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Epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) is a highly invasive and malignant type of tumor. Due to its resistance to HER2-targeted therapy, HER2+ BC has a poor prognosis and a tendency for metastasis. Understanding the mechanisms underlying this resistance and developing effective treatments for HER2+ BC are major research challenges. The phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, which is frequently altered in cancers, plays a critical role in cellular proliferation and drug resistance. This signaling pathway activates various downstream pathways and exhibits complex interactions with other signaling networks. Given the significance of the PI3K/AKT pathway in HER2+ BC, several targeted drugs are currently in development. Multiple drugs have entered clinical trials or gained market approval, bringing new hope for HER2+ BC therapy. However, new drugs and therapies raise concerns related to safety, regulation, and ethics. Populations of different races and disease statuses exhibit varying responses to treatments. Therefore, in this review, we summarize current knowledge on the alteration and biological roles of the PI3K/AKT pathway, as well as its clinical applications and perspectives, providing new insights for advancing targeted therapies in HER2+ BC. [ABSTRACT FROM AUTHOR]

Enterovirus‐D68 (EV‐D68) was first identified in 1962 in pediatric patients with acute respiratory conditions in California, USA (US). From the 1970s to 2005, EV‐D68 was underestimated due to limited data and serotyping methods. In 2014, the United States experienced outbreaks of acute flaccid myelitis (AFM) in children EV‐D68 positive. WIN‐like compounds (pleconaril, pocapavir, and vapendavir) bind to the virus capsid and have been tested against various enteroviruses (EVs) in clinical trials. However, these compounds encountered issues with resistance and adverse effects, which impeded their approval by the Food and Drug Administration (FDA). Presently, the medical field lacks FDA‐approved antiviral treatments or vaccines for EV‐D68. Ongoing research efforts are dedicated to identifying viable therapeutics to address EV‐D68 infections. This review explores the current advancements in antiviral therapies and potential therapeutics to mitigate the significant impact of EV‐D68 infection control. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide, characterized by high malignancy and rapid progression. Most cases are diagnosed at intermediate to advanced stages. Current treatment methods have limited efficacy, resulting in high recurrence rates and poor prognosis. Radical hepatectomy remains the primary treatment for HCC, complemented by radiotherapy, chemotherapy, targeted therapy, and immunotherapy. Despite significant improvement in patient prognosis with radical hepatectomy, the five-year survival rate post-surgery remains low; thus necessitating exploration of more effective therapeutic approaches. Ferroptosis is a recently discovered form of cell death that can modulate the occurrence and development of HCC through various mechanisms. This article aims to elucidate the mechanism of ferroptosis and its impact on HCC development to provide novel insights for diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Poly C Binding Protein 1 (PCBP1) belongs to the heterogeneous nuclear ribonucleoprotein family. It is a multifunctional protein that participates in several functional circuits and plays a variety of roles in cellular processes. Although PCBP1 has been identified in several mammals, its function in porcine was unclear. Results: In this study, we cloned the gene of porcine PCBP1 and analyzed its evolutionary relationships among different species. We found porcine PCBP1 protein sequence was similar to that of other animals. The subcellular localization of PCBP1 in porcine kidney cells 15 (PK-15) cells was analyzed by immunofluorescence assay (IFA) and revealed that PCBP1 was mainly localized to the nucleus. Reverse transcription-quantitative PCR (RT-qPCR) was used to compare PCBP1 mRNA levels in different tissues of 30-day-old pigs. Results indicated that PCBP1 was expressed in various tissues and was most abundant in the liver. Finally, the effects of PCBP1 on cell cycle and apoptosis were investigated following its overexpression or knockdown in PK-15 cells. The findings demonstrated that PCBP1 knockdown arrested cell cycle in G0/G1 phase, and enhanced cell apoptosis. Conclusions: Porcine PCBP1 is a highly conserved protein, plays an important role in determining cell fate, and its functions need further study. [ABSTRACT FROM AUTHOR]

δ-Aminolevulinic acid dehydratase (ALAD) is a key enzyme of the cytoplasmic heme biosynthesis pathway. The primary structure of the ALAD gene, the multimeric structure of the ALAD/hemB protein, and ALAD expression during the annual reproductive cycle were studied in the cold-water marine sponge Halisarca dujardinii. The results implicated the GATA-1 transcription factor and DNA methylation in regulating ALAD expression. Re-aggregation of sponge cells was accompanied by a decrease in ALAD expression and a change in the cell content of an active ALAD/hemB form. Further study of heme biosynthesis and the role of ALAD/hemB in morphogenesis of basal animals may provide new opportunities for treating pathologies in higher animals. [ABSTRACT FROM AUTHOR]

Portal vein tumor thrombosis (PVTT), a common complication of advanced hepatocellular carcinoma (HCC), remains the bottleneck of the treatments. Liver cancer cells potentially experienced multi-steps during PVTT process, including cancer cells leave from cancer nest, migrate in extracellular matrix, invade the vascular barrier, and colonize in the portal vein. Accumulated evidences have revealed numerous of molecular mechanisms including genetic and epigenetic regulation, cancer stem cells, immunosuppressive microenvironment, hypoxia, et al. contributed to the PVTT formation. In this review, we discuss state-of-the-art PVTT research on the potential molecular mechanisms and experimental models. In addition, we summarize PVTT-associated clinical trials and current treatments for PVTT and suppose perspectives exploring the molecular mechanisms and improving PVTT-related treatment for the future. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) have been found to play an important role in the occurrence and development of endometrial carcinoma (EC). Here, using RNA sequencing analysis, we systemically screened and identified the lncRNA eukaryotic translation initiation factor 1A, X‐linked (EIF1AX)‐AS1, which is aberrantly downregulated in clinical EC tissues and closely correlated with tumor type. EIF1AX‐AS1 markedly inhibited EC cell proliferation and promoted apoptosis in vitro and in vivo. Mechanistically, EIF1AX‐AS1 interacts with EIF1AX mRNA and poly C binding protein 1 (PCBP1), which promote EIF1AX mRNA degradation. Intriguingly, by interacting with internal ribosome entry site‐related protein Y‐box binding protein 1 (YBX‐1), EIF1AX promotes c‐Myc translation through the internal ribosome entry site pathway. c‐Myc promotes EIF1AX transcription and thus forms a feed‐forward loop to regulate EC cell proliferation. Taken together, these data reveal new insights into the biology driving EC proliferation and highlights the potential of lncRNAs as biomarkers for prognosis and future therapeutic targets for cancer. [ABSTRACT FROM AUTHOR]

Enterovirus A71 (EVA71) infection continues to remain a vital threat to global public health, especially in the Asia–Pacific region. It is one of the most predominant pathogens that cause hand, foot, and mouth disease (HFMD), which occurs mainly in children below 5 years old. Although EVA71 prevalence has decreased sharply in China with the use of vaccines, epidemiological studies still indicate that EVA71 infection involves severe and even fatal HFMD cases. As a result, it remains more fundamental research into the pathogenesis of EVA71 as well as to develop specific anti-viral therapy. Autophagy is a conserved, self-degradation system that is critical for maintaining cellular homeostasis. It involves a variety of biological functions, such as development, cellular differentiation, nutritional starvation, and defense against pathogens. However, accumulating evidence has indicated that EVA71 induces autophagy and hijacks the process of autophagy for their optimal infection during the different stages of life cycle. This review provides a perspective on the emerging evidence that the "positive feedback" between autophagy induction and EVA71 infection, as well as its potential mechanisms. Furthermore, autophagy may be involved in EVA71-induced nervous system impairment through mediating intracranial viral spread and dysregulating host regulator involved self-damage. Autophagy is a promising therapeutic target in EVA71 infection. [ABSTRACT FROM AUTHOR]

Accumulating evidence show that Poly C Binding Protein 1 (PCBP1) is deleted in distinct types of tumors as a novel tumor suppressor, but its tumor suppression mechanism remains elusive. Here, we firstly describe that downregulation of PCBP1 is significantly associated with clinical ovarian tumor progression. Mechanistically, PCBP1 overexpression affects various autophagy-related genes expression at various expression levels to attenuate the intrinsic cell autophagy, including the autophagy-initiating ULK, ATG12, ATG7 as well as the bona fide marker of autophagosome, LC3B. Accordingly, knockdown of the endogenous PCBP1 in turn enhances autophagy and less cell death. Meanwhile, PCBP1 upregulates p62/SQSTM1 via inhibition p62/SQSTM1 autophagolysome and proteasome degradation as well as its mRNA stability, consequently accompanying with the caspase 3 or 8 activation for tumor cell apoptosis. Importantly, clinical ovary cancer sample analysis consistently validates the relevance of PCBP1 expression to both p62/SQSTM1 and caspase-8 to overall survival, and indicates PCBP1 may be a master player to repress tumor initiation. Taken together, our results uncover the tumorigenic mechanism of PCBP1 depletion and suggest that inhibition of tumor cell autophagy with autophagic inhibitors could be an effective therapeutical strategy for PCBP1-deficient tumor. [ABSTRACT FROM AUTHOR]

The human Phosphatase of Regenerative Liver (PRL) family comprises three members (PRL‐1, ‐2, ‐3; gene name PTP4A1,PTP4A2,PTP4A3) that are highly expressed in a majority of cancers. This review summarizes our current understanding of PRL biology, including an overview of their evolutionary relationships and the regulatory mechanisms controlling their expression. We provide an updated view on our current knowledge on the PRL functions in solid tumors, hematological cancer, and normal physiology, particularly emphasizing on the use of in vivo mouse models. We also highlight a novel relationship positioning PRL as a central node controlling magnesium homeostasis through an association with the CNNM proteins, which are involved in magnesium transport. The three members of the Phosphatase of Regenerative Liver (PRL) family (PRL‐1, ‐2, ‐3) are highly expressed in many human cancers and could have putative functions in parasitic diseases. In this review, we highlight recent advances in our understanding of the PRL biology based on cellular and murine models, which lead to an updated view on their mechanisms of action. [ABSTRACT FROM AUTHOR]

Classical swine fever (CSF), caused by classical swine fever virus (CSFV), is one of the most devastating epizootic diseases of pigs in many countries. Viruses are small intracellular parasites and thus rely on the cellular factors for replication. Fundamental aspects of CSFV-host interactions have been well described, such as factors contributing to viral attachment, modulation of genomic replication and translation, antagonism of innate immunity, and inhibition of cell apoptosis. However, those host factors that participate in the viral entry, assembly, and release largely remain to be elucidated. In this review, we summarize recent progress in the virus-host interactions involved in the life cycle of CSFV and analyze the potential mechanisms of viral entry, assembly, and release. We conclude with future perspectives and highlight areas that require further understanding. [ABSTRACT FROM AUTHOR]

The phosphatase of regenerating liver (PRL)-3 is overexpressed in many human cancer types and tumor metastases when compared with healthy tissues. Different pathways and mechanisms have been suggested to modulate PRL-3 expression levels and activity, giving some valuable insights but still leaving an incomplete picture. Investigating these mechanisms could provide new targets for therapeutic drug development. Here, we present an updated overview and summarize recent findings concerning the different PRL-3 expression regulatory mechanisms and posttranslational modifications suggested to modulate the activity, localization, or stability of this phosphatase. [ABSTRACT FROM AUTHOR]

Background: Depletion of Poly-C binding protein-1(PCBP1) is implicated in various human malignancies. However, the underlying biological effect of PCBP1 in cancers, including acute myeloid leukemia (AML), still remains elusive. The purpose of this study was to examine the expression and clinical outcome of PCBP1in acute myeloid leukemia. Methods: Bone marrow fluids of 88 newly diagnosed AML patients were sampled, and the PCBP1 mRNA expression level was evaluated using quantitative RT-PCR. The association between PCBP1 expression and clinicopathological features or the survival status of the patients was assessed by Chi-square test and Kaplan-Meier method. Results: Comparing newly diagnosed AML patients to normal healthy donors, PCBP1 expression was significantly decreased in AML patients (P < 0.001). Conversely, PCBP1 expression had accordingly recovered back to normal in patients with complete remission (P < 0.001). Clinical feature analyses showed that PCBP1 expression was negatively correlated with white blood cell count (P = 0.024). In addition, patients with low PCBP1 expression had poor disease-free survival (11.8 % vs. 45.3 %; P = 0.01) and overall survival (18.2 % vs. 42.4 %; P = 0.032), respectively. [ABSTRACT FROM AUTHOR]

Cyclophilins are ubiquitously expressed proteins that bind to prolines and can catalyse cis/trans isomerization of proline residues. There are 17 annotated members of the cyclophilin family in humans, ubiquitously expressed and localized variously to the cytoplasm, nucleus or mitochondria. Surprisingly, all eight of the nuclear localized cyclophilins are found associated with spliceosomal complexes. However, their particular functions within this context are unknown. We have therefore adapted three established assays for in vitro pre-mRNA splicing to probe the functional roles of nuclear cyclophilins in the context of the human spliceosome. We find that four of the eight spliceosom-associated cyclophilins exert strong effects on splicing in vitro. These effects are dose-dependent and, remarkably, uniquely characteristic of each cyclophilin. Using both qualitative and quantitative means, we show that at least half of the nuclear cyclophilins can act as regulatory factors of spliceosome function in vitro. The present work provides the first quantifiable evidence that nuclear cyclophilins are splicing factors and provides a novel approach for future work into small molecule-based modulation of pre-mRNA splicing. [ABSTRACT FROM AUTHOR]

Despite several decades of efforts to develop safer, efficacious, and non-addictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary medicine. Morphine and endogenous mu opioid peptides exert their pharmacological actions mainly through the mu opioid receptor (MOR). Analgesic effects of opioids in animals are dependent on the MOR expression levels, as demonstrated by studies of MOR-knockout mice (homo/heterozygotes) and MOR-less expressing mice. Surprisingly, in the course of our investigation to understand the mechanisms involved in the regulation of MOR gene expression, cycloheximide (CHX), a known protein synthesis inhibitor, markedly induced accumulation of MOR mRNAs in both MOR-negative and -positive cells. This induction was blocked by inhibitors of phosphoinositide 3-kinase (PI3-K) and p38 MAPK, but not by a p42/44 MAPK inhibitor. In vitro, CHX was found to activate the MOR promoter and this activation was suppressed by inhibition of PI3-K. The transcriptional activator Sox18 was recruited to the MOR promoter in CHX-treated cells and this recruitment was also inhibited by the PI3-K and p38 MAPK inhibitors, Ly294002 and SB203580, respectively. Consistently, acetylation of histone H3 and induction of H3-K4 methylation were detected while reductions of histone deacetylase 2 binding and H3-K9 methylation were observed on the promoter. Furthermore, the MOR mRNA accumulation was almost completely inhibited in the presence of actinomycin-D, indicating that this effect occurs mainly through activation of the transcriptional machinery. These observations suggest that CHX directly induces MOR gene transcription by recruiting the active transcription factor Sox18 to the MOR promoter through PI3- and/or p38 MAPK pathways. [ABSTRACT FROM AUTHOR]

Pigs play an important role in agriculture and biomedicine. The globally developing swine industry must address the challenges presented by swine-origin viruses, including ASFV (African swine fever virus), PRRSV (porcine reproductive and respiratory syndrome virus), PEDV (porcine epidemic diarrhea virus), PRV (pseudorabies virus), CSFV (classical swine fever virus), TGEV (transmissible gastroenteritis virus), et al. Despite sustained efforts by many government authorities, these viruses are still widespread. Currently, gene-editing technology has been successfully used to generate antiviral pigs, which offers the possibility for increasing animal disease tolerance and improving animal economic traits in the future. Here, we summarized the current advance in knowledge regarding the host factors in virus infection and the current status of genetically modified pigs that are resistant to virus infection in the world. There has not been any report on PEDV-resistant pigs, ASFV-resistant pigs, and PRV-resistant pigs owing to the poor understanding of the key host factors in virus infection. Furthermore, we summarized the remaining problems in producing virus-resistant pigs, and proposed several potential methods to solve them. Using genome-wide CRISPR/Cas9 library screening to explore the key host receptors in virus infection may be a feasible method. At the same time, exploring the key amino acids of host factors in virus infection with library screening based on ABEs and CBEs (Bes) may provide creative insight into producing antiviral pigs in the future. [ABSTRACT FROM AUTHOR]