To investigate the significance of the negative elongation factor complex member C/D (NELFCD) in colon cancer progression.
Immunohistochemistry staining, Western blot analysis, and real-time quantitative polymerase chain reaction (RT-qPCR) were used to quantify the protein/gene levels. NELFCD-protein arginine methyltransferase 5 (PRMT5) interaction was determined by co-immunoprecipitation assay. A chromatin immunoprecipitation (ChIP) assay was performed to determine the interaction between the promoter region of dual specificity phosphatase 2 (DUSP2), NELFCD, and PRMT5. Cell growth and cell cycle progression were assessed using the cell counting kit-8 proliferation assay, colony formation assay, and/or flow cytometry.
NELFCD was upregulated in colon cancer and promoted cancer cell growth. In colon cancer cells, the expression of NELFCD was negatively correlated with DUSP2 expression. The RNA sequencing results indicated that genes in the mitogen-activated protein kinase (MAPK) signaling pathway as well as DUSP2 were affected by NELFCD. The ChIP sequencing results revealed that DUSP2 and genes in the MAPK signaling pathway are direct targets of NELFCD. ChIP assay verified that PRMT5 is enriched at the promoter region of DUSP2 and that NELFCD overexpression promoted this enrichment. A co-immunoprecipitation assay demonstrated that NELFCD was bound to PRMT5, functioning as a macromolecular complex.
This study suggests that NELFCD promotes the progression of colon cancer by recruiting PRMT5 to inhibit DUSP2 expression, which subsequently activates the p38 signaling pathway. Targeting the NELFCD–DUSP2–p38 signaling axis may be a promising therapeutic intervention for patients suffering from NELFCD-amplified tumors.
In the current perspective and review article, we address the human body as a living ecosystem with collecting watersheds and draining hydrosheds; we integrate our discoveries over the past quarter of a century and pose the critical open research questions to be addressed going forward, with the aim to improve cell, tissue, organ and organismal health. First, we address the flow of fluid through the tissues of the musculoskeletal system, after which we describe the interactions of the fluid, at multiple lengths and time scales, with the molecular to macroscopic non-fluid tissue components, discussing bone and tissues in the context of “living” chromatography and/or electrophoresis columns. Thereafter, we discuss the implications of functional barrier integrity, and the effects of cytokines on active barrier function and molecular transport between organ systems, tissue compartments, and within tissues. In addition, we address the fluid and its flow and the multi-physics implications thereof for the living inhabitants of tissues, i.e., the cells. Finally, we describe the implications of the solid and fluid components and the cellular inhabitants on ecosystem health, where the tissues and organs comprise the organism form interacting ecosystems throughout life and in the context of health and disease. By taking convergent approaches to understanding musculoskeletal, human and environmental health (which themselves are interdependent), we hope to pave new paths of innovation and discovery, to improve the lives of our worlds’ inhabitants, from the worlds of our bone and joints and bodies to the interacting ecosystems of our Earth to unknown worlds beyond our current understanding.
Hypertriglyceridemia, characterized by increased triglyceride (TG) concentrations, is considered the most important risk factor for cardiometabolic disorders, including dyslipidemia, atherosclerotic cardiovascular diseases, and non-alcoholic fatty liver disease (NAFLD). Recently, the angiopoietin-like protein (ANGPTL) family, which comprises ANGPTL1 to ANGPTL8, was confirmed to play an important role in modulating lipoprotein lipase (LPL) activity. However, understanding of the underlying mechanisms remains limited. Importantly, emerging evidence has linked several transcriptional and post-transcriptional factors to the potential alteration of TG metabolism via ANGPTL proteins. This review focused on the similarities and differences in the expression, structural features, and modulatory profile of three ANGPTLs: ANGPTL3, ANGPTL4, and ANGPTL8. In addition, the regulatory functions of those three ANGPTLs in modulating LPL were summarized to provide potential therapeutic and clinical strategies for hypertriglyceridemia and its related cardiometabolic disorders.
Sesamin can suppress many cancers, but its effect on nasopharyngeal carcinoma (NPC) is unclear. Herein, we set out to pinpoint the possible changes in NPC due to Sesamin.
The biological function of NPC cells exposed to Sesamin/N-acetyl-L-cysteine (NAC)/3-Methyladenine (3-MA) was detected, followed by evaluation of reactive oxygen species (ROS) production (dichlorodihydrofluorescein diacetate staining) and mitochondrial membrane potential (MMP) (flow cytometry). Proteins pertinent to apoptosis (cleaved caspase-3, cleaved poly (ADP-ribose) polymerase 1 (PARP1)), cell cycle (Cyclin B1), and autophagy (microtubule-associated protein light chain 3 (LC3)-I, LC3-II, Beclin-1, P62) were quantified by Western blot. After the xenografted tumor model in mice was established, the tumor volume and weight were recorded, and Ki-67 and cleaved caspase-3 levels were determined by immunohistochemical analysis.
Sesamin inhibited viability, proliferation, cell cycle progression and migration, induced apoptosis, increased ROS production, and decreased MMP in NPC cells. Sesamin elevated cleaved caspase-3/caspase-3, cleaved PARP1/PARP1, and Beclin-1 expressions as well as LC3-II/LC3-I ratio, while diminishing Cyclin B1 and P62 levels. NAC and 3-MA abrogated Sesamin-induced changes as above in NPC cells. Sesamin inhibited the increase of the xenografted tumor volume and weight, down-regulated Ki-67, and up-regulated cleaved caspase-3 in xenografted tumors.
Sesamin exerts anti-tumor activity in NPC, as demonstrated by attenuated tumor proliferation and xenografted tumor volume and weight, as well as induced apoptosis in tumor tissues, consequent upon the promotion of autophagy and reactive oxygen species production.
Multiple myeloma (MM) is a haematological malignancy originating from terminally differentiated B cells, resulting in significant morbidity and mortality. Currently, MM is regarded as an incurable disease, often exhibiting a relapse-remitting pattern that necessitates multiple lines of therapy. It is now well-established that ineffective immunosurveillance plays a critical role in the progression of MM. Consequently, strategies that redirect immune effector cells against MM have emerged as effective treatment modalities, particularly in cases where standard care therapies fail. T cell-based immunotherapy has gained considerable attention in ongoing clinical trials; however, natural killer (NK) cells, known for their ability to execute cytotoxicity against infected and malignant cells with precision, may offer complementary therapeutic advantages over T cells and possess untapped therapeutic potential. This review seeks to introduce readers to the significance of NK cell-mediated immunosurveillance in the context of MM, explore the potential benefits of redirecting NK cells against MM, and illustrate how current treatment strategies are often reliant on the functionality of NK cells. Most importantly, new promising mechanisms of harnessing NK cell-based immunity against MM are reviewed and put into a clinical perspective to highlight their implications for patient treatment and outcomes.
RNA editing is a crucial post-transcriptional modification that alters the transcriptome and proteome and affects many cellular processes, including splicing, microRNA specificity, stability of RNA molecules, and protein structure. Enzymes from the adenosine deaminase acting on RNA (ADAR) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) protein families mediate RNA editing and can alter a variety of non-coding and coding RNAs, including all regions of mRNA molecules, leading to tumor development and progression. This review provides novel insights into the potential use of RNA editing parameters, such as editing levels, expression of ADAR and APOBEC genes, and specifically edited genes, as biomarkers for cancer progression, distinguishing it from previous studies that focused on isolated aspects of RNA editing mechanisms. The methodological section offers clues to accelerate high-throughput analysis of RNA or DNA sequencing data for the identification of RNA editing events.
Most human diseases have genetic components, frequently single nucleotide variants (SNVs), which alter the wild type characteristics of macromolecules and their interactions. A straightforward approach for correcting such SNVs-related alterations is to seek small molecules, potential drugs, that can eliminate disease-causing effects. Certain disorders are caused by altered protein-protein interactions, for example, Snyder-Robinson syndrome, the therapy for which focuses on the development of small molecules that restore the wild type homodimerization of spermine synthase. Other disorders originate from altered protein-nucleic acid interactions, as in the case of cancer; in these cases, the elimination of disease-causing effects requires small molecules that eliminate the effect of mutation and restore wild type p53-DNA affinity. Overall, especially for complex diseases, pathogenic mutations frequently alter macromolecular interactions. This effect can be direct, i.e., the alteration of wild type affinity and specificity, or indirect via alterations in the concentration of the binding partners. Here, we outline progress made in methods and strategies to computationally identify small molecules capable of altering macromolecular interactions in a desired manner, reducing or increasing the binding affinity, and eliminating the disease-causing effect. When applicable, we provide examples of the outlined general strategy. Successful cases are presented at the end of the work.
Acute macular neuroretinopathy (AMN) is a rare retinal condition that predominantly affects young females. The incidence of AMN increased significantly during the COVID-19 pandemic, thereby providing a unique opportunity to elucidate the etiology of this disease. In the present study, 24 articles reporting 59 patients were reviewed. The average age of the patients was 33.51 ± 14.02 years, ranging from 16 to 75 years, with females comprising 71.19% of the cases. The average duration of ocular symptoms post-infection was 8.22 ± 10.69 days, ranging from 4 to 150 days. This study investigated the potential pathogenesis of AMN, including the impact of COVID-19 on retinal neurovascular structure and function, immune-mediated inflammatory factor production, blood-retinal barrier disruption, and retinal microvascular damage, as well as potential clinical therapeutic interventions. This research provides a theoretical framework that can inform further investigations of AMN.
To identify potential prognostic biomarkers and uncover new mechanisms underlying hepatocellular carcinoma (HCC).
HCC is a prevalent and fatal malignancy originating from hepatic cells, with a consistently rising incidence in recent decades. Objective: To identify potential prognostic biomarkers, specifically focusing on the role of PAK1-interacting protein 1 (PAK1IP1), and to uncover novel mechanistic insights in HCC.
HCC-related datasets (GSE45267 and GSE49515) and data from The Cancer Genome Atlas (TCGA) were retrieved for the analysis of differentially expressed genes (DEGs). The common DEGs were subsequently subjected to weighted gene co-expression network analysis (WGCNA), protein-protein interaction network (PPI), risk model, expression, survival, and prognostic nomogram to determine key genes associated with HCC. Further, the key gene was analyzed using clinical feature analysis, immunoassay, and cell experiments to investigate its exact role in HCC.
Based on the above comprehensive analysis, we targeted the key gene PAK1IP1 with a good prognostic value in HCC. PAK1IP1 showed a remarkably higher increase in tumor samples than in normal samples, which might be related to immune cell infiltration in liver cancer. It was up-regulated in HCC cells, and its knockdown could suppress HCC proliferation and migration. Besides, enzyme-linked immunosorbent assay (ELISA) showed that PAK1IP1 could regulate lipopolysaccharide (LPS)—induced pyroptosis of HCC cells. Knocking down PAK1IP1 could lead to increased expression of caspase 3 (CASP-3), gasdermin E (GSDME)-N, cleaved caspase-1, and gasdermin-D (GSDMD)-N in HCC cells, inducing pyroptosis, thereby inhibiting the development of HCC.
To summarize, PAK1IP1 was identified as a promising prognostic biomarker, and the knockdown of PAK1IP1 can induce pyroptosis to suppress HCC development, which sheds new light on HCC tumorigenesis.
Ageing comprises a cascade of processes that are inherent in all living creatures. There are fourteen general hallmarks of cellular ageing, the majority of which occur at a molecular level. A significant disturbance in the regulation of genome activity is commonly observed during cellular ageing. Overall confusion and disruption in the proper functioning of the genome are also well-known prerogatives of cancerous cells, and it is believed that this genomic instability provides a direct link between aging and cancer. The spatial organization of nuclear DNA in chromatin is the foundation of the fine-tuning and refined regulation of gene activity, and it changes during ageing. Therefore, chromatin is the platform on which genes and the environment meet and interplay. Different protein factors, small molecules and metabolites affect this chromatin organization and, through it, drive cellular deterioration and, finally, ageing. Hence, studying chromatin structural organization and dynamics is crucial for understanding life, presumably the ageing process. The complex interplay among DNA and histone proteins folds, organizes, and adapts chromatin structure. Among histone proteins, the role of the family of linker histones comes to light. Recent data point out that linker histones play a unique role in higher-order chromatin organization, which, in turn, impacts ageing to a prominent degree. Here, we discuss emerging evidence that suggests linker histones have functions that extend beyond their traditional roles in chromatin architecture, highlighting their critical involvement in genome stability, cellular ageing, and cancer development, thereby establishing them as promising targets for therapeutic interventions.
The microbiota-gut-brain axis has been proposed as a potential modulator of mood disorders such as major depression. Complex bidirectional biochemical activities in this axis have been posited to participate in adverse mood disorders. Environmental and genetic factors have dominated recent discussions on depression. The prescription of antibiotics, antidepressants, adverse negative DNA methylation reactions and a dysbiotic gut microbiome have been cited as causal for the development and progression of depression. While research continues to investigate the microbiome-gut-brain axis, this review will explore the state of persistence of gut bacteria that underpins bacterial dormancy, possibly due to adverse environmental conditions and/or pharmaceutical prescriptions. Bacterial dormancy persistence in the intestinal microbial cohort could affect the role of bacterial epigenomes and DNA methylations. DNA methylations are highly motif driven exerting significant control on bacterial phenotypes that can disrupt bacterial metabolism and neurotransmitter formation in the gut, outcomes that can support adverse mood dispositions.
Breast cancer (BC) is the second leading cause of death among women worldwide. Immunotherapy has become an effective treatment for BC patients due to the rapid development of medical technology. Considerable breakthroughs have been made in research, marking the beginning of a new era in cancer treatment. Among them, various cancer immunotherapies such as immune checkpoint inhibitors (ICIs), cancer vaccines, and adoptive cell transfer are effective and have good prospects. The tumor microenvironment (TME) plays a crucial role in determining the outcomes of tumor immunotherapy. Tumor-associated macrophages (TAMs) are a key component of the TME, with an immunomodulatory effect closely related to the immune evasion of tumor cells, thereby affecting malignant progression. TAMs also significantly affect the therapeutic effect of ICIs (such as programmed death 1/programmed death ligand 1 (PD-1/PD-L1) inhibitors). TAMs are composed of multiple heterogeneous subpopulations, including M1 phenotypes macrophages (M1) and M2 phenotypes macrophages (M2). Furthermore, they mainly play an M2-like role and moderate a variety of harmful consequences such as angiogenesis, immunosuppression, and metastasis. Therefore, TAMs have become a key area of focus in the development of tumor therapies. However, several tumor immunotherapy studies demonstrated that ICIs are effective only in a small number of solid cancers, and tumor immunotherapy still faces relevant challenges in the treatment of solid tumors. This review explores the role of TAMs in BC immunotherapy, summarizing their involvement in BC development. It also explains the classification and functions of TAMs, outlines current tumor immunotherapy approaches and combination therapies, and discusses the challenges and potential strategies for TAMs in immuno-oncology treatments.
Male infertility represents a major health concern, accounting for approximately 50% of all infertility cases in couples. This condition arises from multiple etiologies, with oxidative stress gaining increasing attention in recent studies. During the final stages of sperm maturation, the majority of the cytoplasm is discarded, leaving sperm with a diminished antioxidant defense system, which makes them highly susceptible to the detrimental effects of reactive oxygen species (ROS). ROS can be generated from both intrinsic and extrinsic sources. Intrinsically, ROS are primarily produced by mitochondrial activity, while extrinsic factors include alcohol consumption, smoking, circadian rhythm disruption, gut microbiota imbalance, and leukocyte infiltration. Excessive ROS production leads to DNA damage, apoptosis, and epigenetic modifications in sperm, ultimately impairing sperm motility and contributing to infertility. This review provides a comprehensive examination of ROS sources and examines the mechanisms by which ROS induce sperm damage. Furthermore, it explores the therapeutic potential of antioxidants in mitigating oxidative stress and improving sperm quality.
Prolonged psychic stress leads to immune suppression, which preferentially affects the cellular immune response. Yolkin is an egg-derived protein with firmly established immunoregulatory activities in rodent models.
The aim of this work was to evaluate the effects of oral administration of yolkin, when mice experience prolonged exposure to immobilization stress, on in vivo and in vitro parameters of contact sensitivity (CS) to oxazolone (OXA).
BALB/c mice were exposed to 5-day immobilization stress, followed by immunization with OXA. Yolkin was applied in drinking water during stress. Ear thickness and auricle histology, concanavalin A (Con A)- and lipopolysaccharide (LPS)-stimulated production of interferon-gamma (IFN γ) and interleukin 6 (IL-6) in splenocyte cultures, Con A-induced splenocyte proliferation, as well as serum corticosterone levels and thymocyte number were analyzed.
We showed that the treatment with stress alone led to a lower thymocyte number and a decreased thickness of the auricle skin. Control mice that were stressed also exhibited an increase in the number and area of pustules in the epidermis. The treatment of stressed mice with yolkin resulted in a partial normalization of several parameters that were lowered in stressed mice, such as auricle thickness, thymus cell content, Con A-induced splenocyte proliferation, production of IFN γ and IL-6. The serum levels of corticosterone were correlated with several histological parameters.
Oral administration of yolkin normalizes the antigen-specific and nonspecific parameters of the immune system altered by chronic psychic stress in mice.
Acute myocardial infarction (AMI) is accompanied by damage to heart tissues and some cell death. Stem cells are localized in the affected area and contribute to tissue repair. Studies have previously shown that the concentration of cell-free DNA (cfDNA) in the blood (ami-cfDNA) increases significantly in patients with AMI, and GC-rich and oxidized DNA fragments accumulate in the composition of ami-cfDNA. As a result, ami-cfDNA exhibits biological activity in vitro against various types of differentiated human cells. Potentially, ami-cfDNA can influence the functional activity and direction of stem cell differentiation. To verify this assumption, we investigated the effect of ami-cfDNA fragments isolated from the blood of patients with AMI on human adipose tissue mesenchymal stem cells (MSCs) in vitro.
The MSC line was used and characterized by stem cell surface markers. Ami-cfDNA and control (hc-cfDNA) samples were isolated from the blood plasma of seven AMI patients and ten healthy donors. The early (0.5–3 hours) and late (1–3 weeks) responses of MSCs to cfDNA action were analyzed. The level of reactive oxygen species, the expression level of numerous genes (NOX4, NRF2, BRCA1, BCL2, BAX, MYOD1, MYOG, MYF5, MRF4, RUNX2, SPP1, OCN, LPL, AP2), the level of double-stranded DNA breaks in nuclei, and changes in the spatial organization of the chromatin in the nucleus were determined using the quantitative (real-time) polymerase chain reaction (qPCR), flow cytometry, fluorescence microscopy, fluorescent in situ hybridization (FISH) assays.
Introducing ami-cfDNA fragments into the cell culture medium stimulates rapid and transient induction of oxidative stress in MSCs (early response). Oxidative stress stimulates the spatial reorganization of chromatin to develop an adaptive response (AR). The adaptive response includes an antioxidant and anti-apoptotic response and activation of repair genes. The ami-cfDNA fragments, unlike hc-cfDNA, stimulate the myogenic differentiation of MSCs under prolonged exposure (late response).
The ami-cfDNA increases the survival of MSCs in the model system by inducing a pronounced adaptive cellular response. Prolonged exposure to ami-cfDNA provokes myogenic differentiation of MSCs. Under acute stress conditions caused by AMI in the body, ami-cfDNA may positively affect the restoration of damaged heart muscle.
Diabetic nephropathy (DN) is a prevalent complication of diabetes, with current treatment options offering limited effectiveness, particularly in advanced stages. Human pluripotent stem cells (hPSCs), particularly induced PSCs (iPSCs), show promising potential in the treatment of DN due to their pluripotency, capacity for differentiation into kidney-specific cells, and suitability for personalized therapies. iPSC-based personalized approaches can effectively mitigate immune rejection, a common challenge with allogeneic transplants, thus enhancing therapeutic outcomes. Clustered regularly interspaced short palindromic repeats (CRISPR) gene editing further enhances the potential of hPSCs by enabling the precise correction of disease-associated genetic defects, increasing both the safety and efficacy of therapeutic cells. In addition to direct treatment, hPSCs have proven valuable in disease modeling and drug screening, particularly for identifying and validating disease-specific targets. Kidney organoids derived from hPSCs replicate key features of DN pathology, making them useful platforms for validating therapeutic targets and assessing drug efficacy. Comparatively, both hPSCs and mesenchymal SCs (MSCs) have shown promise in improving renal function in preclinical models, with hPSCs offering broader differentiation capacity. Integration with tissue engineering technologies, such as three-dimensional bioprinting and bioengineered scaffolds, expands the regenerative potential of hPSCs by supporting the formation of functional renal structures and enhancing in vivo integration and regenerative capacity. Despite current challenges, such as tumorigenicity, genomic instability, and limited direct research, advances in gene editing, differentiation protocols, and tissue engineering promise to address these barriers. Continued optimization of these approaches will likely lead to successful clinical applications of hPSCs, potentially revolutionizing treatment options for DN.
Mycoplasmas are the smallest cell-wall-less self-replicating prokaryotes. Mycoplasma species can be found within and outside cells as “silent parasites” that live intracellularly and as membrane surface parasites. The pathogen’s impact on respiratory health seems primarily caused by its capacity to alter immune responses, cause airway inflammation, and damage epithelial barriers. Much progress has been made in understanding Mycoplasma-induced inflammation and oxidative stress. However, there are still issues in therapeutic management, such as the development of strains that are resistant to antibiotics, the shortcomings of the available diagnostic techniques, and possible long-term respiratory consequences. On the other hand, to combat oxidative stress, inflammation, and metabolic abnormalities, activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is becoming a more appealing therapeutic strategy. Nrf2 activation coordinates a thorough defense through its transcriptional targets, enabling adaptability and survival under a variety of cellular stressors. Nrf2 is regarded as a therapeutic target, and pharmacological Nrf2 activators have demonstrated protective effects in multiple pathological consequences and advantages in clinical trials. In this review, we discussed the rationale for targeting Nrf2 in a series of inflammatory responses caused by Mycoplasma species.
Traumatic brain injury (TBI) is a disease caused by external forces that damage brain structure and function. After TBI, iron accumulation and reactive oxygen species (ROS) increase lipid peroxidation, promoting ferroptosis. Methyltransferase-like 3 (METTL3) inhibits ferroptosis by modulating related signaling pathways. This study investigates the effects of METTL3 on neuronal ferroptosis in TBI, offering new insights and potential therapies.
TBI mouse and neuron cell models were established and treated with METTL3 overexpression. The Morris Water Maze (MWM) test evaluated cognitive function. Histological staining of brain tissues was conducted to assess brain injury, nuclear pyknosis, and iron accumulation. The activation of neurons, microglia, and astrocytes were detected using immunofluorescence staining. Neuron cell proliferation was measured using the Cell Counting Kit 8 (CCK-8). Quantitative PCR (qPCR) and western blot detected the mRNA and protein expression. Ferroptosis was assessed by measuring the accumulation of iron, malondialdehyde (MDA), superoxide dismutase (SOD), and ROS. The quantification of the N6-methyladenosine (m6A) RNA methylation levels in cells was quantified using the m6A-ELISA assay. Methylated RNA immunoprecipitation (MeRIP) assays were conducted to analyze the m6A modification on GPX4 mRNA. The interaction between YTHDF2 and GPX4 mRNA was measured using RNA pulldown and RNA immunoprecipitation (RIP) assays.
METTL3 expression was downregulated in TBI-injured brain tissues. Overexpression of METTL3 improved cognitive function and brain recovery while simultaneously reducing ferroptosis and neuroinflammation. METTL3 overexpression upregulated GPX4 expression both in vitro and in vivo. Further studies indicated that m6A reader protein YTHDF2 binds to GPX4 mRNA, consequently mediating the METTL3-regulated m6A enrichment and RNA stability of GPX4. Knockdown of GPX4 and treatment with ferroptosis inducer abolished the protective effects of METTL3 on neurons.
METTL3 exhibits anti-ferroptosis properties and promotes brain injury recovery after TBI by regulating the m6A modification and RNA stability of GPX4.
Retinoblastoma (Rb) is a rare cancer, yet it is the most common eye tumor in children. It can occur in either a familial or sporadic form, with the sporadic variant being more prevalent, though its downstream effects on epigenetic markers remain largely unclear. Currently, the treatment for retinoblastoma typically involves aggressive chemotherapy and surgical resection. The identification of specific epigenetic characteristics of non-hereditary (sporadic) Rb has led to the development of advanced, high-throughput methods to explore its epigenetic profile. Our previous research demonstrated that treatment with the demethylating agent 5-Aza-2′-deoxycytidine (decitabine; DAC) induced cell cycle arrest and apoptosis in a well-characterized retinoblastoma model (WERI-Rb-1). Our analysis of time-dependent gene expression in WERI-Rb-1 cells following DAC exposure has led to the development of testable hypotheses to further investigate the epigenetic impact on the initiation and progression of retinoblastoma tumors.
Gene expression analysis of publicly available datasets from patients’ primary tumors and normal retina have been compared with those found in WERI-Rb-1 cells to assess the relevance of DAC-driven genes as markers of primary retinoblastoma tumors. The effect of DAC treatment has been evaluated in vivo, both in subcutaneous xenografts and in orthotopic models. qPCR analysis of gene expression and Methylation-Specific PCR (MSP) was performed.
Our analysis of network maps for differentially expressed genes in primary tumors compared to DAC-driven genes identified 15 hub/driver genes that may play a pivotal role in the genesis and progression of retinoblastoma. DAC treatment induced significant tumor growth arrest in vivo in both subcutaneous and orthotopic xenograft retinoblastoma models. This was associated with changes in gene expression, either through the direct switching-on of epigenetically locked genes or through the indirect regulation of linked genes, suggesting the potential use of DAC as an epigenetic anti-cancer drug for the treatment of retinoblastoma patients.
There is a pressing need to develop innovative treatments for retinoblastoma. Our research revealed that DAC can effectively suppress the growth and progression of retinoblastoma in in vivo models, offering a potential new therapeutic approach to battle this destructive disease. This discovery highlights the impact of this epigenetic therapy in reprogramming tumor dynamics, and thus its potential to preserve both the vision and lives of affected children.
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. The hypoxic microenvironment in HCC enhances glycolysis and co-directed lactate accumulation, which leads to increased lactylation. However, the exact biological pattern remains to be elucidated. Therefore, we sought to identify hypoxia-glycolysis-lactylation (HGL) prognosis-related signatures and validate this in vitro.
Transcriptomic data of patients with HCC were collected from The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases. Differentially expressed HGL genes between HCC and normal tissues were obtained by DEseq2. The consensus clustering algorithm was employed to stratify patients into two distinct clusters. Subsequently, the single sample Gene Set Enrichment Analysis (ssGSEA), Tumor Immune Estimation Resource (TIMER) and Tumor Immune Dysfunction and Exclusion (TIDE) algorithms were utilized to assess immune infiltration and immune evasion. Least Absolute Shrinkage and Selection Operator (LASSO) and COX regression analysis were used to identify an HGL prognosis-related signature. Based on spatial transcriptome and histological data, we analyzed the expression of these genes in HCC and explored the function of Homer Scaffold Protein 1 (HOMER1) in HCC cells.
We identified 72 differentially expressed HGL genes and two HGL clusters. Cluster2, with better survival (p < 0.001), was significantly enriched in metabolic-related pathways. The HGL prognosis-related signature exhibited great predictive efficacy for patients in TCGA, ICGC, and GSE148355 databases (3-year area under the curve (AUC) = 0.822, 0.738, and 0.707, respectively). The elevated expression of HOMER1 in HCC was revealed by the combination of spatial transcriptome and histological data. Knocking down HOMER1 significantly inhibited the malignant progression of HCC cells.
We identified a signature with great predictive efficacy and discovered a gene, HOMER1, that influences the malignant progression of HCC with the potential to become a novel therapeutic target.
The mechanisms underlying the effects of pharmacological mitochondrial ATP-sensitive K+ channel (mKATP) channel openers on the functional effects of the mKATP channels opening remain disputable. Earlier we have shown that the mKATP channel activation by diazoxide (DZ) occurred at submicromolar concentrations and did not require a MgATP in liver mitochondria. This work aimed to evaluate a requirement of a MgATP for the mKATP channel opening by DZ and its blocking by glibenclamide (Glb) and 5-hydroxy decanoate (5-HD) in rat brain mitochondria and to find the effects of the mKATP channels opening on mitochondrial Ca2+ uptake, reactive oxygen species (ROS) production, and the mitochondrial permeability transition pore (mPTP).
The mKATP and the mPTP channels activity was assessed by the light scattering; polarography was applied to quantify K+ transport; Ca2+ transport and ROS production were monitored with fluorescent probes, chlortetracycline, and dichlorofluorescein, respectively; one-way ANOVA was used for reliability testing.
ATP-sensitive K+ transport in native mitochondria was fully activated by DZ at <0.5 μM and blocked by Glb and 5-HD in the absence of a MgATP, however, Mg2+ was indispensable for the blockage of the mKATP channel by ATP. DZ increased Ca2+ uptake, but ROS production was regulated differently: suppressed in mitochondria respiring on glutamate, but activated on succinate. However, in the presence of rotenone, ROS production was suppressed by DZ, which indicated the involvement of reverse electron transport (RET) in the modulation of ROS production. In all cases, the mKATP channel blockers reversed the effects of DZ. The impact of DZ on the mPTP opening strongly correlated with its effects on ROS production. DZ inhibited the mPTP activity on glutamate but elevated on succinate, which was strongly suppressed by rotenone. In the presence of rotenone, the mPTP was strongly inhibited by DZ, which indicated the involvement of ROS and RET in the mechanism of mPTP regulation by DZ.
Brain mKATP channel exhibited high sensitivity to DZ on the low sub-micromolar scale; its regulation by DZ and Glb did not require a MgATPase activity; the impact of DZ on the mPTP activity was critically dependent on the regulation of ROS production by ATP-sensitive K+ transport.
Skeletal muscle atrophy is a common musculoskeletal disorder that significantly reduces patient quality of life. Long non-coding RNA (lncRNA) XLOC_015548 has been identified as a pivotal regulator of C2C12 myoblast proliferation and differentiation. However, its role in mitigating denervation-induced muscle atrophy and the underlying mechanisms remain unclear.
We employed lentiviral-mediated stable expression of XLOC_015548 in C2C12 myoblasts and skeletal muscle-specific XLOC_015548-edited mouse models to investigate the function of this lncRNA. Muscle atrophy models were established in vitro by glucocorticoid-induced atrophy with dexamethasone (DEX) and in vivo by sciatic nerve transection-induced denervation. The MEK inhibitor U0126 was used to assess the role of the growth arrest and DNA damage-inducible 45 gamma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Gadd45g/MEK/ERK) signaling pathway.
Overexpression of XLOC_015548 significantly activated the MEK/ERK signaling pathway (p < 0.05) by downregulating Gadd45g expression (p < 0.05) and promoting its cytoplasmic localization, thereby enhancing cell proliferation and myotube formation. Furthermore, XLOC_015548 reduced the level of reactive oxygen species (ROS) (p < 0.01), stabilized the mitochondrial membrane potential, and alleviated DEX-induced oxidative stress. These protective effects were partially reversed by U0126, confirming the involvement of the MEK/ERK pathway. Skeletal muscle-specific overexpression of XLOC_015548 in vivo significantly reduced denervation-induced muscle atrophy (q < 0.05) and increased the muscle fiber cross-sectional area.
XLOC_015548 plays a critical role in promoting myogenic differentiation and protecting against muscle atrophy by regulating Gadd45g expression, activating the MEK/ERK signaling pathway, and reducing oxidative stress. These findings underscore the therapeutic potential of XLOC_015548 in skeletal muscle atrophy, and provide a foundation for lncRNA-based treatment strategies.
The implementation of proton beam irradiation (PBI) for breast cancer (BC) treatment is rapidly advancing due to its enhanced target coverage and reduced toxicities to organs at risk. However, the effects of PBI can vary depending on the cell type. This study aimed to explore the effects of PBI on two BC cell lines, MCF7 and MDA-MB-231.
The relative biological effectiveness (RBE) of PBI was assessed using a clonogenic assay. DNA double-strand break (DSB) repair, epithelial–mesenchymal transition (EMT), and filamentous actin (F-actin) were evaluated using immunofluorescence analysis. The extent of entosis and the senescence-associated β-galactosidase (SA-β-gal) activity were estimated by cytochemistry analysis. The influence of the extracellular matrix was evaluated by cultivating cells in both adherent two-dimensional (2D) environments and within 3D fibrin gels of varying stiffness. The metastatic propensity of cells was investigated using migration tests and the cell encapsulation of carboxylate-modified fluorescent nanoparticles. The comparative tumorigenic potential of cells was investigated using an in vivo model of the chick embryo chorioallantoic membrane (CAM).
PBI demonstrated superior efficacy in eliminating MCF7 and MDA-MB-231 cells with RBE 1.7 and 1.75, respectively. Following PBI, MDA-MB-231 cells exhibited significantly lower clonogenic survival compared to MCF7, which was accompanied by the accumulation of phosphorylated histone H2AX (γH2AX), p53-binding protein 1 (53BP1) and Rad51 foci of DNA DSBs repair proteins. After surviving 7 days post-PBI, MCF7 cells exhibited 2.5-fold higher levels of the senescence phenotype and entosis compared to the MDA-MB-231 offspring. Both PBI-survived cell lines had greater capability for 2D collective migration, but their metastatic potential was significantly reduced. A significant influence of extracellular matrix stiffness on the correlation between F-actin expression in PBI-survived cells—an indicator of cell stiffness—and their ability to uptake nanoparticles, a trait associated with metastatic potential, was observed. PBI-survived MDA-MB-231RP subline exhibited a hybrid EMT phenotype and a 70% reduction in tumor growth in the in vivo model of the chick embryo CAM. In contrast, PBI-survived MCF7RP cells exhibit mesenchymal-to-epithelial transition (MET)-like features, and their in vivo tumor growth increased by 66% compared to parental cells.
PBI triggers various cellular responses in different BC cell lines, influencing tumor growth through mechanisms like DNA damage repair, stress-induced premature senescence (SIPS), and alterations in the stiffness of tumor cell membranes. Our insights into entosis and the effect of extracellular matrix stiffness on metastatic propensity (nanoparticle uptake) enhance the understanding of the role of PBI in BC cells, emphasizing the need for more research to optimize its therapeutic application.
Suppressor of cytokine signaling (SOCS)3 is a regulatory protein that participates in an important negative feedback loop downstream of several critical cytokines, especially members of the interleukin-6 (IL-6) family. As a result, SOCS3 has been shown to impact the development and function of blood and immune cells. Zebrafish harbor duplicates of SOCS3, Socs3a and Socs3b, both of which possess conserved functional domains.
This study explored the role of zebrafish Socs3a by creating a whole genome knockout using CRISPR/Cas9, with a focus on hematopoiesis and neuromast formation.
A zebrafish Socs3a knockout mutant was successfully generated. Characterization of this mutant revealed that normal hematopoiesis was not impacted nor was neutrophils lacking Socs3a displayed normal responses to injury or their production during emergency granulopoiesis. Neuromast formation was severely impacted in Socs3a knockout zebrafish.
Zebrafish Socs3a mutants display normal hematopoiesis and myeloid function, but the formation of the lateral line neuromast was affected by the absence of Socs3a.
Tumor-associated telocytes (TATCs) perform a pivotal role in hepatocellular carcinoma (HCC) progression and correlate with poor patient outcomes. This study aims to identify specific markers of TATCs in HCC using single-nucleus RNA sequencing (snRNA-seq) and transcriptomic analyses.
Comprehensive snRNA-seq and transcriptomic profiling were performed on HCC and adjacent non-cancerous tissues to detect differential expressed genes (DEGs) in TATCs. Bioinformatics tools, including STING and Cytoscape software, were employed to analyze protein–protein interactions and hub genes. Immune cell interactions were assessed via ligand-receptor network analysis.
TATCs constituted 0.35% of cells in HCC tissues, with reduced proportions compared to para-cancerous tissues (0.35% vs 8.19%). Hub genes, including TOP2A (DNA topoisomerase Ⅱ alpha), BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B), KIF11 (kinesin family member 11), and CENPF (centromere protein F) were identified in telocytes (TCs). Transcriptomics revealed 622 upregulated and 758 downregulated genes in TATCs versus TCs. TMC5 (transmembrane channel like 5) and SLC35F3 (solute carrier family 35 member F3) emerged as unique TATCs biomarkers, revealing significant associations with poor overall survival (OS) in HCC patients (HR = 1.499 for TMC5; HR = 1.562 for SLC35F3).
TMC5 and SLC35F3 are promising biomarkers for TATCs in HCC, warranting further validation to explore their clinical and therapeutic implications.
Alzheimer’s disease (AD) is a neurodegenerative disease which significantly and negatively affects families and society. Aerobic exercise serves as a non-pharmacological strategy, potentially safeguarding against cognitive decline and lowering the risk of AD. However, how aerobic exercise ameliorates AD remains unknown. This study investigated the effects of two types of aerobic exercise, including aerobic interval training (AIT) and aerobic continuous training (ACT), on cognitive and exploratory function, brain histopathology, and hepatic amyloid beta (Aβ) clearance in amyloid precursor protein/presenilin-1 double transgenic (APP/PS1) transgenic mice.
Twenty-four six-month-old male APP/PS1 transgenic mice (body weight: 20–22 g) were used to establish the AD model. APP/PS1 transgenic mice were randomly assigned to one of the three groups: rest (AD group, n = 8), aerobic interval training (AIT group, n = 8), and aerobic continuous training (ACT group, n = 8). The exploration ability and anxiety of AD mice were measured using the open-field test. Learning and memory of AD mice were detected using the novel object recognition test, Y-maze test, and Morris water maze test. Neuronal damage was analyzed using hematoxylin and eosin staining and Nissl staining. Aβ deposition in the brain was detected using a thioflavin-S fluorescence assay and immunofluorescence. The mechanisms underlying hepatic Aβ clearance were investigated using an immunofluorescence assay and western blotting. Data were analyzed using one-way ANOVA with Tukey’s post hoc test, and p < 0.05 was deemed statistically significant.
The results revealed that both AIT and ACT improved the recognition memory and exploration ability of mice after 8 weeks of intervention. Additionally, both forms of aerobic exercise significantly mitigated neuronal damage and Aβ deposition in the brain and improved the hepatic clearance of Aβ.
Our findings indicated that AIT and ACT can improve cognitive deficits in APP/PS1 mice, potentially by increasing the hepatic phagocytic capacity of Aβ. Hepatic clearance of Aβ may serve as a supplementary mechanism by which aerobic exercise can improve AD.
m6Am is a specific RNA modification that plays an important role in regulating mRNA stability, translational efficiency, and cellular stress response. m6Am’s precise identification is essential to gain insight into its functional mechanisms at transcriptional and post-transcriptional levels. Due to the limitations of experimental assays, the development of efficient computational tools to predict m6Am sites has become a major focus of research, offering potential breakthroughs in RNA epigenetics. In this study, we present a robust and reliable deep learning model, DTC-m6Am, for identifying m6Am sites across the transcriptome.
Our proposed DTC-m6Am model first represents RNA sequences by One-Hot coding to capture base-based features and provide structured inputs for subsequent deep learning models. The model then combines densely connected convolutional networks (DenseNet) and temporal convolutional network (TCN). The DenseNet module leverages its dense connectivity property to effectively extract local features and enhance information flow, whereas the TCN module focuses on capturing global time series dependencies to enhance the modeling capability for long sequence features. To further optimize feature extraction, the Convolutional Block Attention Module (CBAM) is used to focus on key regions through spatial and channel attention mechanisms. Finally, a fully connected layer is used for the classification task to achieve accurate prediction of the m6Am site. For the data imbalance problem, we use the focal loss function to balance the learning effect of positive and negative samples and improve the performance of the model on imbalanced data.
The deep learning-based DTC-m6Am model performs well on all evaluation metrics, achieving 87.8%, 50.3%, 69.1%, 41.1%, and 76.5% for sensitivity (Sn), specificity (Sp), accuracy (ACC), Mathew’s correlation coefficient (MCC), and area under the curve (AUC), respectively, on the independent test set.
We critically evaluated the performance of DTC-m6Am using 10-fold cross-validation and independent testing and compared it to existing methods. The MCC value of 41.1% was achieved when using the independent test, which is 19.7% higher than the current state-of-the-art prediction method, m6Aminer. The results indicate that the DTC-m6Am model has high accuracy and stability and is an effective tool for predicting m6Am sites.
Escherichia coli (E. coli) is a common opportunistic bacterial pathogen in both human and animal populations. Fatty acids serve as the central carbon and energy source, a process mediated by fatty acid-coenzyme A (CoA) ligases encoded by fad genes such as FadK. However, the function and the mechanism of FadK remain unclear.
The three-dimensional structure of FadK was modeled using AlphaFold2. After expression and purification, monomeric FadK was successfully isolated. The enzymatic activity was assayed, and real-time quantitative polymerase chain reaction (RT-qPCR) was performed to quantify FadK expression levels.
In enzymatic assays of fatty acid CoA ligase activity, caprylic acid was found to be the optimal substrate for FadK. We determined the optimal catalytic conditions for FadK, which include a pH of 7.4, ATP concentration of 0.6 mM, CoA concentration of 0.8 mM, and Mg2+ concentration of 0.8 mM at 37 °C. Notably, the activity of FadK showed a decrease with increasing concentrations of dodecyl-AMP, which was further confirmed by the RT-qPCR results.
Our findings will serve as a fundamental framework for the development of innovative therapeutics that target E. coli infections.
Ischemic stroke is a leading cause of mortality and disability worldwide, yet the interplay between peripheral and central immune responses is still only partially understood. Emerging evidence suggests that myeloid cells, when activated in the periphery, infiltrate the ischemic brain and contribute to the disruption of the blood-brain barrier (BBB) through both inflammatory and metabolic mechanisms.
In this study, we integrated bulk RNA-sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), spatial transcriptomics, and flow cytometry data from human and mouse models of ischemic stroke. Mouse stroke models were induced by transient middle cerebral artery occlusion (tMCAO), and brain tissues were later collected at specified time points for analysis. We examined time-dependent transcriptional changes in the peripheral blood, delineated cell-type-specific responses by single-cell profiling, and validated myeloid infiltration into the ischemic brain. We also investigated endothelial metabolic reprogramming and oxidative stress by combining scMetabolism analyses (a computational R package for inferring metabolic pathway activity at the single-cell level) with in vitro oxygen-glucose deprivation/reperfusion (OGD/R) experiments.
Cross-species bulk RNA-seq revealed a modest early immune shift at 3 h post-stroke, escalating significantly by 24 h, with robust myeloid-centric gene signatures conserved in humans and mice. Single-cell analyses confirmed a pronounced expansion of neutrophils, monocytes, and megakaryocytes in peripheral blood, coupled with a decrease in T and B lymphocytes. Spatial transcriptomics and flow cytometry demonstrated substantial infiltration of CD11b+ myeloid cells into the infarct core, which showed extensive interaction with endothelial cells. Endothelial scRNA-seq data showed reductions in the oxidative phosphorylation, glutathione, and nicotinate metabolic pathways, together with elevated pentose phosphate pathway activity, suggestive of oxidative stress and compromised antioxidant capacity. Functional scoring further indicated diminished endothelial inflammation/repair potential, while in vitro OGD/R experiments revealed morphological disruption, CD31 downregulation, and increased 4-hydroxynonenal (4-HNE), underscoring the importance of endothelial oxidative damage in BBB breakdown.
These multi-omics findings highlight the existence of a coordinated peripheral-central immune axis in ischemic stroke, wherein myeloid cell recruitment and endothelial metabolic vulnerability jointly exacerbate inflammation and oxidative stress. The targeting of endothelial oxidative injury and myeloid-endothelial crosstalk may represent a promising strategy to mitigate secondary brain injury in ischemic stroke.
As pivotal immunoregulatory sentinels in pulmonary defense systems, alveolar macrophages (AMs) play dual roles in mediating inflammatory responses and tissue repair processes during various phases of inflammatory cascades. The present investigation focuses on elucidating the regulatory influence of Notch pathway activation within AM populations on the pathophysiological mechanisms underlying acute lung injury (ALI) development.
To investigate the regulatory roles of Notch intracellular domain (NICD) and C-C chemokine receptor type 5 (CCR5) in pulmonary inflammation, an ALI model was established through lipopolysaccharide (LPS) administration. Complementary studies used macrophage-specific Notch1 knockout mice and immortalized bone marrow-derived macrophages (iBMDMs). Molecular profiling of CCR5 and inflammatory mediators was performed through real-time quantitative reverse transcription PCR (qRT-PCR) and immunofluorescence staining. Functional assessments of macrophage migration were carried out using scratch wound healing assays and transwell migration assays.
In the LPS-induced ALI model, pulmonary tissues exhibited elevated expression of both NICD and CCR5. Conversely, Notch1 knockout mice attenuated CCR5 expression, reduced macrophage infiltration and downregulated transcription of pro-inflammatory mediators compared to wild-type controls (p < 0.05). Lung injury was milder in the Notch1-deficient mice model compared to wild mice (p < 0.05). In vitro experiments demonstrated that inhibiting the Notch pathway in macrophages reduced CCR5 expression and attenuated CCL5-induced macrophage migration.
Notch signaling regulates macrophage infiltration and the inflammatory response by modulating CCR5 expression in ALI induced by LPS.
Oxidative stress and neuroinflammation are important secondary injury mechanisms in intracranial hemorrhage (ICH). V-set and immunoglobulin domain-containing 4 (VSIG4) has an inhibitory effect on oxidative stress and the inflammatory response. This study aimed to explore the possible role of VSIG4 in ICH-related neuropathology.
In this study, VSIG4 levels were investigated in an ICH mouse model and lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Moreover, we examined oxidative stress levels, pro-inflammatory cytokine production, neuronal damage, inflammatory cell activation, brain water content, and neurological function. We performed these assays in ICH mice and macrophages with different VSIG4 levels. Additionally, the critical role of the nuclear factor erythroid 2 related factor 2/heme oxygenase-1 (NRF2/HO-1) signaling pathway in VSIG4 function was verified.
VSIG4 ameliorated neurological deficits in ICH mice (p < 0.01), alleviated cerebral edema (p < 0.05), and increased glutathione (p < 0.05) and decreased superoxide dismutase (SOD) levels (p < 0.01) in the perihematomal area and LPS-stimulated RAW264.7 cells. It also reduced Malondialdehyde (MDA) accumulation (p < 0.01), alleviated oxidative stress, and decreased interleukin-1β (IL-1β) (p < 0.01) and tumor necrosis factor-alpha (TNF-α) levels (p < 0.01), thereby attenuating the inflammatory response. Additionally, treatment of LPS-stimulated RAW264.7 cells with VSIG4 resulted in less damage to HT22 cells (p < 0.05). To further validate the involvement of the NRF2/HO-1 pathway in VSIG4-mediated neuroprotection, brusatol (an NRF2 inhibitor) was administered.
Our study demonstrates the neuroprotective effect and mechanism of action of VSIG4 in ICH.
The vesicular nucleotide transporter Solute Carrier Family 17 Member 9 (SLC17A9) has recently been recognized as a significant modulator of oncogenic pathways, with its elevated expression levels being closely linked to the aggressiveness of clear cell renal cell carcinoma (ccRCC). A comprehensive understanding of the role of SLC17A9 and its associated protein markers presents substantial potential for the advancement of targeted therapeutic interventions.
Our study commenced with a comprehensive bioinformatics analysis to identify differentially expressed genes potentially associated with ccRCC. Leveraging The Cancer Genome Atlas (TCGA) database, we predicted the clinical relevance of these cancer-associated genes and validated their expression profiles through multiple experimental methodologies. Functional assays were conducted to assess the impact of these genes on renal cancer cell lines. Additionally, we generated cell lines overexpressing oncogenes and identified downstream targets through RNA sequencing, followed by mechanistic exploration of their interactions. Finally, bioinformatics tools were subsequently employed to assess the diagnostic and prognostic significance of these genes in patients with ccRCC.
The bioinformatics analysis revealed SLC17A9 as a highly expressed oncogene in ccRCC, serving as a robust prognostic marker. Experimental validation demonstrated that SLC17A9 promotes ccRCC cell growth, proliferation, and migration. Lentivirus-based experiments revealed Potassium Voltage-Gated Channel Subfamily H Member 1 (KCNH1) as a downstream target regulated by SLC17A9 (p < 0.05). Database analysis further confirmed KCNH1’s oncogenic role in ccRCC, with significant implications for patient survival. Notably, SLC17A9 and KCNH1 collaboratively drive the initiation and progression of renal cancer. Elevated expression of SLC17A9 and KCNH1 correlates with poorer prognosis (p < 0.001), whereas lower expression levels are associated with favorable outcomes in ccRCC patients. These findings highlight SLC17A9 and KCNH1 as critical biomarkers and potential therapeutic targets in ccRCC.
SLC17A9 and KCNH1 serve as critical prognostic biomarkers in ccRCC, with SLC17A9 driving tumor progression through KCNH1 regulation. Their upregulated expression predicts poor clinical outcomes, while reduced levels correlate with improved survival, highlighting their dual role as therapeutic targets.
Neurodegenerative disorders (NDs), including dementia, Alzheimer’s disease (AD), and Parkinson’s disease (PD), are age-related diseases closely associated with chronic inflammation, oxidative stress, gene mutations, autoimmune-derived inflammation, and other external risk factors. They are characterized by progressive neuronal loss, cognitive decline, and/or motor dysfunction, with chronic inflammation being a key player in intensifying NDs’ occurrence. One of the most important molecular inflammatory mediators linking inflammation to NDs is the platelet-activating factor (PAF) and its pivotal signaling for regulating neuroinflammation, apoptosis, and neuronal damage. Dysregulation of PAF activity and metabolism/levels, along with overexpression of its receptor (PAF-R) have been associated with exacerbated inflammatory responses, further aggravating neurodegeneration. This article highlights the role of PAF in neurodegeneration, with a particular focus on novel insights into the potential medicinal use of PAF inhibitors for the prevention and treatment of neurodegenerative diseases. We evaluate the recently proposed concept of targeting the PAF signaling pathway through either natural and/or synthetic inhibitors or a combination of both. It explores the potential of these inhibitors to offer significant preventative and therapeutic benefits against NDs, likely through anti-inflammatory anti-aging effects and by slowing down the disease progression and preserving cognitive and motor dysfunction. Current status and future perspectives of such therapeutic approaches are also discussed.