Cell Proliferation In Response Research Articles

Regulation of autophagy by non-coding RNAs in human glioblastoma.

Glioblastoma, a lethal form of brain cancer, poses substantial challenges in treatment due to its aggressive nature and resistance to standard therapies like radiation and chemotherapy. Autophagy has a crucial role in glioblastoma progression by supporting cellular homeostasis and promoting survival under stressful conditions. Non-coding RNAs (ncRNAs) play diverse biological roles including, gene regulation, chromatin remodeling, and the maintenance of cellular homeostasis. Emerging evidence reveals the intricate regulatory mechanisms of autophagy orchestrated by non-coding RNAs (ncRNAs) in glioblastoma. The diverse roles of these ncRNAs in regulating crucial autophagy-related pathways, including AMPK/mTOR signaling, the PI3K/AKT pathway, Beclin1, and other autophagy-triggering system regulation, sheds light on ncRNAs biological mechanisms in the proliferation, invasion, and therapy response of glioblastoma cells. Furthermore, the clinical implications of targeting ncRNA-regulated autophagy as a promising therapeutic strategy for glioblastoma treatment are in the spotlight of ongoing studies. In this review, we delve into our current understanding of how ncRNAs regulate autophagy in glioblastoma, with a specific focus on microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), and their intricate interplay with therapy response.

A comparative study on the toxic effects of lead pollution and nanoplastic-lead mixed pollution on red drum and their detoxification strategies

Nanoplastics and heavy metals pose various adverse effects on marine organisms. However, the combined toxicity of nanoplastics and lead pollution to marine fish is not fully understood. This study investigates the toxic effects and detoxification strategies of lead pollution (p07) compared to nanoplastic-lead mixed pollution (m07) in red drum during exposure and recovery phases. Under m07 pollution, the maximum lead content in muscle was 22.61 mg/kg, which was significantly higher than the 15.82 mg/kg observed under p07 pollution. This finding demonstrated that nanoplastics significantly enhance lead accumulation, leading to more severe toxic effects on red drum. Histological analyses revealed that lipid droplets in the liver and epithelial lifting in the gills were the primary lesion types. During the exposure periods, red drum primarily detoxified lead through cellular renewal and the removal of damaged proteins under p07 pollution. Conversely, under m07 pollution, detoxification relied on cellular senescence, apoptosis, endocytosis, and the removal of damaged proteins. In the recovery phases, red drum predominantly recovered through cell proliferation and antioxidant responses under p07 pollution. Under m07 pollution, the focus shifted to functional protein synthesis, apoptosis, endocytosis, and lipid metabolism. This study offers valuable insights into the monitoring and management of combined environmental pollution.

The role of SIRT1 in autophagy and drug resistance: unveiling new targets and potential biomarkers in cancer therapy

Cancer, the world’s second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1’s regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy.

Development of human amniotic epithelial cell-derived extracellular vesicles as cell-free therapy for dry eye disease

PurposeThis study aimed to investigate the therapeutic potential of extracellular vesicles (EVs) derived from human amniotic epithelial cells (hAEC-EVs) for Dry Eye Disease (DED) treatment. MethodsHighly purified EVs were isolated from the culture supernatants of hAECs, which obtained from term placenta and characterized. Proteomic contents were analyzed for assessing its biological function related to the therapeutic potentials for DED. Subsequently, we examined the therapeutic efficacy of hAEC-EVs on human corneal epithelial cells exposed to hyperosmotic stress and in an experimental DED mouse model induced by desiccation stress. ResultsProteomic analysis of hAEC-EVs revealed proteins linked to cell proliferation and anti-inflammatory responses. We demonstrated efficient uptake of hAEC-EVs by ocular surface cells. Under DED conditions, EV treatment increased corneal epithelial cell proliferation and migration, and concurrently reducing inflammatory cytokines. In the DED mouse model, hAEC-EVs showed significant improvements in corneal staining score, tear secretion, corneal irregularity, and conjunctival goblet cell density. Additionally, hAEC-EVs exhibited a mitigating effect on ocular surface inflammation induced by desiccation. ConclusionsThese findings suggest that hAEC-EVs hold potential as a cell-free therapy for corneal epithelial defects and ocular surface diseases, presenting a promising treatment option for DED.

Paricalcitol prevents MAPK pathway activation and inflammation in adriamycin-induced kidney injury in rats.

Activation of the mitogen-activated protein kinase (MAPK) pathway induces uncontrolled cell proliferation in response to inflammatory stimuli. Adriamycin (ADR)-induced nephropathy (ADRN) in rats triggers MAPK activation and pro-inflammatory mechanisms by increasing cytokine secretion, similar to chronic kidney disease (CKD). Activation of the vitamin D receptor (VDR) plays a crucial role in suppressing the expression of inflammatory markers in the kidney and may contribute to reducing cellular proliferation. This study evaluated the effect of pre-treatment with paricalcitol on ADRN in renal inflammation mechanisms. Male Sprague-Dawley rats were implanted with an osmotic minipump containing activated vitamin D (paricalcitol, Zemplar, 6 ng/day) or vehicle (NaCl 0.9%). Two days after implantation, ADR (Fauldoxo, 3.5 mg/kg) or vehicle (NaCl 0.9%) was injected. The rats were divided into four experimental groups: control, n = 6; paricalcitol, n = 6; ADR, n = 7 and, ADR + paricalcitol, n = 7. VDR activation was demonstrated by increased CYP24A1 in renal tissue. Paricalcitol prevented macrophage infiltration in the glomeruli, cortex, and outer medulla, prevented secretion of tumor necrosis factor-α, and interleukin-1β, increased arginase I and decreased arginase II tissue expressions, effects associated with attenuation of MAPK pathways, increased zonula occludens-1, and reduced cell proliferation associated with proliferating cell nuclear antigen expression. Paricalcitol treatment decreased the stromal cell-derived factor 1α/chemokine C-X-C receptor type 4/β-catenin pathway. Paricalcitol plays a renoprotective role by modulating renal inflammation and cell proliferation. These results highlight potential targets for treating CKD.

Roles and action mechanisms of NRIP1 in pre-eclampsia.

Pre-eclampsia (PE) is characterized by the onset of hypertension and proteinuria during pregnancy. Here, we aimed to explore the functions of nuclear receptor-interacting protein 1 (NRIP1) in PE mice and human placental JEG-3 cells. We evaluated its effects on JEG-3 cell proliferation, apoptosis, invasion, and inflammatory response and regulation of Wnt/β-catenin pathway. NRIP1 levels in human serum and placental tissues, JEG-3 cells, and mouse models were assessed via quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting. JEG-3 cell growth, apoptosis, migration, and invasion were evaluated via 5-ethynyl-2'-deoxyuridine, flow cytometry, and transwell assays. Levels of the inflammatory factors, matrix metalloproteinase (MMP)-2, tumor necrosis factor (TNF)-α, and interleukin (IL)-6, were determined via enzyme-linked immunosorbent assay. Wnt/β-catenin pathway was assessed via western blotting and qRT-PCR. Systolic blood pressure and proteinuria were measured using the non-invasive tail cuff method and Coomassie brilliant blue assay, respectively. TdT-mediated dUTP nick-end labeling assay was used to assess cell apoptosis in the placental tissues of PE mice. NRIP1 levels were upregulated in the serum and placental tissues of patients with PE. In vitro experiments revealed that NRIP1-small interfering RNA (siRNA) increased the cell viability, migration, and invasion and reduced the cell apoptosis compared to the control siRNA. Moreover, NRIP1-siRNA activated the Wnt/β-catenin signaling pathway, as indicated by the increased Wnt3a, β-catenin, p-glycogen synthase kinase-3β, c-Myc, and cyclin D1 levels. Levels of the inflammatory factors, IL-6, TNF-α, and MMP-2, were decreased in the NRIP1-siRNA-treated group. Notably, NRIP1 downregulation improved the PE-like symptoms, inhibited the inflammatory responses, and reduced apoptosis in PE mice. This study revealed the crucial roles of NRIP1 in PE. Our findings revealed that NRIP1 downregulation relieved PE symptoms by inhibiting cell proliferation, migration, and invasion via the Wnt/β-catenin pathway, thus providing a novel candidate for PE treatment.

Novel Therapeutic Target for ALI/ARDS: Forkhead Box Transcription Factors.

ALI/ARDS can be a pulmonary manifestation of a systemic inflammatory response or a result of overexpression of the body's normal inflammatory response involving various effector cells, cytokines, and inflammatory mediators, which regulate the body's immune response through different signalling pathways. Forkhead box transcription factors are evolutionarily conserved transcription factors that play a crucial role in various cellular processes, such as cell cycle progression, proliferation, differentiation, migration, metabolism, and DNA damage response. Transcription factors control protein synthesis by regulating gene transcription levels, resulting in diverse biological outcomes. The Fox family plays a role in activating or inhibiting the expression of various molecules related to ALI/ARDS through phosphorylation, acetylation/deacetylation, and control of multiple signalling pathways. An in-depth analysis of the integrated Fox family's role in ALI/ARDS can aid in the development of potential diagnostic and therapeutic targets for the condition.

2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside–stimulated dental pulp stem cells-derived exosomes for wound healing and bone regeneration

Background/purpose-2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) is a bioactive component in the Chinese herb Polygonum multiflorum, recognized for its anti-inflammatory and lipid-lowering properties. Human dental pulp stem cells (hDPSCs) have excellent capabilities in tooth regeneration, wound healing, and neural repair. The exosomes (Exo) released by hDPSCs contain bioactive molecules that influence cell proliferation, differentiation, and immune responses. Therefore, we aimed to unveil the potential of THSG-Exo and evaluate its regenerative capabilities through the in vitro experiment and rat bone defect model. Materials and methodsThe effects of hDPSC-derived exosomes, with or without THSG treatment, on repair and bone regeneration were evaluated through in vitro and in vivo studies. Finally, we conducted a proteomic analysis to meticulously compare the compositional contents of the two types of exosomes. ResultsIn vitro data showed that 10 and 100 μM THSG-Exo enhanced cell proliferation and osteogenic differentiation, reducing wound size to 40 % of its original size. In our maxillary bone defect rat model, THSG-Exo significantly increased bone volume, trabecular thickness, and bone density in the bone defect area. In addition, proteomic analysis of THSG-Exo revealed diverse proteins linked to bone differentiation and tissue repair, including bone morphogenetic protein-1 (BMP-1) and tumor necrosis factor (TNF)-α-stimulated gene 6 (TNFAIP6). Our searches in functional databases revealed that THSG-Exo is involved in numerous biological pathways. ConclusionTHSG-Exo enhanced cell proliferation, wound healing, and osteogenesis in vitro, while also expediting tissue repair and bone regeneration in vivo. The protein diversity of THSG-Exo contributes significant value in both basic and regenerative medicine.

MicroRNA-506 as a tumor suppressor in prostate cancer by regulation of Hippo signaling pathway

IntroductionProstate cancer (PCa) is considered as one of the leading causes of cancer related deaths among males globally. There is a high rate of tumor relapse and metastasis in PCa patients that is associated with chemo-resistance. Beside the elimination of tumor cells, chemotherapy has an adverse effect in normal cells. Therefore, it is required to clarify the molecular tumor biology to introduce novel markers to predict the drug response in PCa patients. Hippo signaling pathway is an important regulator of cell proliferation, migration, and drug response that can be modulated by microRNAs (miRNAs). Since, miR-506 deregulation has been reported in PCs, in the present study we assessed a probable role of miR-506 in regulation of Hippo signaling pathway during prostate tumor cell migration and drug resistance. Materials and methodsThe mRNA expression levels of Hippo signaling components were assessed in miR-506 ectopic expressed in comparison with control PC3 cells. Apoptosis assay, drug response, and cell migration were also assessed to find the role of miR-506 in prostate tumor cell aggressiveness. ResultsMiR-506 promoted the Hippo signaling pathway via TAZ and CTGF up regulations, while BIRC5, FAT, and C-MYC down regulations in PC3 cells. MiR-506 significantly reduced prostate tumor cell migration (p = 0.019) and Paclitaxel (TXL) resistance (p = 0.0006), while promoted apoptosis (p < 0.0001). ConclusionmiR-506 exerted a tumor suppressor role during PCa progression by activation of Hippo pathway. MiR-506 targeted the FAT to activate the YAP/TAZ and nuclear translocation where it can bind with TEAD to up regulate the CTGF that resulted in reduced PCa cell migration. The WNT inhibition and C-MYC down regulation by the CTGF resulted in BIRC5 down regulation that induced apoptosis in PCa cells. Therefore, miR-506 can be introduced as a therapeutic marker in PCa following the confirmation by the animal studies and further clinical trials.

Roles of intralesional bacteria in the initiation and progression of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the predominant form of head and neck cancer, often diagnosed at late stages, resulting in a poor prognosis. Recent studies indicate a potential association between OSCC and microbial presence. Microorganisms have been identified in various tumors and lesions, including OSCC and oral potentially malignant disorders (OPMDs). Intralesional microbiota are considered important components of the tumor microenvironment (TME) and may contribute to carcinogenesis. Sources were collected through thorough searches of databases PubMed and Embase. The review focused on microbial characteristics, potential origins, and their impact on cancer progression. Bacteria display varying abundance and diversity throughout the stages of OSCC and OPMDs. Intraleisional bacteria may have diverse sources, including not only oral plaque and saliva but also potentially the gut. Intralesional bacteria have both pro-carcinogenic and anti-carcinogenic effects, affecting processes like cell proliferation, invasion, and immune response. Intralesional microbiota are crucial in OSCC and OPMDs, influencing both disease progression and treatments. Despite their significance, challenges like inconsistent sampling and microbial identification remain. Future research is required to fully understand their role and improve clinical applications.

Epithelial-Mesenchymal Transition Related Score Functions as a Predictive Tool for Immunotherapy and Candidate Drugs in Glioma.

Gliomas are aggressive CNS tumors where the epithelial-mesenchymal transition (EMT) is crucial for prognosis. We developed an EMT-based score predicting overall survival (OS) and conducted pathway analyses, revealing functions such as cell proliferation and immune response in glioma progression. The EMT score, correlated with immune functions and cell infiltration, shows potential as an immune response indicator. We identified two promising compounds, BIX02189 and QL-XI-92, as potential glioma treatments based on candidate gene analysis.

The growth-blocking peptide is a dual regulator of development and immunity with biocontrol potential in Spodoptera frugiperda (Lepidoptera: Noctuidae)

Insect growth-blocking peptides (GBPs) are a family of cytokines found in several insect orders and are known for their roles in regulating development, paralysis, cell proliferation, and immune responses. Despite their diverse functions, the potential of GBPs as biocontrol targets against the pest Spodoptera frugiperda (Lepidoptera: Noctuidae) has not been fully explored. In this study, S. frugiperda GBP (SfGBP) was identified and functionally characterized. SfGBP is synthesized as a 146 amino acid proprotein with a 24 amino acid C-terminal active peptide (Glu123-Gly146). Predominant expression of SfGBP occurs in fourth to sixth instar larvae and in the larval fat body, with significant upregulation in response to pathogens and pathogen-associated molecular patterns. Injection of the synthetic active peptide into larvae induced growth retardation, delayed pupation, and increased survival against Beauveria bassiana infection. Conversely, RNA interference-mediated knockdown of SfGBP resulted in accelerated growth, earlier pupation, and decreased survival against B. bassiana infection. Further analysis revealed that SfGBP promoted SF9 cell proliferation and spreading, enhanced bacteriostatic activity of larval hemolymph, and directly inhibited germination of B. bassiana conidia. In addition, SfGBP enhanced humoral responses, such as upregulation of immunity-related genes and generation of reactive oxygen species, and cellular responses, such as nodulation, phagocytosis, and encapsulation. These results highlight the dual regulatory role of SfGBP in development and immune responses and establish it as a promising biocontrol target for the management of S. frugiperda.

Dynamics of the thymic transcriptome at stages of acute thymic involution in Japanese Black calves with a poor prognosis

Transcriptome analysis was performed on the thymus of Japanese Black calves that were necropsied due to poor prognosis, to characterize changes associated with acute thymic involution. Gene expression profiles obtained by DNA microarray analysis of eight calf thymuses were classified into three patterns that correlated with the histopathological stage of acute thymic involution. Using principal component analysis, the first principal component of the global gene expression levels in the calf thymus was associated with the stage of acute thymic involution, suggesting that histopathological changes greatly influence the gene expression profile. Gene ontology enrichment analysis revealed that genes related to cell proliferation, wound healing, and inflammatory responses were the main contributors to the first principal component. Real-time RT-PCR showed that the thymus had lower expression of PCNA, KIFC1, and HES6, and higher expression of SYNPO2, PDGFRB, and TWIST1 during acute thymic involution. Immunohistochemistry demonstrated a decrease in the rate of Ki67-positive cells in the thymic cortex during the late stage of acute thymic involution. The rate of cleaved caspase-1-positive cells increased in the thymic cortex at an earlier stage than the increase in the rate of cleaved caspase-3-positive cells. Vimentin, which was almost absent in the non-involuted thymic cortex, appeared in the thymic cortex during acute thymic involution. These results suggest that in farmed calves with a poor prognosis, inflammatory responses and impaired thymocyte proliferation are primarily involved in acute thymic involution.

Berberine and berberine nanoformulations in cancer therapy: Focusing on lung cancer.

Lung cancer is the second most prevalent cancer and ranks first in cancer-related death worldwide. Due to the resistance development to conventional cancer therapy strategies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, various natural products and their extracts have been revealed as alternatives. Berberine (BBR), which is present in the stem, root, and bark of various trees, could exert anticancer activities by regulating tumor cell proliferation, apoptosis, autophagy, metastasis, angiogenesis, and immune responses via modulating several signaling pathways within the tumor microenvironment. Due to its poor water solubility, poor pharmacokinetics/bioavailability profile, and extensive p-glycoprotein-dependent efflux, BBR application in (pre) clinical studies is restricted. To overcome these limitations, BBR can be encapsulated in nanoparticle (NP)-based drug delivery systems, as monotherapy or combinational therapy, and improve BBR therapeutic efficacy. Nanoformulations also facilitate the selective delivery of BBR into lung cancer cells. In addition to the anticancer activities of BBR, especially in lung cancer, here we reviewed the BBR nanoformulations, including polymeric NPs, metal-based NPs, carbon nanostructures, and others, in the treatment of lung cancer.

IL-10 Is Critical for Regulation of Cytotoxic CD4+NKG7+ T Cells in Lung Allograft Rejection but Is Not Required for Allograft Acceptance.

Lung transplant remains the primary therapeutic option for patients with end-stage lung disease, but long-term survival rates remain suboptimal compared with other solid organ transplants. Acute cellular rejection (ACR) is a significant challenge in lung transplant recipients, with T cell-mediated mechanisms playing a major role. IL-10 is known for its immunoregulatory function, although its specific role in lung allograft rejection remains unclear. Using the mouse orthotopic lung transplant model, we investigated the role of IL-10 in regulating alloeffector T cell responses. Unexpectedly, we found that IL-10 was not required for early costimulation blockade-induced allograft acceptance. However, IL-10 deficiency or blockade resulted in increased CD4+ T cell numbers, proliferation, graft infiltration, and alloeffector responses. In the absence of IL-10, CD4+ T cell responses predominated over CD8 responses during ACR in contrast to wild-type mice. Type 1 immunity (IFN-γ) responses along with elevated CD4+NKG7+ and CD4+CD107a+ responses predominated during ACR, highlighting a critical regulatory role for IL-10 in modulating CD4+ T cell alloimmune responses. We further demonstrated increased colocalization of NKG7 and CD107a in CD4+ T cells from IL-10-deficient allografts, suggesting coordination in cytotoxic activity. Together, our findings highlight a critical role for IL-10 in regulation of cytotoxic CD4+NKG7+ T cells, an effector population that needs further investigation to elucidate their role in lung allograft rejection.

Transcriptomic and proteomic differences in BTK-WT and BTK-mutated CLL and their changes during therapy with pirtobrutinib

AbstractCovalent Bruton tyrosine kinase inhibitors (cBTKis), which bind to the BTK C481 residue, are now primary therapeutics for chronic lymphocytic leukemia (CLL). Alterations at C481, primarily C481S, prevent cBTKi binding and lead to the emergence of resistant clones. Pirtobrutinib is a noncovalent BTKi that binds to both wild-type (WT) and C481S-mutated BTK and has shown efficacy in BTK-WT and -mutated CLL patient groups. To compare baseline clinical, transcriptomic, and proteomic characteristics and their changes during treatment in these 2 groups, we used 67 longitudinal peripheral blood samples obtained during the first 3 cycles of treatment with pirtobrutinib from 18 patients with CLL (11 BTK-mutated, 7 BTK-WT) enrolled in the BRUIN (pirtobrutinib in relapsed or refractory B-cell malignancies) trial. Eastern Cooperative Oncology Group performance status, age, and Rai stage were similar in both groups. At baseline, lymph nodes were larger in the BTK-mutated cohort. All patients achieved partial remission within 4 cycles of pirtobrutinib. Lactate dehydrogenase and β2-microglobulin levels decreased in both cohorts after 1 treatment cycle. Expression analysis demonstrated upregulation of 35 genes and downregulation of 6 in the BTK-mutated group. Gene set enrichment analysis revealed that the primary pathways enriched in BTK-mutated cells were involved in cell proliferation, metabolism, and stress response. Pathways associated with metabolism and proliferation were downregulated in both groups during pirtobrutinib treatment. Proteomic data corroborated transcriptomic findings. Our data identified inherent differences between BTK-mutated and -WT CLL and demonstrated molecular normalization of plasma and omics parameters with pirtobrutinib treatment in both groups.

Long noncoding RNA MALAT1 in dermatologic disorders: a comprehensive review.

Dermatologic disorders, affecting the integumentary system, involve diverse molecular mechanisms such as cell proliferation, apoptosis, inflammation and immune responses. Long noncoding RNAs, particularly Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1), are crucial regulators of gene expression. MALAT1 influences inflammatory responses, immune cell function and signaling pathways, impacting various physiological and pathological processes, including dermatologic disorders. Dysregulation of MALAT1 is observed in skin conditions like psoriasis, atopic dermatitis and systemic lupus erythematosus. However, its precise role remains unclear. This review consolidates knowledge on MALAT1's impact on skin biology and pathology, emphasizing its potential diagnostic and therapeutic implications in dermatologic conditions.

Glycogen synthase kinase-3β: A multifaceted player in ischemia-reperfusion injury and its therapeutic prospects.

Ischemia-reperfusion injury (IRI) results in irreversible metabolic dysfunction and structural damage to tissues or organs, posing a formidable challenge in the field of organ implantation, cardiothoracic surgery, and general surgery. Glycogen synthase kinase-3β (GSK-3β) a multifunctional serine/threonine kinase, is involved in a variety of biological processes, including cell proliferation, apoptosis, and immune response. Phosphorylation of its tyrosine 216 and serine 9 sites positively and negatively regulates the activation and inactivation of the enzyme. Significantly, inhibition or inactivation of GSK-3β provides protection against IRI, making it a viable target for drug development. Though numerous GSK-3β inhibitors have been identified to date, the development of therapeutic treatments remains a considerable distance away. In light of this, this review summarizes the complicated network of GSK-3β roles in IRI. First, we provide an overview of GSK-3β's basic background. Subsequently, we briefly review the pathological mechanisms of GSK-3β in accelerating IRI, and highlight the latest progress of GSK-3β in multiorgan IRI, encompassing heart, brain, kidney, liver, and intestine. Finally, we discuss the current development of GSK-3β inhibitors in various organ IRI, offering a thorough and insightful reference for GSK-3β as a potential target for future IRI therapy.

Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma.

Aging is the primary risk factor for many individual cancer types, including lung adenocarcinoma (LUAD). To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival outcomes, we built individual (person)-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for both non-cancerous lung tissue samples from the Genotype Tissue Expression (GTEx) project and LUAD samples from The Cancer Genome Atlas (TCGA). In GTEx, we found that pathways involved in cell proliferation and immune response are increasingly targeted by regulatory transcription factors with age; these aging-associated alterations are accelerated by tobacco smoking and resemble oncogenic shifts in the regulatory landscape observed in LUAD and suggests that dysregulation of aging pathways might be associated with an increased risk of LUAD. Comparing normal adjacent samples from individuals with LUAD with healthy lung tissue samples from those without LUAD, we found that aging-associated genes show greater aging-biased targeting patterns in younger individuals with LUAD compared to their healthy counterparts of similar age, a pattern suggestive of age acceleration. This implies that an accelerated aging process may be responsible for tumor incidence in younger individuals. Using drug repurposing tool CLUEreg, we found small molecule drugs with potential geroprotective effects that may alter the accelerating aging profiles we found. We also observed that, in contrast to chronological age, a network-informed aging signature was associated with survival and response to chemotherapy in LUAD.

Prenatal blood metals, per- and polyfluoroalkyl substances and antigen- or mitogen-stimulated cord blood lymphocyte proliferation and cytokine secretion

BackgroundEvidence suggests that prenatal per- and polyfluoroalkyl substances (PFAS) and metals, two classes of chemicals found ubiquitously in human populations, influence immune system development and response. ObjectiveWe evaluated whether first trimester blood PFAS and metals were associated with antigen- or mitogen-stimulated cord blood lymphocyte proliferation and cytokine secretion. MethodsWe measured six PFAS, as well as six nonessential and four essential metals, in first trimester blood from participants in the longitudinal pre-birth Project Viva cohort, recruited between 1999 and 2000 in eastern Massachusetts. We measured antigen- or mitogen-stimulated cord blood mononuclear cell proliferation responses (n = 269–314) and cytokine secretion (n = 217–302). We used covariate-adjusted least absolute shrinkage and selection operator (LASSO) for variable selection and multivariable regression to estimate associations with the immune markers. ResultsEach ng/mL of MeFOSAA was associated with a 3.6% (1.4, 5.8) higher lymphocyte proliferation response after stimulation with egg antigen, as well as 0.8 (0.7, 1.0) reduced odds of having IFN-γ detected in response to dust mite. Each ng/g increment of cesium was associated with 27.8% (−45.1, −4.9) lower IL-10 levels in response to dust mite. Each ng/g increment of mercury was associated with 12.0% (1.3, 23.8) higher IL-13 levels in response to mitogen PHA. Each ng/g increment of selenium and zinc was associated with 0.2% (0.01, 0.4) and 0.01% (0.002, 0.02) higher TNF-α in response to mitogen PHA, respectively. ConclusionsPrenatal metals and PFAS influence cord blood lymphocyte proliferation and cytokine secretion in ways that may increase risk for atopic disease in childhood.