ALKBH5 regulates chicken adipogenesis by mediating LCAT mRNA stability depending on m6A modification.

BACKGROUND: Previous studies have demonstrated the role of N6-methyladenosine (m6A) RNA methylation in various biological processes, our research is the first to elucidate its specific impact on LCAT mRNA stability and adipogenesis in poultry. RESULTS: The 6 100-day-old female chickens were categorized into high (n = 3) and low-fat chickens (n = 3) based on their abdominal fat ratios, and their abdominal fat tissues were processed for MeRIP-seq and RNA-seq. An integrated analysis of MeRIP-seq and RNA-seq omics data revealed 16 differentially expressed genes associated with to differential m6A modifications. Among them, ELOVL fatty acid elongase 2 (ELOVL2), pyruvate dehydrogenase kinase 4 (PDK4), fatty acid binding protein 9 (PMP2), fatty acid binding protein 1 (FABP1), lysosomal associated membrane protein 3 (LAMP3), lecithin-cholesterol acyltransferase (LCAT) and solute carrier family 2 member 1 (SLC2A1) have ever been reported to be associated with adipogenesis. Interestingly, LCAT was down-regulated and expressed along with decreased levels of mRNA methylation methylation in the low-fat group. Mechanistically, the highly expressed ALKBH5 gene regulates LCAT RNA demethylation and affects LCAT mRNA stability. In addition, LCAT inhibits preadipocyte proliferation and promotes preadipocyte differentiation, and plays a key role in adipogenesis. CONCLUSIONS: In conclusion, ALKBH5 mediates RNA stability of LCAT through demethylation and affects chicken adipogenesis. This study provides a theoretical basis for further understanding of RNA methylation regulation in chicken adipogenesis.

Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.

Semaglutide alleviates early brain injury following subarachnoid hemorrhage by suppressing ferroptosis and neuroinflammation via SIRT1 pathway.

OBJECTIVES: Subarachnoid hemorrhage (SAH) is a major cause of incapacity and death, imposing a significant economic burden globally. Additionally, SAH is the third most prevalent form of stroke. Semaglutide affects oxidative stress, inflammation, and mitochondrial biogenesis. Specifically, the potential neuroprotective effect of semaglutide in SAH and its underlying mechanism is unclear. Accordingly, the present research intended to explore the neuroprotective effect of semaglutide in SAH and its potential molecular mechanisms. METHODS: We constructed a C57BL/6 mouse model of SAH. The parameters assessed were neuronal ferroptosis, neuroinflammatory cytokine levels, reactive oxygen species (ROS) levels, glutathione (GSH) and malondialdehyde (MDA) levels, brain water content, and neurological score. RESULTS: The results showed that the activation of semaglutide significantly increased neurological scores, relieved cerebral edema, decreased the levels of inflammatory cytokine nuclear factor kappa B, interleukin (IL)-1ß, IL-6, tumor necrosis factor-alpha, MDA, and ROS, and increased the levels of GSH. Suppression of SIRT1 reversed these effects, indicating that semaglutide activated SIRT1 to reduce neuroinflammation, ferroptosis, and neuronal cell death after SAH. Thus, the activation of the Nrf2/HO-1 signaling pathway contributes to the neuroprotective properties of semaglutide. CONCLUSIONS: Semaglutide can improve murine neurological outcomes and reduce neuronal damage against neuroinflammation and ferroptosis.

Case report and literature review of rezvilutamide in the treatment of hormone-sensitive prostate cancer.

Background: Prostate cancer represents a major health concern worldwide, with the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) and locally advanced prostate cancer posing a particular challenge. Rezvilutamide, a new androgen receptor antagonist from China, has shown early promise; however, its real-world effectiveness and safety profile require further evidence. This case series evaluates the preliminary clinical outcomes of rezvilutamide in combination with androgen deprivation therapy (ADT), focusing on PSA response and radiological findings across various stages of prostate cancer in four patients. Case description: Case 1 details a 68-year-old male with low-volume mHSPC who exhibited a positive therapeutic response, demonstrated by decreasing PSA levels and improved radiographic results, despite experiencing mild side effects related to the drug. Case 2 describes a 71-year-old male with high-volume mHSPC who had a favorable outcome, with no significant changes in tumor size or metastatic spread and no negative reactions to the drug. Case 3 involves a 55-year-old male with locally advanced prostate cancer, who saw a reduction in PSA levels and a small decrease in tumor volume, yet with ongoing bladder involvement. Genetic testing showed no significant mutations. Case 4 presents a 74-year-old male with extensive metastatic disease who initially responded to the treatment but later exhibited disease advancement and an ATM gene mutation, signaling a shift to metastatic castration-resistant prostate cancer (mCRPC). This finding underscores the crucial role of genetic testing in directing future treatment, with therapies such as olaparib or chemotherapy being advised. Conclusions: Rezvilutamide has shown a potential benefit in the management of mHSPC and locally advanced prostate cancer, generally with a mild safety profile. Initial positive responses, particularly in PSA decline and radiographic progression, are promising. Nevertheless, the varying responses, notably concerning genetic mutations, highlight the necessity for tailored treatment approaches. Due to the small cohort and brief follow-up period, more extensive research with larger populations and prolonged monitoring is essential to conclusively determine the benefits and safety of rezvilutamide. The utilization of genetic insights is key to refining treatment decisions and enhancing outcomes for patients with advanced prostate cancer.

Matrine Enhances the Antitumor Efficacy of Chidamide in CTCL by Promoting Apoptosis.

BACKGROUND: Cutaneous T-cell Lymphoma (CTCL) is a rare group of non-Hodgkin lymphoma originating from the skin, which is characterized by T-cell lymphoproliferative disorders. Chidamide, a Chinese original antineoplastic agent with independent intellectual property rights, and matrine, an extract of Chinese herbal medicine, both have been reported to exert effects on the treatment of tumors individually. However, chidamide combined with matrine has not been tested for the treatment of CTCL. METHODS: Both HH and Hut78 CTCL cell lines were treated with chidamide (0.4 µmol/L), matrine (0.6 g/L), or chidamide combined with matrine for 24, 48, and 72 h. Cell viability was estimated by MTS assay at each time point. Flow cytometry was then conducted to detect cell apoptosis. The exact mechanism of chidamide combined with matrine on CTCL cells was detected by Western blotting and further validated in xenograft models of NOD/SCID mice. RESULTS AND DISCUSSION: Compared to the single drug, chidamide combined with matrine showed a more significant effect on proliferation inhibition and apoptosis induction on CTCL cells both in vitro and in vivo. The results from the in vitro and in vivo studies suggested that matrine could enhance the anti-tumor effect of chidamide by increasing the protein expression of cleaved caspase- 3 and decreasing the expression of E-cadherin, NF-κB, p-Bad, and Bcl-2 to activate apoptosis. CONCLUSION: Our data have demonstrated chidamide combined with matrine to exhibit elevated antitumor activity in both CTCL cells and xenograft models of NOD/SCID mice, which may be a potential treatment option for CTCL.

Highly pathogenic PRRSV upregulates IL-13 production through nonstructural protein 9-mediated inhibition of N6-methyladenosine demethylase FTO.

Porcine reproductive and respiratory syndrome virus (PRRSV), a highly infectious virus, causes severe losses in the swine industry by regulating the inflammatory response, inducing tissue damage, suppressing the innate immune response, and promoting persistent infection in hosts. Interleukin-13 (IL-13) is a cytokine that plays a critical role in regulating immune responses and inflammation, particularly in immune-related disorders, certain types of cancer, and numerous bacterial and viral infections; however, the underlying mechanisms of IL-13 regulation during PRRSV infection are not well understood. In this study, we demonstrated that PRRSV infection elevates IL-13 levels in porcine alveolar macrophages. PRRSV enhances m6A-methylated RNA levels while reducing the expression of fat mass and obesity associated protein (FTO, an m6A demethylase), thereby augmenting IL-13 production. PRRSV nonstructural protein 9 (nsp9) was a key factor for this modulation. Furthermore, we found that the residues Asp567, Tyr586, Leu593, and Asp595 were essential for nsp9 to induce IL-13 production via attenuation of FTO expression. These insights delineate PRRSV nsp9's role in FTO-mediated IL-13 release, advancing our understanding of PRRSV's impact on host immune and inflammatory responses.

Aß-Aggregation-Generated Blue Autofluorescence Illuminates Senile Plaques as well as Complex Blood and Vascular Pathologies in Alzheimer's Disease.

Senile plaque blue autofluorescence was discovered around 40 years ago, however, its impact on Alzheimer's disease (AD) pathology has not been fully examined. We analyzed senile plaques with immunohistochemistry and fluorescence imaging on AD brain sections and also Aß aggregation in vitro. In DAPI or Hoechst staining, the nuclear blue fluorescence could only be correctly assigned after subtracting the blue plaque autofluorescence. The flower-like structures wrapping dense-core blue fluorescence formed by cathepsin D staining could not be considered central-nucleated neurons with defective lysosomes since there was no nuclear staining in the plaque core when the blue autofluorescence was subtracted. Both Aß self-oligomers and Aß/hemoglobin heterocomplexes generated blue autofluorescence. The Aß amyloid blue autofluorescence not only labels senile plaques but also illustrates red cell aggregation, hemolysis, cerebral amyloid angiopathy, vascular plaques, vascular adhesions, and microaneurysms. In summary, we conclude that Aß-aggregation-generated blue autofluorescence is an excellent multi-amyloidosis marker in Alzheimer's disease.

Linc-smad7 is involved in the regulation of lipid synthesis in mouse mammary epithelial cells.

Long intergenic non-coding RNA(lincRNA) is transcribed from the intermediate regions of coding genes and plays a pivotal role in the regulation of lipid synthesis. N6-methyladenosine (m6A) modification is widely prevalent in eukaryotic mRNAs and serves as a regulatory factor in diverse biological processes. This study aims to delineate the mechanism by which Linc-smad7 mediates m6A methylation to regulate milk fat synthesis. Tissue expression analysis in this study revealed a high expression of Linc-smad7 in breast tissue during pregnancy. Cell proliferation assays, including CCK8 and EdU assays, demonstrated that Linc-smad7 had no significant impact on the proliferation of mammary epithelial cells. However, during mammary epithelial cell differentiation, the overexpression of Linc-smad7 led to reduced lipid formation, whereas interference with Linc-smad7 promoted lipogenesis. Mechanistically, Linc-smad7 was found to modulate RNA m6A levels, as evidenced by dot blot assays and methylated RNA immunoprecipitation sequencing (MeRIP-Seq). Subsequent validation through RT-qPCR corroborated these findings, aligning with the m6A sequencing outcomes. Furthermore, co-transfection experiments elucidated that Linc-smad7 regulates lipid synthesis in mammary epithelial cells by influencing the expression of METTL14. In summary, these findings underscore the regulatory role of Linc-smad7 in controlling METTL14 gene expression, thereby mediating m6A modifications to regulate lipid synthesis in mammary epithelial cells.

Mechanochemically Reprogrammed Interface Orchestrates Neutrophil Bactericidal Activity and Apoptosis for Preventing Implant-Associated Infection.

The onset of implant-associated infection (IAI) triggers a cascade of immune responses, which are initially dominated by neutrophils. Bacterial aggregate formation and hypoxic microenvironment, which occur shortly after implantation, may be two major risk factors that impair neutrophil function and lead to IAI. Here, the implant surface with phytic acid-Zn2+ coordinated TiO2 nanopillar arrays (PA-Zn@TiNPs) and oxygen self-supporting CaO2 nanoparticles, named as CPZTs, is mechanochemically reprogrammed. The engineered CPZTs interface integrates multiple properties to inhibit the formation of nascent biofilm, encompassing antibacterial adhesion, mechanobactericidal effect, and chemobiocidal effect. Meanwhile, continuous oxygenation fuels the neutrophils with reactive oxygen species (ROS) for efficient bacterial elimination on the implant surface and inside the neutrophils. Furthermore, this surface modulation strategy accelerates neutrophil apoptosis and promotes M2 macrophage-mediated osteogenesis both in vitro and in a rat model of IAI. In conclusion, targeting neutrophils for immunomodulation is a practical and effective strategy to prevent IAI and promote bone-implant integration.

mTORC1 Mediates Biphasic Mechano-Response to Orchestrate Adhesion-Dependent Cell Growth and Anoikis Resistance.

Cells constantly sense and respond to not only biochemical but also biomechanical changes in their microenvironment, demanding for dynamic metabolic adaptation. ECM stiffening is a hallmark of cancer aggressiveness, while survival under substrate detachment also associates with poor prognosis. Mechanisms underlying this, non-linear mechano-response of tumor cells may reveal potential double-hit targets for cancers. Here, an integrin-GSK3ß-FTO-mTOR axis is reported, that can integrate stiffness sensing to ensure both the growth advantage endowed by rigid substrate and cell death resistance under matrix detachment. It is demonstrated that substrate stiffening can activate mTORC1 and elevate mTOR level through integrins and GSK3ß-FTO mediated mRNA m6 A modification, promoting anabolic metabolism. Inhibition of this axis upon ECM detachment enhances autophagy, which in turn conveys resilience of tumor cells to anoikis, as it is demonstrated in human breast ductal carcinoma in situ (DCIS) and mice malignant ascites. Collectively, these results highlight the biphasic mechano-regulation of cellular metabolism, with implications in tumor growth under stiffened conditions such as fibrosis, as well as in anoikis-resistance during cancer metastasis.

Leukocyte telomere length mediates the association between cadmium exposure and cognitive function in US older adults.

BACKGROUND: Long-term exposure to cadmium-polluted environments may lead to shortened leukocyte telomere length and cognitive decline. This study aims to investigate (1) the associations among blood cadmium levels, leukocyte telomere length, and cognitive function, and (2) the mediating role of leukocyte telomere length between blood cadmium levels and cognitive function among older adults in the United States. METHODS: Using data from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Cadmium exposure level was assessed by measuring cadmium levels in blood samples. Leukocyte telomere length was measured by quantitative polymerase chain reaction, and cognitive function was measured by the digit symbol substitution test (DSST). RESULTS: A total of 2185 older adults aged over 60 were included in this study, comprising 1109 (49.65%) males. Elevated blood cadmium levels were significantly associated with the risk of a decline in cognitive function (ß = - 2.842, p = 0.018). Shorter leukocyte telomere lengths were significantly associated with a higher risk of a decline in cognitive function (ß = 4.144, p = 0.020). The total indirect effect on the blood cadmium level and cognitive function via leukocyte telomere length was - 0.218 (p = 0.012). The mediation effect was estimated to be 0.218/2.084 × 100% = 10.46%. CONCLUSION: The findings suggest that cadmium exposure may increase the risk of cognitive impairment by causing shortened leukocyte telomere length.

Machine learning and experiments identifies SPINK1 as a candidate diagnostic and prognostic biomarker for hepatocellular carcinoma.

Machine learning techniques have been widely used in predicting disease prognosis, including cancer prognosis. One of the major challenges in cancer prognosis is to accurately classify cancer types and stages to optimize early screening and detection, and machine learning techniques have proven to be very useful in this regard. In this study, we aimed at identifying critical genes for diagnosis and outcomes of hepatocellular carcinoma (HCC) patients using machine learning. The HCC expression dataset was downloaded from GSE65372 datasets and TCGA datasets. Differentially expressed genes (DEGs) were identified between 39 HCC and 15 normal samples. For the purpose of locating potential biomarkers, the LASSO and the SVM-RFE assays were performed. The ssGSEA method was used to analyze the TCGA to determine whether there was an association between SPINK1 and tumor immune infiltrates. RT-PCR was applied to examine the expression of SPINK1 in HCC specimens and cells. A series of functional assays were applied to examine the function of SPINK1 knockdown on the proliferation of HCC cells. In this study, 103 DEGs were obtained. Based on LASSO and SVM-RFE analysis, we identified nine critical diagnostic genes, including C10orf113, SPINK1, CNTLN, NRG3, HIST1H2AI, GPRIN3, SCTR, C2orf40 and PITX1. Importantly, we confirmed SPINK1 as a prognostic gene in HCC. Multivariate analysis confirmed that SPINK1 was an independent prognostic factor for overall survivals of HCC patients. We also found that SPINK1 level was positively associated with Macrophages, B cells, TFH, T cells, Th2 cells, iDC, NK CD56bright cells, Th1 cells, aDC, while negatively associated with Tcm and Eosinophils. Finally, we demonstrated that SPINK1 expression was distinctly increased in HCC specimens and cells. Functionally, silence of SPINK1 distinctly suppressed the proliferation of HCC cells via regulating Wnt/ß-catenin pathway. The evidence provided suggested that SPINK1 may possess oncogenic properties by inducing dysregulated immune infiltration in HCC. Additionally, SPINK1 was identified as a novel biomarker and therapeutic target for HCC.

Composition and Bioactivity of Chlorogenic Acids in Vegetable and Conventional Sweet Potato Vine Tips.

Sweet potato vine tips are abundant in chlorogenic acid (CGA). In this study, CGA was extracted from vegetable and conventional sweet potato vine tips using ethanol, followed by subsequent purification of the extract through a series of sequential steps. Over 4 g of the purified product was obtained from 100 g of sweet potato vine tip powder, producing more than 85% of purified CGA. The LC-MS analysis of all samples indicated that 4-CQA was the predominant isomer in both sweet potato cultivars. Significant variations of p-coumaroyl quinic acids, feruloyl quinic acids, dicaffeoyl quinic acids, and tricaffeoyl quinic acid were identified, whereas the mono-caffeoyl quinic acids did not vary when the two sweet potato varieties were compared. Compared to conventional sweet potatoes, vegetable sweet potatoes exhibit a high negative correlation between 4-CQA and 5-pCoQA, while showing a high positive correlation between 3,5-CQA and 3-pCoQA. A series of principal component analyses (PCA) using CGA isomers enables a clear differentiation between vine tips derived from vegetable and conventional sweet potatoes. The model of linear discriminant analysis, based on the characteristic CGA, achieved a 100% accuracy rate in distinguishing between vegetable and conventional sweet potatoes. The high purity of sweet potato CGA (SCGA) exhibited potent anti-breast cancer activity. The results demonstrated that SCGA significantly suppressed the clonogenicity of MB231 and MCF7 cells, and impeded the migratory, invasive, and lung metastatic potential of MB231 cells.

An 8-year follow-up of IgG4-related skin disease presented with generalized ALHE-like eruptions: successful treatment of glucocorticoid and cyclophosphamide.

Immunoglobulin gamma (IgG) type 4-related disease (IgG4-RD) is a chronic immunologic systemic disorder that could affect multiple organs, which may cause irreversible organ damage or even death. Skin involvement is rare and associated especially with systemic disease. The dermatologist must be equipped to recognize IgG4-RD to prevent delayed identification and treatment. This case reports a very rare case of IgG4-related skin disease (IgG4-RSD) presenting with a generalized angiolymphoid hyperplasia with eosinophilia (ALHE)-like lesions in a middle-aged male patient with no other organ involvement. He was treated with oral glucocorticoid and cyclophosphamide, which resulted in complete remission. No relapse and disease progression were seen with a follow-up for 8 years.

Capping Layer Determined Self-assembly of Au-Ag Bimetallic Janus Nanoparticles at An Oil/Water Interface by Molecular Dynamics Simulations.

Bimetallic Janus nanoparticles (BJNPs) have gained more attention due to their unique catalytic and optical properties. The self-assembly of BJNPs is expected as an effective way to fabricate metamaterials suitable for different potential applications. However, the self-assembly dynamic process of BJNPs, which is key to achieving a controllable synthesis, is limited in both experimental and theoretical investigations. Herein, all-atom molecular dynamics (MD) simulations were employed to investigate the self-assembly process of 1-dodecanethiol (DDT)-decorated Au-Ag BJNPs at an oil-water interface. We demonstrate that DDT's van der Waals (vdW) interaction dominates the self-assembly process. BJNPs form close-packed structures at both fast and slow evaporation rates. Au-Ag BJNPs exhibit relatively larger rotations at a low evaporation rate than those at a high evaporation rate, suggesting that the evaporation rate influences the orientation of the Au-Ag BJNPs. BJNPs tend to orient their electric dipole moments toward the external electric field, according to the ab initio MD simulation results. Based on the energy comparison and model analysis, it is found that the parallel array is more stable than the antiparallel one for the Au-Ag BJNP arrays. The dipole-dipole interaction difference between the parallel and antiparallel BJNP arrays obtained according to dipole moment obtained from ab initio calculation is qualitatively consistent with that obtained from MD simulations, indicating that the dipole plays a decisive role in determining the orientation of the BJNP array. This work uncovers the self-assembly dynamic process of BJNPs, paving the way for future applications.

Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis.

BACKGROUND: Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with the initiation and progression of Triple-negative breast cancer (TNBC). The publicly available TCGA database of breast cancer data was used to analyze the OTUD deubiquitinating family members that were correlated with survival of breast cancer and ovarian tumor domain-containing 2 (OTUD-2), or YOD1 was identified. The aim of present study was to assess YOD1 expression and function in human TNBC and then explored the underlying molecular events. METHODS: We detected the expression of YOD1 in 32 TNBC and 44 NTNBC samples by qRT-PCR, Western blot and immunohistochemistry. Manipulation of YOD1 expression was assessed in vitro and in vivo for TNBC cell proliferation, migration, invasion, cell-cycle and drug resistance, using colony formation assay, transwell assay, CCK8 assay, TUNEL assay, flow cytometric analysis and xenograft tumor assay. Next, proteomic analysis, Western blot, proximity ligation assay, Immunoprecipitation, and Immunofluorescence were conducted to assess downstream targets. RESULTS: It was found that YOD1 was significantly upregulated in TNBC tissues compared with non-triple-negative breast cancer (NTNBC), which was positively correlated with poor survival in TNBC patients. Knockdown of YOD1 effectively inhibited TNBC cell migration, proliferation, cell cycle and resistance to cisplatin and paclitaxel. Mechanistically, YOD1 promoted TNBC progression in a manner dependent on its catalytic activity through binding with CDK1, leading to de-polyubiquitylation of CDK1 and upregulation of CDK1 expression. In addition, YOD1 overexpression was found to be correlated with CDK1 overexpression in human TNBC specimens. Finally, in vivo study demonstrated that YOD1 knockdown or YOD1 inhibitor could inhibit CDK1 expression and suppress the growth and metastasis of TNBC tumors. CONCLUSION: Our study highlights that YOD1 functions as an oncogene in TNBC via binding to CDK1 and mediated its stability and oncogenic activity. Interfering with YOD1 expression or YOD1 inhibitor could suppress TNBC cells in vitro and in vivo, suggesting that YOD1 may prove to be a promising therapeutic target for TNBC.

A novel genes-based signature with prognostic value and predictive ability to select patients responsive to Atezolizumab treatment in bladder cancer: an analysis on data from real-world studies.

Background: There is a lack of molecular markers that effectively predict response to treatment with immune checkpoint inhibitors in patients with uroepithelial bladder carcinoma. The purpose of this study was to explore molecular markers that effectively predict the efficacy of Atezolizumab in the treatment of uroepithelial bladder carcinoma based on real-world clinical trial data. Methods: Gene expression and clinical information of two groups of patients in two datasets, IMvigor210 and GSE176307, who were treated effectively and ineffectively with the programmed cell death 1 ligand 1 (PD-L1) inhibitor Atezolizumab, were obtained. Bioinformatic methods were used to screen out differentially expressed genes and detect the correlation between their expression and immune-related indicators. Subsequently, we assessed the ability of differentially expressed genes to predict the therapeutic response and prognosis of bladder cancer patients following Atezolizumab treatment. Results: A total of 2 differentially expressed genes, CXC motif chemokine ligand 9 (CXCL9) and CXC motif chemokine ligand 10 (CXCL10) [all P<0.05, log|fold change (FC)| >1], which were co-upregulated, were screened as study targets. In The Cancer Genome Atlas (TCGA) database, CXCL9/10 mRNA expression was positively correlated with both PD-L1 and tumor mutation burden (TMB) (all P<0.05). In the IMvigor210 dataset, the area under the receiver operating characteristic (ROC) curve for CXCL9, CXCL10 and PD-L1 mRNA expression to predict response to treatment with Atezolizumab were 0.645, 0.636 and 0.566, respectively; And CXCL9/10 mRNA was effective in predicting overall survival in patients receiving treatment (all P<0.05). In the GSE176307 dataset, the area under the ROC curve for CXCL9, CXCL10 and PD-L1 mRNA expression to predict response to treatment with Atezolizumab were 0.829, 0.829 and 0.765, respectively; And CXCL9/10 mRNA was not effective in predicting overall survival in patients receiving treatment (all P>0.05). Conclusions: The mRNA expression levels of CXCL9/10 have the potential to serve as a molecular marker for predicting the therapeutic response and overall survival outcomes of bladder cancer patients treated with Atezolizumab.

Comprehensive Genome and Transcriptome Analysis Identifies SLCO3A1 Associated with Aggressive Behavior in Pigs.

Copy number variation (CNV) represents a significant reservoir of genetic diversity within the genome and exhibits a strong association with economically valuable traits in livestock. The manifestation of aggressive behavior in pigs has detrimental effects on production efficiency, immune competency, and meat quality. Nevertheless, the impact of CNV on the aggressive behavior of pigs remains elusive. In this investigation, we employed an integrated analysis of genome and transcriptome data to investigate the interplay between CNV, gene expression changes, and indicators of aggressive behavior in weaned pigs. Specifically, a subset of pigs comprising the most aggressive pigs (MAP, n = 12) and the least aggressive pigs (LAP, n = 11) was purposefully selected from a herd of 500 weaned pigs following a mixing procedure based on their composite aggressive score (CAS). Subsequently, we thoroughly analyzed copy number variation regions (CNVRs) across the entire genome using next-generation sequencing techniques, ultimately revealing the presence of 6869 CNVRs. Using genome-wide association study (GWAS) analysis and evaluating variance-stabilizing transformation (VST) values, we successfully identified distinct CNVRs that distinguished the MAP and LAP counterparts. Among the prioritized CNVRs, CNVR-4962 (designated as the top-ranked p-value and VST value, No. 1) was located within the Solute Carrier Organic Anion Transporter Family Member 3A1 (SLCO3A1) gene. The results of our analyses indicated a significantly higher (p < 0.05) copy number of SLCO3A1 in the MAP compared to the LAP. Furthermore, this increased copy number exhibited a positive correlation with the CAS of the pigs (p < 0.05). Furthermore, we integrated genomic data with transcriptomic data from the temporal lobe to facilitate the examination of expression quantitative trait loci (eQTL). Importantly, these observations were consistent with the mRNA expression pattern of SLCO3A1 in the temporal lobe of both MAP and LAP (p < 0.05). Consequently, our findings strongly suggest that CNVs affecting SLCO3A1 may influence gene expression through a dosage effect. These results highlight the potential of SLCO3A1 as a candidate gene associated with aggressive traits in pig breeding programs.

Amelioration effects of α-viniferin on hyperuricemia and hyperuricemia-induced kidney injury in mice.

BACKGROUND: α-Viniferin, the major constituent of the roots of Caragana sinica (Buc'hoz) Rehder with a trimeric resveratrol oligostilbenoid skeleton, was demonstrated to possess a strong inhibitory effect on xanthine oxidase in vitro, suggesting it to be a potential anti-hyperuricemia agent. However, the in vivo anti-hyperuricemia effect and its underlying mechanism were still unknown. PURPOSE: The current study aimed to evaluate the anti-hyperuricemia effect of α-viniferin in a mouse model and to assess its safety profile with emphasis on its protective effect on hyperuricemia-induced renal injury. METHODS: The effects were assessed in a potassium oxonate (PO)- and hypoxanthine (HX)-induced hyperuricemia mice model by analyzing the levels of serum uric acid (SUA), urine uric acid (UUA), serum creatinine (SCRE), serum urea nitrogen (SBUN), and histological changes. Western blotting and transcriptomic analysis were used to identify the genes, proteins, and signaling pathways involved. RESULTS: α-Viniferin treatment significantly reduced SUA levels and markedly mitigated hyperuricemia-induced kidney injury in the hyperuricemia mice. Besides, α-viniferin did not show any obvious toxicity in mice. Research into the mechanism of action of α-viniferin revealed that it not only inhibited uric acid formation by acting as an XOD inhibitor, but also reduced uric acid absorption by acting as a GLUT9 and URAT1 dual inhibitor as well as promoted uric acid excretion by acting as a ABCG2 and OAT1 dual activator. Then, 54 differentially expressed (log2 FPKM ≥ 1.5, p ≤ 0.01) genes (DEGs) repressed by the treatment of α-viniferin in the hyperuricemia mice were identified in the kidney. Finally, gene annotation results revealed that downregulation of S100A9 in the IL-17 pathway, of CCR5 and PIK3R5 in the chemokine signaling pathway, and of TLR2, ITGA4, and PIK3R5 in the PI3K-AKT signaling pathway were involved in the protective effect of α-viniferin on the hyperuricemia-induced renal injury. CONCLUSIONS: α-Viniferin inhibited the production of uric acid through down-regulation of XOD in hyperuricemia mice. Besides, it also down-regulated the expressions of URAT1 and GLUT9 and up-regulated the expressions of ABCG2 and OAT1 to promote the excretion of uric acid. α-Viniferin could prevent hyperuricemia mice from renal damage by regulating the IL-17, chemokine, and PI3K-AKT signaling pathways. Collectively, α-viniferin was a promising antihyperuricemia agent with desirable safety profile. This is the first report of α-viniferin as an antihyperuricemia agent.