conclusion. PROSPERO REGISTRATION: CRD42023463210.

Skeletal interoception in osteoarthritis.

The interoception maintains proper physiological conditions and metabolic homeostasis by releasing regulatory signals after perceving changes in the internal state of the organism. Among its various forms, skeletal interoception specifically regulates the metabolic homeostasis of bones. Osteoarthritis (OA) is a complex joint disorder involving cartilage, subchondral bone, and synovium. The subchondral bone undergoes continuous remodeling to adapt to dynamic joint loads. Recent findings highlight that skeletal interoception mediated by aberrant mechanical loads contributes to pathological remodeling of the subchondral bone, resulting in subchondral bone sclerosis in OA. The skeletal interoception is also a potential mechanism for chronic synovial inflammation in OA. In this review, we offer a general overview of interoception, specifically skeletal interoception, subchondral bone microenviroment and the aberrant subchondral remedeling. We also discuss the role of skeletal interoception in abnormal subchondral bone remodeling and synovial inflammation in OA, as well as the potential prospects and challenges in exploring novel OA therapies that target skeletal interoception.

Research on the potential mechanism of Deapioplatycodin D against pulmonary fibrosis based on bioinformatics and experimental verification.

BACKGROUND: Pulmonary fibrosis (PF) is a group of respiratory diseases that are extremely complex and challenging to treat. Due to its high mortality rate and short survival, it's often referred to as a "tumor-like disease" that poses a serious threat to human health. OBJECTIVE: We aimed validate the potential of Deapioplatycodin D (DPD) to against PF and clarify the underlying mechanism of action of DPD for the treatment of PF based on bioinformatics and experimental verification. This finding provides a basis for the development of safe and effective therapeutic PF drugs based on DPD. METHODS: We used LPS-induced early PF rats as a PF model to test the overall efficacy of DPD in vivo. Then, A variety of bioinformatics methods, such as WGCNA, LASSO algorithm and immune cell infiltration (ICI), were applied to analyze the gene microarray related to PF obtained from Gene Expression Omnibus (GEO) to obtained key targets of PF. Finally, an in vitro PF model was constructed based on BEAS-2B cells while incorporating rat lung tissues to validate the regulatory effects of DPD on critical genes. RESULTS: DPD can effectively alleviate inflammatory and fibrotic markers in rat lungs. WGCNA analysis resulted in a total of six expression modules, with the brown module having the highest correlation with PF. Subsequently, seven genes were acquired by intersecting the genes in the brown module with DEGs. Five key genes were identified as potential biomarkers of PF by LASSO algorithm and validation dataset verification analysis. In the ICI analysis, infiltration of activated B cell, immature B cell and natural killer cells were found to be more crucial in PF. Ultimately, it was observed that DPD could modulate key genes to achieve anti-PF effects. CONCLUSION: In short, these comprehensive analysis methods were employed to identify critical biomarkers closely related to PF, which helps to elucidate the pathogenesis and potential immunotherapy targets of PF. It also provides essential support for the potential of DPD against PF.

[Brain magnetic resonance image registration based on parallel lightweight convolution and multi-scale fusion].

Medical image registration plays an important role in medical diagnosis and treatment planning. However, the current registration methods based on deep learning still face some challenges, such as insufficient ability to extract global information, large number of network model parameters, slow reasoning speed and so on. Therefore, this paper proposed a new model LCU-Net, which used parallel lightweight convolution to improve the ability of global information extraction. The problem of large number of network parameters and slow inference speed was solved by multi-scale fusion. The experimental results showed that the Dice coefficient of LCU-Net reached 0.823, the Hausdorff distance was 1.258, and the number of network parameters was reduced by about one quarter compared with that before multi-scale fusion. The proposed algorithm shows remarkable advantages in medical image registration tasks, and it not only surpasses the existing comparison algorithms in performance, but also has excellent generalization performance and wide application prospects.

Prognostic value of different radiation-related cell death genes in patients with lung adenocarcinoma.

BACKGROUND AND AIMS: Radiotherapy is widely applied for lung adenocarcinoma (LUAD), while individualized differences led to different outcomes. This study aimed to establish a multi-gene risk scoring model to predict the benefits of LUAD patients from radiotherapy, based on different types of cell death respectively. RESULTS: Other than autophagy, pyroptosis, ferroptosis and Immunogenic cell death (ICD), the LUAD prognostic model based on apoptosis had the best performance, and the area under curves (AUCs) of the receiver operating curve (ROC) for 1-, 3-, and 5-year OS were 0.700,0.736,0.723,respectively. Such genes were involved as SLC7A5, EXO1, ABAT, NLRP1 and GAR1. Then patients were divided into high and low risk groups by the median apoptosis-LUAD risk score. For patients in the high-risk group, i.e., the radiotherapy-tolerant group, we screened adjuvant chemotherapy and found that besides the conventional first-line chemotherapy regimen, drugs such as Fludarabine, Pevonedistat, and Podophyllotoxin Bromide may also have potential therapeutic value. CONCLUSION: The multi-gene risk scoring model based on apoptosis might predict the radiotherapy benefits of LUAD patients and for those radioresistant patients classified by the model we also provided effective adjuvant chemicals, which would be used to guide clinical treatment.

A dominant negative mutation of GhMYB25-like alters cotton fiber initiation, reducing lint and fuzz.

Cotton (Gossypium hirsutum) fibers, vital natural textile materials, are single-cell trichomes that differentiate from the ovule epidermis. These fibers are categorized as lint (longer fibers useful for spinning) or fuzz (shorter, less useful fibers). Currently, developing cotton varieties with high lint yield but without fuzz remains challenging due to our limited knowledge of the molecular mechanisms underlying fiber initiation. This study presents the identification and characterization of a naturally occurring dominant negative mutation GhMYB25-like_AthapT, which results in a reduced lint and fuzzless phenotype. The GhMYB25-like_AthapT protein exerts its dominant negative effect by suppressing the activity of GhMYB25-like during lint and fuzz initiation. Intriguingly, the negative effect of GhMYB25-like_AthapT could be alleviated by high expression levels of GhMYB25-like. We also uncovered the role of GhMYB25-like in regulating the expression of key genes such as GhPDF2 (PROTODERMAL FACTOR 2), CYCD3; 1 (CYCLIN D3; 1) and PLD (Phospholipase D), establishing its significance as a pivotal transcription factor in fiber initiation. We identified other genes within this regulatory network, expanding our understanding of the determinants of fiber cell fate. These findings offer valuable insights for cotton breeding and contribute to our fundamental understanding of fiber development.

Self-Assembled Monolayers of a Fluorinated Phosphonic Acid as a Protective Coating on Aluminum.

Aluminum (Al) placed in hot water (HW) at 90 °C is roughened due to its reaction with water, forming Al hydroxide and Al oxide, as well as releasing hydrogen gas. The roughened surface is thus hydrophilic and possesses a hugely increased surface area, which can be useful in applications requiring hydrophilicity and increased surface area, such as atmospheric moisture harvesting. On the other hand, when using HW to roughen specified areas of an Al substrate, ways to protect the other areas from HW attacks are necessary. We demonstrated that self-assembled monolayers (SAMs) of a fluorinated phosphonic acid (FPA, CF3(CF2)13(CH2)2P(=O)(OH)2) derivatized on the native oxide of an Al film protected the underneath metal substrate from HW attack. The intact wettability and surface morphology of FPA-derivatized Al subjected to HW treatment were examined using contact angle measurement, and scanning electron microscopy and atomic force microscopy, respectively. Moreover, the surface and interface chemistry of FPA-derivatized Al before and after HW treatment were investigated by time-of-flight secondary ion mass spectrometry (ToF-SIMS), verifying that the FPA SAMs were intact upon HW treatment. The ToF-SIMS results therefore explained, on the molecular level, why HW treatment did not affect the underneath Al at all. FPA derivatization is thus expected to be developed as a patterning method for the formation of hydrophilic and hydrophobic areas on Al when combined with HW treatment.

A Multifunctional Bimetallic Nanoplatform for Synergic Local Hyperthermia and Chemotherapy Targeting HER2-Positive Breast Cancer.

Anti-HER2 (human epidermal growth factor receptor 2) therapies significantly increase the overall survival of patients with HER2-positive breast cancer. Unfortunately, a large fraction of patients may develop primary or acquired resistance. Further, a multidrug combination used to prevent this in the clinic places a significant burden on patients. To address this issue, this work develops a nanotherapeutic platform that incorporates bimetallic gold-silver hollow nanoshells (AuAg HNSs) with exceptional near-infrared (NIR) absorption capability, the small-molecule tyrosine kinase inhibitor pyrotinib (PYR), and Herceptin (HCT). This platform realizes targeted delivery of multiple therapeutic effects, including chemo-and photothermal activities, oxidative stress, and immune response. In vitro assays reveal that the HCT-modified nanoparticles exhibit specific recognition ability and effective internalization by cells. The released PYR inhibit cell proliferation by downregulating HER2 and its associated pathways. NIR laser application induces a photothermal effect and tumor cell apoptosis, whereas an intracellular reactive oxygen species burst amplifies oxidative stress and triggers cancer cell ferroptosis. Importantly, this multimodal therapy also promotes the upregulation of genes related to TNF and NF-κB signaling pathways, enhancing immune activation and immunogenic cell death. In vivo studies confirm a significant reduction in tumor volume after treatment, substantiating the potential effectiveness of these nanocarriers.

Esketamine Prevents Postoperative Emotional and Cognitive Dysfunction by Suppressing Microglial M1 Polarization and Regulating the BDNF-TrkB Pathway in Ageing Rats with Preoperative Sleep Disturbance.

Postoperative depression (POD) and postoperative cognitive dysfunction (POCD) have placed heavy burden on patients' physical and mental health in recent years. Sleep disturbance before surgery is a common phenomenon that has been increasingly believed to affect patients' recovery, especially in aged patients, while little attention has been paid to sleep disruption before surgery and the potential mechanism remains ambiguous. Ketamine has been reported to attenuate POCD after cardiac surgery and elicit rapid-acting and sustained antidepressant actions. The present study aimed to clarify the effect of esketamine's (the S-enantiomer of ketamine) protective effects and possible mechanisms of action in POCD and POD. Our results showed that sleep disturbance before surgery exacerbated microglial M1 polarization and microglial BDNF-TrkB signalling dysfunction induced by surgery, resulting in postoperative emotional changes and cognitive impairments. Notably, treatment with esketamine reversed the behavioural abnormalities through inhibiting the M1 polarization of microglia and the inflammatory response thus improving BDNF-TrkB signalling in vivo and vitro. In addition, esketamine administration also reversed the impaired hippocampal synaptic plasticity which has been perturbed by sleep disturbance and surgery. These findings warrant further investigations into the interplay of esketamine and may provide novel ideas for the implication of preoperative preparations and the prevention of postoperative brain-related complications.

Non-additive effects on biodegradation of moso bamboo litter- and broadleaf tree litter-leached dissolved organic matter mixtures in a subtropical forest of southern China.

Phyllostachys pubescens (moso bamboo) has extensively expanded to subtropical broadleaf forests. However, how moso bamboo expansion influences litter-leached dissolved organic matter (DOM) biodegradation is unclear. In this study, we collected fresh leaf litter of moso bamboo and 10 broadleaf tree species from a subtropical forest in southern China and extracted litter-leached dissolved organic carbon (DOC), dissolved total nitrogen (DTN), and dissolved total phosphorus (DTP). Then, using a 42-day incubation experiment, we measured litter-leached DOM biodegradation of the selected 11 species and assessed the relative mixing effects on biodegradation of bamboo litter- and broadleaf tree litter-leached DOM mixtures with volume mixing ratios of 1:3, 1:1, and 3:1. In the litter leachates, bamboo had lower DOC:DTN ratio, DOC:DTP ratio, and DOM aromaticity (i.e., lower SUVA254 and SUVA350 values) than most broadleaf tree species. Litter-leached DOM biodegradation did not differ among bamboo, Liquidambar formosana, Vernicia fordii, and Cyclobalanopsis glauca, but was greater for bamboo than for the other seven broadleaf tree species. Leaf litter-leached DOM biodegradation correlated negatively with DOC:DTN and DOC:DTP ratios, but exhibited no significant relationship with DOM aromaticity. Regardless of volume mixing ratios, antagonistic effects were observed when bamboo litter-leached DOM was mixed with broadleaf tree litter-leached DOM with comparable biodegradation, whereas synergistic effects occurred when bamboo litter-leached DOM was mixed with broadleaf tree litter-leached DOM with lower biodegradation. The relative mixing effects on DOM biodegradation increased linearly with elevated interspecific difference in litter-leached DOM biodegradation between bamboo and broadleaf tree species across the incubation periods. These findings indicate that moso bamboo expansion will substantially alter litter-leached DOM biodegradation by improving substrate quality and changing species interactions, and the magnitudes of such changing trends are dependent on the native tree litter-leached DOM biodegradation in subtropical broadleaf forests.

Lactobacillus reuteri inhibits Staphylococcus aureus-induced mastitis by regulating oxytocin releasing and gut microbiota in mice.

Mastitis is the most frequent disease of cows and has well-recognized detrimental effects on animal wellbeing and dairy farm profitability. With the advent of the postantibiotic era, alternative antibiotic agents, especially probiotics, have received increasing attention in the treatment of mastitis. Based on research showing that Lactobacillus reuteri (L. reuteri) has anti-inflammatory effects, this study explored the protective effects and mechanisms of L. reuteri against mastitis induced by Staphylococcus aureus (S. aureus) in mice. First, mice with S. aureus-induced mastitis were orally administered L. reuteri, and the inflammatory response in the mammary gland was observed. The results showed that L. reuteri significantly inhibited S. aureus-induced mastitis. Moreover, the concentration of oxytocin (OT) and protein expression of oxytocin receptor (OTR) were measured, and inhibition of OTR or vagotomy reversed the protective effect of L. reuteri or its culture supernatant (LCS) on S. aureus-induced mastitis. In addition, in mouse mammary epithelial cells (MMECs), OT inhibited the inflammation induced by S. aureus by inhibiting the protein expression of OTR. It was suggested that L. reuteri protected against S. aureus-induced mastitis by releasing OT. Furthermore, microbiological analysis showed that the composition of the microbiota was altered, and the relative abundance of Lactobacillus was significantly increased in gut and mammary gland after treatment with L. reuteri or LCS. In conclusion, our study found the L. reuteri inhibited the mastitis-induced by S. aureus via promoting the release of OT, and treatment with L. reuteri increased the abundance of Lactobacillus in both gut and mammary gland.

Identification of methane cycling pathways in Quaternary alluvial-lacustrine aquifers using multiple isotope and microbial indicators.

Groundwater rich in dissolved methane is often overlooked in the global or regional carbon cycle. Considering the knowledge gap in understanding the biogeochemical behavior of methane in shallow aquifers, particularly those in humid alluvial-lacustrine plains with high organic carbon content, we investigated methane sources and cycling pathways in groundwater systems at the central Yangtze River basins. Composition of multiple stable isotopes (2H/18O in water, 13C in dissolved inorganic carbon, 13C/2H in methane, and 13C in carbon dioxide) was combined with the characteristics of microbes and dissolved organic matter (DOM) in the study. The results revealed significant concentrations of biogenic methane reaching up to 13.05 mg/L in anaerobic groundwater environments with abundant organic matter. Different pathways for methane cycling (methanogenic CO2-reduction and acetate-fermentation, and methane oxidation) were identified. CO2-reduction dominated acetate-fermentation in the two methanogenic pathways primarily associated with humic DOM, while methane oxidation was more closely associated with microbially derived DOM. The abundance of obligate CO2-reduction microorganisms (Methanobacterium and Methanoregula) was higher in samples with substantial CO2-reduction, as indicated by isotopic composition. The obligate acetate-fermentation microorganism (Methanosaeta) was more abundant in samples exhibiting evident acetate-fermentation. Additionally, a high abundance of Candidatus Methanoperedens was identified in samples with apparent methane oxidation. Comparing our findings with those in other areas, we found that various factors, such as groundwater temperature, DOM abundance and types, and hydrogeological conditions, may lead to differences in groundwater methane cycling. This study offered a new perspective and understanding of methane cycling in worldwide shallow alluvial-lacustrine aquifer systems without geothermal disturbance.

Exosomes from bone marrow mesenchymal stem cells ameliorate glucocorticoid-induced osteonecrosis of femoral head by transferring microRNA-210 into bone microvascular endothelial cells.

OBJECTIVES: Bone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model. METHODS: BMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague-Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-ExosmiRNA-210 mimic or BMSC-ExosmiRNA-210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model. RESULTS: Different concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-ExosmiRNA-210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-ExosmiRNA-210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-ExosmiRNA-210 mimic, could increase microvascular density and enhance bone remodeling of femoral heads. CONCLUSIONS: BMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.

Hexadecanamide alleviates Staphylococcus aureus-induced mastitis in mice by inhibiting inflammatory responses and restoring blood-milk barrier integrity.

Subacute ruminal acidosis (SARA) has been demonstrated to promote the development of mastitis, one of the most serious diseases in dairy farming worldwide, but the underlying mechanism is unclear. Using untargeted metabolomics, we found hexadecanamide (HEX) was significantly reduced in rumen fluid and milk from cows with SARA-associated mastitis. Herein, we aimed to assess the protective role of HEX in Staphylococcus aureus (S. aureus)- and SARA-induced mastitis and the underlying mechanism. We showed that HEX ameliorated S. aureus-induced mastitis in mice, which was related to the suppression of mammary inflammatory responses and repair of the blood-milk barrier. In vitro, HEX depressed S. aureus-induced activation of the NF-κB pathway and improved barrier integrity in mouse mammary epithelial cells (MMECs). In detail, HEX activated PPARα, which upregulated SIRT1 and subsequently inhibited NF-κB activation and inflammatory responses. In addition, ruminal microbiota transplantation from SARA cows (S-RMT) caused mastitis and aggravated S. aureus-induced mastitis, while these changes were reversed by HEX. Our findings indicate that HEX effectively attenuates S. aureus- and SARA-induced mastitis by limiting inflammation and repairing barrier integrity, ultimately highlighting the important role of host or microbiota metabolism in the pathogenesis of mastitis and providing a potential strategy for mastitis prevention.

LINC02532 by Mediating miR-541-3p/HMGA1 Axis Exerts a Tumor Promoter in Breast cancer.

The newly discovered LINC02532 is abnormally expressed in a variety of cancers and promotes cancer progression. The research proposed to discover the biological and molecular mechanisms of LINC02532 in breast cancer (BCa). In the resected BCa tissue samples and adjacent normal tissues, LINC02532, miR-541-3p, and High Mobility Group A1 (HMGA1) levels were determined. Cell function experiments were carried out on the premise of cell transfection with relevant plasmids. Based on that, the influence of LINC02532, miR-541-3p, and HMGA1 on MCF-7 cell activities (proliferation, migration, invasion, cell cycle, and apoptosis) was determined, as well as on EMT. Additionally, animal experiments were allowed to support cell experimental conclusions on LINC02532. Finally, the mechanistic network of LINC02532, miR-541-3p, and HMGA1 was identified. It was BCa tissues highly expressing LINC02532 and HMGA1, while lowly expressing miR-541-3p. Functionally, LINC02532 depletion repressed the activities and EMT process of MCF-7 cells. Silencing LINC02532 delayed tumor growth in mice. In terms of mechanism, LINC02532 mainly existed in the cytoplasm and could mediate HMGA1 expression by absorbing miR-541-3p. The findings offer new insights into the molecular mechanisms of LINC02532 in BCa and, more importantly, new strategies for the clinical treatment of BCa.

Retinoic acid ameliorates low-grade endotoxemia-induced mastitis by limiting inflammatory responses in mice.

Mastitis is a serious disease for humans and animals, which causes huge economic losses in the dairy industry and is hard to prevent due to the complex and unclear pathogenesis. Subacute ruminal acidosis (SARA) has contributed to the development of mastitis by inducing ruminal dysbiosis and subsequent low-grade endotoxemia (LGE), however, how ruminal metabolic changes regulate this progress is still unclear. Our previous study revealed that cows with SARA had increased ruminal retinoic acid (RA) levels, a metabolic intermediate of vitamin A that plays an essential role in mucosal immune responses. Hence, the aim of this study was to investigate the protective effect of RA on LGE-induced mastitis and the underlying mechanisms in mice. The results showed that RA alleviated LGE-induced mastitis, as evidenced by RA significantly reduced the increase in mammary proinflammatory cytokines and improved blood-milk barrier injury caused by LGE. In addition, RA increased the expression of tight junction proteins, including ZO-1, occludin and claudin-3. Furthermore, we found that RA limited the mammary inflammatory responses by inhibiting the activation of NF-κB and NLRP3 signaling pathways. These findings suggest that RA effectively alleviates LGE-induced mastitis and implies a potential strategy for the treatment and prevention of mastitis and other diseases.

ITPR1-AS1 promotes small cell lung cancer metastasis by facilitating P21HRAS splicing and stabilizing DDX3X to activate the cRaf-MEK-ERK cascade.

The mechanisms underlying the involvement of long non-coding RNAs (lncRNAs) in the metastasis of small cell lung cancer (SCLC) remain largely unknown. Here, we identified that the lncRNA ITPR1-AS1 was upregulated in SCLC and lymph node metastasis tissues and positively correlated with SCLC malignant features. The overexpression of ITPR1-AS1 in SCLC was an independent risk factor for the overall survival of patients with SCLC. Our data confirmed that ITPR1-AS1 induces SCLC cell metastasis both in vitro and in vivo. Mechanistically, ITPR1-AS1 acts as a scaffold to enhance the interaction between SRC-associated in mitosis 68 kDa and heterogeneous nuclear ribonucleoprotein A1, which facilitates the alternative splicing of the H-Ras proto-oncogene (HRAS) pre-mRNA (P21HRAS). Moreover, we observed that ITPR1-AS1 could associate in a complex with and maintain the stability of DEAD-box polypeptide 3 (DDX3X), which inhibited the latter's ubiquitination and degradation. Our data provide evidence that ITPR1-AS1 activates the cRaf-MEK-ERK cascade by upregulating P21HRAS production and stabilizing DDX3X, to promote SCLC metastasis.

Efficacy of creatine nitrate supplementation on redox status and mitochondrial function in pectoralis major muscle of preslaughter transported broilers.

This study was purposed to investigate the efficacy of dietary creatine nitrate (CrN) supplementation on redox status and mitochondrial function in pectoralis major (PM) muscle of broilers that experienced preslaughter transport. A total of 288 Arbor Acres broilers (28-day-old) were randomly assigned into five dietary treatments, including a basal diet or the basal diet supplemented with 600 mg/kg guanidinoacetic acid (GAA), 300, 600, or 900 mg/kg CrN for 14 days, respectively. On the transportation day, the basal diet group was divided into two groups on average, resulting in six groups. The control group was transported for 0.5 h and the other groups for 3 h (identified as Control, T3h, GAA600, CrN300, CrN600, and CrN900 group, respectively), and all crates were randomly placed on the truck travelling at an average speed of 80 km/h. Our results showed that GAA600 and CrN treatments decreased the muscle ROS level and MDA content (P < 0.05) and increased the mitochondrial membrane potential (P < 0.001), as well as a higher mRNA expression of avUCP (P < 0.001) and lower mRNA expressions of Nrf2 (P < 0.001), Nrf2 and PGC-1α (P < 0.05) compared with T3h group. Meanwhile, the mRNA and protein expressions of Nrf1, TFAM, and PGC-1α in CrN600 and CrN900 groups were lower than those in the T3h group (P < 0.05). Conclusively, dietary supplementation with GAA and CrN decreased muscle oxidative products and enhanced mitochondrial uncoupling mechanism and mtDNA copy number, which relieved muscle oxidative damage and maintained mitochondrial function.

Assessing the Casual Association between Sex Hormone Levels and Fracture Risk: A Two-Sample Mendelian Randomization Study.

OBJECTIVE: Prior observational studies have reported that levels of sex hormones constitute a risk factor for the fracture. The aim of this study was to ascertain whether there is a causal relationship between the levels of sex hormones and the risk of fracture through Mendelian randomization (MR). METHODS: Single-nucleotide polymorphisms (SNPs) associated with two indicators of sex hormone levels, circulating sex hormone-binding globulin (SHBG) and bioavailable testosterone levels, as exposures were selected from a large genome-wide association study (GWAS) from UK Biobank. The summary statistics for 11 different types of fracture as outcomes from the FinnGen consortium. This study employed the two-sample MR approach. For the main analysis, the inverse-variance-weighted (IVW) method was utilized. To assess the heterogeneity of MR results, the IVW method and MR-Egger method were utilized. To evaluate potential pleiotropy, MR-Egger regression was conducted. Additionally, a leave-one-SNP-out test was performed to assess the robustness of MR results to the exclusion of any individual SNP. RESULTS: The MR analyses demonstrated a conspicuous impact of SHBG on the risk of pathological fracture with osteoporosis (OP). We found that an increase of one standard deviation (SD) in SHBG correspondingly increased the risk of pathological fracture with OP [odds ratio (OR) 2.42, 95% confidence interval (CI), 1.52-3.85; p = 1.93 × 10-4 ]. The bioavailable testosterone showed the negative casual genetic associations with fractures of foot and forearm. An increase of one SD in the genetically predetermined bioavailable testosterone was associated with a reduction of 37% in the risk of fracture of foot (OR 0.63, 95% Cl 0.49 to 0.81; p = 3.37 × 10-4 ), as well as a 39% decrease in the risk of fracture of forearm (OR 0.61, 95% Cl 0.50 to 0.76; p = 5.40 × 10-6 ). CONCLUSIONS: Our study confirms that individuals experiencing elevated SHBG concentrations showed a major causal effect on pathological fracture with OP. High bioavailable testosterone levels play an important role in preventing the fractures of foot and forearm. Although increasing bioavailable testosterone and decreasing SHBG levels had no casual effect on most fractures in the general population, they are likely to have the most clinically relevant effect on certain fracture risk reduction.