Alternative splicing (AS) is fundamental to transcriptome and proteome richness, and data from recent studies suggested a critical association between AS and oncogenic processes. To date, no systematic analysis has been conducted on AS from the perspective of different sexes and subtypes in non-small-cell lung cancer (NSCLC). Thus, we integrated the information of NSCLC patients from The Cancer Genome Atlas (TCGA) and evaluated AS profiles from the perspectives of sex and subtype. Eventually, a total of 813 and 1020 AS events were found to be significantly related to the overall survival (OS) of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. Four prognostic prediction models performed well at 1, 3, and 5 years, with an area under the receiver operating characteristic (ROC) curve (AUC) greater than 0.75. Notably, we explored the upstream splicing factors (SFs) and downstream regulatory mechanisms of the OS-associated AS events and verified four differentially expressed alternative splicing (DEAS) events via qPCR. These findings can provide important guidance for subsequent studies. In addition, we also constructed nomograms to facilitate early screening by clinicians and to determine patient outcomes in NSCLC.

Immune checkpoint inhibitors (ICIs) have become the standard treatment for advanced non-small cell lung cancer (NSCLC). ICIs can provide durable responses and prolong survival for some patients. With the increasing routine of next-generation sequencing (NGS) in clinical practice, it is essential to integrate prognostic factors to establish novel nomograms to improve clinical prediction ability in NSCLC with ICIs treatment.

Endothelin B receptor (ETBR) deficiency may contribute to the progression of diabetic nephropathy (DN) in a streptozotocin (STZ) model, but the underlying mechanism is not fully revealed. In this study, STZ-diabetic ETBR-/- mice was characterized by increased serum creatinine and urinary albumin, enhanced glomerulosclerosis, and upregulated ET-1 expression compared with STZ-diabetic WT mice. In vitro, HG conditioned media (CM) of ETBR-/- GENs promoted mesangial cell proliferation and upregulated ECM-related proteins, and ET-1 knockout in GENs or inhibition of ET-1/ETAR in mesangial cell suppressed mesangial cell proliferation and collagen IV formation. In addition, ET-1 was over-expressed in ETBR-/- GENs and was regulated by NF-kapapB pathway. ET-1/ETBR suppressed NF-kappaB to modulate ET-1 in GENs. Furthermore, ET-1/ETAR promoted RhoA/ROCK pathway in mesangial cells, and accelerated mesangial cell proliferation and ECM accumulation. Finally, in vivo experiments proved inhibition of NF-kappaB pathway ameliorated DN in ETBR-/- mice. These results suggest that in HG-exposed ETBR-/- GENs, suppression of ET-1 binding to ETBR activated NF-kappaB pathway, thus to secrete large amount of ET-1. Due to the communication between GENs and mesangial cells in diabetes, ET-1 binding to ETAR in mesangial cell promoted RhoA/ROCK pathway, thus to accelerate mesangial cell proliferation and ECM accumulation.

Splicing dysregulation, which leads to apoptosis resistance, has been recognized as a major hallmark for tumorigenesis and cancer progression. Targeting alternative splicing by either increasing pro-apoptotic proteins or inhibiting anti-apoptotic proteins in tumor cells may be an effective approach for gastric cancer (GC) therapy. However, the role of modulation of alternative splicing in GC remains poorly understood. In this study, to the best of our knowledge, the unbalanced expression of the myeloid cell leukemia-1 (Mcl-1) splicing variants, Mcl-1L and Mcl-1S, was identified in GC patients for the first time. Increasing anti-apoptotic Mcl-1L and decreasing pro-apoptotic Mcl-1S expression levels were correlated with tumor proliferation and poor survival. In vitro data showed that a shift in splicing from Mcl-1L to Mcl-1S induced by treatment with Mcl-1-specific steric-blocking oligonucleotides (SBOs) efficiently decreased Mcl-1L expression, increased Mcl-1S expression, and accelerated tumor cell apoptosis in a dose-dependent manner. Additionally, mouse xenotransplant models confirmed that modification of Mcl-1 alternative splicing increased tumor cell death and suppressed tumor proliferation. This study demonstrated that the modification of Mcl-1 splicing might stimulate the pro-apoptotic factor and inhibit the anti-apoptotic protein to induce significant apoptosis. Thus, this finding provided a strategy for cancer therapy, according to which SBOs could be used to change the Mcl-1 splicing pattern, thereby inducing apoptosis.

Hepatic ischemia-reperfusion injury (IRI) remains a common complication during liver transplantation (LT), partial hepatectomy and hemorrhagic shock in patients. As a member of the G protein-coupled receptors adaptors, ARRB2 has been reported to be involved in a variety of physiological and pathological processes. However, whether β-arrestin-2 affects the pathogenesis of hepatic IRI remains unknown. The goal of the present study was to determine whether ARRB2 protects against hepatic IR injury and elucidate the underlying mechanisms. To this end, 70% hepatic IR models were established in ARRB2 knockdown mice and wild-type littermates, with blood and liver samples collected at 1, 6 and 12 h after reperfusion to evaluate liver injury. The effect of ARBB2 on PI3K/Akt signaling during IR injury was evaluated in vivo, and PI3K/Akt pathway regulation by ARRB2 was further assessed in vitro. Our results showed that ARRB2 knockdown aggravates hepatic IR injury by promoting the apoptosis of hepatocytes and inhibiting their proliferation. In addition, ARRB2 deficiency inhibited PI3K/Akt pathway activation, while the administration of the PI3K/Akt inhibitor PX866 resulted in severe IR injury in mice. Furthermore, the liver-protecting effect of ARRB2 was shown to depend on PI3K/Akt pathway activation. In summary, our results suggest that β-Arrestin-2 protects against hepatic IRI by activating PI3K/Akt signaling, which may provide a novel therapeutic strategy for treating liver ischemia-reperfusion injury.

Typically, peripheral T-cell lymphoma (PTCLs) prognosis is estimated using overall survival before treatment. However, these estimates cannot show how prognosis evolves with the changing hazard rate over time. Patients (n = 650) with newly diagnosed PTCLs were enrolled retrospectively. After a median follow-up of 5.4 years, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) and NK/T cell lymphoma had initially lower 3-year conditional overall survival (COS3; i.e., the 3-year conditional overall survival was defined as the probability of surviving an additional 3 years) and higher hazards of death (26-44.3%). However, after 2 years, the COS3 increased and the death risk decreased over time, whereas anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma constantly had a lower risk over time (0-19.5%). For patients with complete remission after initial treatment, prognosis varied by histological subtypes, with PTCL, NOS having a negative impact. Our data suggested that the risk stratification using the International Prognostic Index might not accurately predict the COS3 for survivors of PTCLs. The COS3 provided time-dependent prognostic information for PTCLs, representing a possible surrogate prognosis indicator for long-term survivors after systemic chemotherapy.

There has been increasing evidence that microRNAs (miRNAs) are related to glioma progression, and that genetically engineered mesenchymal stem cells (MSCs) can inhibit the growth of gliomas. However, the underlying mechanism of bone marrow-MSCs (BM--MSCs) and miRs in gastric cancer still remains unclear. Patients with gastric cancer treated in Shijiazhuang First Hospital as well as healthy individuals undergoing physical examinations were recruited to measure the expression of exosomal miR-1228. Receiver operating characteristic (ROC) curves were plotted and the patients were followed up. BM--MSCs from healthy subjects were collected and exosomes were extracted. The MSC cells were transfected with lentiviral vectors carrying miR-1228 and MMP-14 over-expression sequences and scramble sequence, followed by exosome extraction. The exosomes were co-cultured with SGC-7901 and MGC-823 cells to detect cell proliferation, invasion, apoptosis and migration. The correlation between miR-1228 and MMP-14 was determined by dual-luciferase reporter assay. miR-1228 was highly expressed in serum exosomes of patients with gastric cancer with a area under ROC curve (AUC) of 0.865. The exosomes derived from BM-MSCs are expected to be efficient nanocarriers. Up-regulation of miR-1228 can down-regulate the expression of MMP-14 and effectively hinders the development and progression of gastric cancer.

Cuproptosis is a new type of programmed cell death involved in the regulation of neuroendocrine tumors, immune microenvironment, and substance metabolism. However, the role of cuproptosis-related genes (CRGs) in Hepatocellular carcinoma (HCC) remains unclear.

Novel agents have made the management of chronic lymphocytic leukemia (CLL) more promising and personalized. However, long-term treatment is still warranted which may result in toxicity and resistance. Thus, new combination therapy may help achieve deeper remission and limited-duration therapy. Histone deacetylase inhibitors (HDACi) can affect many tumors by modulating key biological functions including autophagy. Studies have shown that some novel targeted agents including ibrutinib induce autophagy. This study aimed to explore the effect of oral HDAC inhibitor, chidamide, on CLL cells as well as the role of autophagy in this process. Here, we showed that autophagy flux in CLL cells was inhibited by chidamide via post-transcriptional modulation and chidamide had cytostatic and cytotoxic effects on CLL cells. Besides, the pro-survival role of autophagy in CLL cells was validated by using autophagy inhibitor and knocking down critical autophagy gene. Notably, a combination of chidamide and ibrutinib showed significant synergism and downregulated ibrutinib-induced autophagy. This work highlights the therapeutic potential of chidamide via its effect on autophagy, especially in combination with ibrutinib.

Deficits in coordinated motor behavior and mitochondrial complex V activity have been observed in aged males. Testosterone supplementation can improve coordinated motor behavior in aged males. We investigated the effects of testosterone supplementation on mitochondrial complex V function in the substantia nigra (a brain region that regulates motor activity) in aged male rats. These rats exhibited diminished ATP levels, attenuated mitochondrial complex V activity, and reduced expression of 3 of the 17 mitochondrial complex V subunits (ATP6, ATP8 and ATP5C1) in the substantia nigra. Testosterone supplementation increased ATP levels, mitochondrial complex V activity, and ATP6, ATP8 and ATP5C1 expression in the substantia nigra of the rats. Conversely, orchiectomy reduced mitochondrial complex V activity, downregulated ATP6 and ATP8 expression, and upregulated ATP5C1, ATP5I and ATP5L expression in the substantia nigra. Testosterone replacement reversed those effects. Thus, testosterone enhanced mitochondrial complex V function in the substantia nigra of aged male rats by upregulating ATP6 and ATP8. As potential testosterone targets, these two subunits may to some degree maintain nigrostriatal dopaminergic function in aged males.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. Exercise is a therapeutic strategy for preventing NAFLD. However, the underlying molecular mechanisms by which NAFLD can be ameliorated through exercise are still not clear. This study investigates the mechanisms by which exercise suppresses NAFLD development induced by a high-fat diet (HFD) in mice. Male 6-week-old C57BL/6J mice were fed a normal diet or HFD for 12 weeks and then induced to swim or remain sedentary for 8 weeks. Histomorphology, inflammatory factors, fat metabolizing enzymes, fibrosis, and steatosis were determined in HFD-fed mouse liver, and levels of hepatic enzymes and molecules in the related pathways were analyzed. NAFLD mice showed evident steatosis, fibrosis, and liver injury, and an increased expression of HMGCS2, Wnt3a/ β-catenin, and phosphorylated (p)-AMPK in the liver. Exercise significantly attenuated these symptoms and downregulated the level of Wnt3a/β-catenin in lipotoxic liver tissue. Inhibition of HMGCS2 expression decreased the activation of the Wnt3a/β-catenin pathway and lowered p-AMPK in palmitate-treated HepG2. Our results suggest that exercise prevents NAFLD-associated liver injury, steatosis, and fibrosis. Exercise-mediated hepatoprotection was achieved partly via the blocking of the upregulation of HMGCS2 and the attenuation of the Wnt3a/β-catenin pathway.

Bone metastasis (BM) is one of the main manifestations of advanced breast cancer (BC), causing complications such as pathological fractures, which seriously affects the quality of life of patients and even leads to death. In our study, a global single-cell landscape of the tumor microenvironment was constructed using single cell RNA sequencing data from BM. BC cells were found to be reduced in the BM, while mesenchymal stem cells (MSCs), Fibroblasts and other cells were significantly more abundant in the BM. The subpopulations of these cells were further identified, and the pathways, developmental trajectories and transcriptional regulation of different subpopulations were discussed. The results suggest that with the development of BM, BC cells were vulnerable to oxidative damage, showing a high level of oxidative stress, which played a key role in cell apoptosis. Fibroblasts were obviously involved in the biological processes (BPs) related to ossification and bone remodeling, and play an important role in tumor cell inoculation to bone marrow and growth. MSC subpopulations were significantly enriched in a number of BPs associated with bone growth and development and oxidative stress and may serve as key components of BC cells homing and adhesion to the ecological niche of BM. In conclusion, our research results describe the appearance of tumor microenvironment cell subpopulations in breast cancer patients, reveal the important role of some cells in the balance of BM bone remodeling and the imbalance of BM development, and provide potential therapeutic targets for BM.

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous cancer characterized by difficulties in early diagnosis and outcome prediction. Aberrant glycosylated structures produced by the aberrant expression of glycosyltransferases are prevalent in HNSCC. In this study, we aim to construct glycosyltransferase-related gene signatures with diagnostic and prognostic value to better stratify patients with HNSCC and improve their diagnosis and prognosis.

MicroRNA (miRNA) function via base-pairing with complementary sequences within mRNA molecules. This study aims to identify critical miRNA-mRNA regulation pairs contributing to lung adenocarcinoma (LUAD) pathogenesis.

Increasing evidence suggests that the pathogenesis of chronic obstructive pulmonary disease (COPD) is associated with FUN14 domain protein 1 (FUNDC1)-mediated mitophagy. Recently, studies have reported that puerarin has protective effects against excessive oxidative damage in cells. Therefore, we hypothesized that puerarin may be involved in COPD progression via regulating FUNDC1 mediated mitophagy. We found that the viability of cigarette smoke extract (CSE)-stimulated human bronchial epithelial cells (HBECs) was enhanced and apoptosis was reduced after treatment with different concentrations of puerarin. Puerarin reversed mitochondrial membrane potential (MMP) levels and ATP content, and decreased reactive oxygen species (ROS) content in CSE stimulated HBECs. Moreover, puerarin significantly inhibited apoptosis related proteins, as well as the expression of mitophagy related proteins. After inhibition of FUNDC1 phosphorylation by protein phosphatase inhibitor (PH0321), puerarin restored MMP level, decreased ROS content, promoted ATP synthesis, and downregulated autophagy related protein expression in HBECs. In addition, mitochondrial division inhibitor (Mdivi) inhibited the expression of autophagy related proteins and reduced apoptosis after blocking cell autophagy, which was the same as the inhibition of puerarin. Finally, puerarin activated the PI3K/Akt/mTOR signaling pathway to participate in COPD progression by up regulating the phosphorylation levels of PI3K, Akt and mTOR.

Hepatocellular carcinoma (HCC) is a major human health concern. Increasing evidence has demonstrated that ubiquitin ligase E4B (UBE4B) may be involved in the occurrence and development of various human cancers and may affect prognosis. However, the specific role and mechanism of UBE4B in HCC is unclear.

High-grade serous ovarian cancer (HGSOC) is a heterogeneous disease with diverse clinical outcomes, highlighting a need for prognostic biomarker identification. Here, we combined tumor microenvironment (TME) scores with HGSOC characteristics to identify immune-related prognostic genes through analysis of gene expression profiles and clinical patient data from The Cancer Genome Atlas and the International Cancer Genome Consortium public cohorts. We found that high TME scores (TMEscores) based on the fractions of immune cell types correlated with better overall survival. Furthermore, differential expression analysis revealed 329 differentially expressed genes between patients with high vs. low TMEscores. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that these genes participated mainly in immune-related functions and, among them, 48 TME-related genes predicted overall survival in HGSOC. Seven of those genes were associated with prognosis in an independent HGSOC database. Finally, the two genes with the lowest p-values in the prognostic analysis (GBP1, ETV7) were verified through in vitro experiments. These findings reveal specific TME-related genes that could serve as effective prognostic biomarkers for HGSOC.

Acute ischemic stroke (AIS) is a major public health problem in China. Impaired angiogenesis plays crucial roles in the development of ischemic cerebral injury. Recent studies have identified that microRNAs (miRNAs) are important regulators of angiogenesis, but little is known the exact effects of angiogenesis-associated miRNAs in AIS. In the present study, we detected the expression levels of angiogenesis-associated miRNAs in AIS patients, middle cerebral artery occlusion (MCAO) rats, and oxygen-glucose deprivation/reoxygenation (OGD/R) human umbilical vein endothelial cells (HUVECs). MiR-191 was increased in the plasma of AIS patients, OGD/R HUVECs, and the plasma and brain of MCAO rats. Over-expression of miR-191 promoted apoptosis, but reduced the proliferation, migration, tube-forming and spheroid sprouting activity in HUVECs OGD/R model. Mechanically, vascular endothelial zinc finger 1 (VEZF1) was identified as the direct target of miR-191, and could be regulated by miR-191 at post-translational level. In vivo studies applying miR-191 antagomir demonstrated that inhibition of miR-191 reduced infarction volume in MCAO rats. In conclusion, our data reveal a novel role of miR-191 in promoting ischemic brain injury through inhibiting angiogenesis via targeting VEZF1. Therefore, miR-191 may serve as a biomarker or a therapeutic target for AIS.

Circular RNAs (circRNAs) have recently been reported to play crucial roles in various regulatory processes and involved in cancer onset and progression. However, the potential mechanism of circRNAs in chronic lymphocytic leukemia (CLL) remains largely unknown. Here, we observed hsa_circ_0132266 (circ_0132266), a circRNA significantly decreased in the peripheral blood mononuclear cells (PBMCs) of CLL patients compared with healthy donors, could act as an endogenous sponge of hsa-miR-337-3p (miR-337-3p) and regulate its activity, which resulted in a downstream change of target-gene PML and a consequent influence on cell viability. Taken together, our data indicated the regulatory mechanism of circ_0132266 in CLL progression through circ_0132266/miR-337-3p/PML axis, suggesting that it may serve as a biomarker as well as an exploitable therapeutic target for CLL.

Ovarian carcinoma (OC) is the deadliest gynecologic malignancy in females worldwide. Circular RNA Foxo3 (Foxo3) plays essential roles in various cancers. However, the detailed function of Foxo3 in OC remains unclear. This study aimed to investigate the role of Foxo3 in OC and the underlying molecular mechanism.