Accumulation Of Cells Research Articles

New insights into the mechanisms of aspirin-exacerbated respiratory disease.

Aspirin-exacerbated respiratory disease (AERD), a syndrome characterized clinically by asthma, chronic rhinosinusitis with nasal polyposis, and respiratory reactions to aspirin and other cyclooxygenase-1 inhibitors, is an inflammatory condition of the respiratory tract that is often severe and challenging to treat. There have been several recent advances in our understanding of the underlying pathology of the disease. These have been paralleled by welcome advances in the availability of targeted treatment options for patients with AERD. Spurred in part by results from trials of targeted biologic therapies, along with single cell genomics, there is now clear evidence that the chronic respiratory inflammation in AERD is driven by combination of local tissue factors. These include abnormalities in effector cell populations, with increased accumulation and activation of mast cells and plasma cells in the nasal polyp, along with notable epithelial barrier dysregulation. The key mediators now identified include high levels of both type 2 inflammatory cytokines (IL-4, IL-5, IL-13) and cytokines involved in broader inflammatory pathways (IL-33, TSLP, IL-6, oncostatin M), as well as the overproduction of cysteinyl leukotrienes, and the underproduction of prostaglandin E2. This review covers the latest insights into the immunopathogenesis of and targeted treatment of AERD, including the roles of lipids, effector cells, and inflammatory cytokines, and discusses unanswered questions regarding its pathogenesis and potential future therapies.

Emerging influence of RNA post-transcriptional modifications in the synovial homeostasis of rheumatoid arthritis

Rheumatoid arthritis (RA) is an important autoimmune disease that affects synovial tissues, accompanied by redness, pain, and swelling as main symptoms, which will limit the quality of daily life and even cause disability. Multiple coupling effects among the various cells in the synovial micro-environment modulate the poor progression and development of diseases. Respectively, synovium is the primary target tissue of inflammatory articular pathologies; synovial hyperplasia, and excessive accumulation of immune cells lead to joint remodelling and destroyed function. In general, epigenetic modification is an effective strategy to regulate dynamic balance of synovial homeostasis. Several typical post-transcriptional changes in cellular RNA can control the post-transcriptional modification of RNA structure. It can inhibit important processes, including degradation of RNA and nuclear translocation. Recent studies have found that RNA modification regulates the homeostasis of the synovial micro-environment and forms an intricate network in the “bone-cartilage-synovium” feedback loop. Aberrant regulation of RNA methylation triggers the pathological development of RA. Collectively, this review summarises recent advanced research about RNA modification in modulating synovial homeostasis by making close interaction among resident synovial macrophages, fibroblasts, T cells, and B cells, which could display the dramatic role of RNA modifications in RA pathophysiological process and perform the promising therapeutic target for treating RA.

The Circadian Rhythm of Intracellular Protoporphyrin IX Accumulation Through Heme Synthesis Pathway in Bladder Urothelial Cancer Cells Exposed to 5-Aminolevulinic Acid

Background/Objectives: The standard recommendation for patients with non-muscle invasive bladder cancer is 5-aminolevulinic acid-mediated photodynamic diagnosis. The intensity of the fluorescence caused by the intracellular accumulation of protoporphyrin IX (PPIX) varies among tumors and patients. This study investigated the circadian rhythm of intracellular PPIX accumulation in bladder urothelial cancer cells exposed to 5-aminolevulinic acid. Methods: The expression of two clock genes, PER2 and BMAL1, and their impact on intracellular PPIX accumulation were evaluated in two bladder cancer cell lines, UM-UC-3 and J82, and mouse xenograft models. We evaluated the enzymes involved in the heme synthesis pathway that potentially affect the circadian rhythm of intracellular PPIX accumulation. The red fluorescence intensity of the images captured during photodynamic diagnosis-assisted transurethral resection of bladder tumors was quantified and compared among the four groups according to surgery start time: 9 a.m.–11 a.m., 11 a.m.–1 p.m., 1–3 p.m., and 3–5 p.m. Results: We observed the circadian rhythm of intracellular PPIX accumulation, which was potentially regulated by the clock genes PER2 and BMAL1. Two enzymes involved in the heme synthesis pathway, coproporphyrinogen oxidase and ferrochelatase, exhibit a circadian rhythm. The fluorescence intensity started gradually increasing at 12 p.m., and the highest level was observed in patients who underwent surgery between 3 and 5 p.m. Conclusions: Our findings suggest that it may be possible to optimize the timing of the photodynamic diagnosis in photodynamic diagnosis-assisted transurethral resection of bladder cancer based on the circadian rhythm to improve tumor detection and treatment outcomes.

Cytotoxic effects of the standardized extract from Curcuma aromatica Salisb. rhizomes via induction of mitochondria-mediated caspase-dependent apoptotic pathway and p21-mediated G0/G1 cell cycle arrest on human gastric cancer AGS cells

ABSTRACT Curcuma aromatica Salisb. (C. aromatica) is one of the traditional herbs used to treat microbial infection, skin eruption, coronary heart disease, and other diseases, including cancer. However, the inhibitory effects and underlying mechanisms of action of C. aromatica on gastric cancer cells have not yet been fully elucidated. Our study aimed to examine the possible molecular mechanisms underlying the cytotoxic effects attributed to C. aromatica rhizome standardized extract against gastric cancer cells. The components of two major active compounds in C. aromatica rhizome extract were quantitatively analyzed using a simple and validated HPLC method. Cytotoxicity was determined in different gastric cancer and non-cancer cell lines. The biological activities of the extract targeting apoptosis and cell cycle-related genes on gastric cancer AGS cells were also investigated to elucidate the mechanisms relating to the anti-proliferative effect of C. aromatica rhizomes. The two major active compounds curdione and germacrone, in the C. aromatica extract were standardized to 0.64% and 1.12% w/w, respectively. The standardized extract (CAE) exerted cytotoxic effects on various cancer cells, whereas minimal effects at equivalent doses were noted for normal cells. CAE concentration-dependently suppressed growth of gastric cancer AGS cells via induction of apoptosis. Further studies revealed that CAE treatment disrupted mitochondrial membrane potential (ΔΨm), increased Bax/Bcl-2 ratio, and cytochrome c release, resulting in activation of caspase-9/-3 and subsequent cleavage of PARP. Further, the inhibitory effects of caspase-9/-3 expression by a synthetic pan-caspase inhibitor partially protected cells against apoptosis following CAE treatment. In addition, CAE significantly promoted cell death in AGS cells via an accumulation of cells in the G0/G1 phase. This effect was associated with upregulation of the CDK inhibitor p21 and downregulation of cyclin D1, cyclin E, CDK4, and CDK2 expression. Our data indicated that CAE exerted anti-proliferative activity by activating the mitochondria-mediated caspase-dependent apoptotic pathway and arresting the p21-mediated G0/G1 cell cycle on human gastric cancer AGS cells.

Cysteine Rich Intestinal Protein 2 is a copper-responsive regulator of skeletal muscle differentiation and metal homeostasis.

Copper (Cu) is essential for respiration, neurotransmitter synthesis, oxidative stress response, and transcription regulation, with imbalances leading to neurological, cognitive, and muscular disorders. Here we show the role of a novel Cu-binding protein (Cu-BP) in mammalian transcriptional regulation, specifically on skeletal muscle differentiation using murine primary myoblasts. Utilizing synchrotron X-ray fluorescence-mass spectrometry, we identified murine cysteine-rich intestinal protein 2 (mCrip2) as a key Cu-BP abundant in both nuclear and cytosolic fractions. mCrip2 binds two to four Cu+ ions with high affinity and presents limited redox potential. CRISPR/Cas9-mediated deletion of mCrip2 impaired myogenesis, likely due to Cu accumulation in cells. CUT&RUN and transcriptome analyses revealed its association with gene promoters, including MyoD1 and metallothioneins, suggesting a novel Cu-responsive regulatory role for mCrip2. Our work describes the significance of mCrip2 in skeletal muscle differentiation and metal homeostasis, expanding understanding of the Cu-network in myoblasts. Copper (Cu) is essential for various cellular processes, including respiration and stress response, but imbalances can cause serious health issues. This study reveals a new Cu-binding protein (Cu-BP) involved in muscle development in primary myoblasts. Using unbiased metalloproteomic techniques and high throughput sequencing, we identified mCrip2 as a key Cu-BP found in cell nuclei and cytoplasm. mCrip2 binds up to four Cu+ ions and has a limited redox potential. Deleting mCrip2 using CRISPR/Cas9 disrupted muscle formation due to Cu accumulation. Further analyses showed that mCrip2 regulates the expression of genes like MyoD1, essential for muscle differentiation, and metallothioneins in response to copper supplementation. This research highlights the importance of mCrip2 in muscle development and metal homeostasis, providing new insights into the Cu-network in cells.

Aberrantly Expressed Mitochondrial Lipid Kinase, AGK Activates JAK2-Histone H3 Axis and BCR Signal: A Mechanistic Study with Implication in CLL Therapy.

Although the B-cell receptor (BCR) signal plays a critical role in CLL cell survival and a target of current therapies (ibrutinib targets Bruton's tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the "CLL cell-survival signaling network" is largely undefined. CLL patients were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism. We detected that compared to normal B-cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its non-canonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR-signal in CLL cells via LYN/BTK axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR-inhibitors or venetoclax (a BCL2-inhibitor) induced apoptosis synergistically in CLL cells. These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some CLL patients.

A Vaccine Against Fibroblast Activation Protein Improves Murine Cardiac Fibrosis by Preventing the Accumulation of Myofibroblasts.

Myofibroblasts are primary cells involved in chronic response-induced cardiac fibrosis. Fibroblast activation protein (FAP) is a relatively specific marker of activated myofibroblasts and a potential target molecule. This study aimed to clarify whether a vaccine targeting FAP could eliminate myofibroblasts in chronic cardiac stress model mice and reduce cardiac fibrosis. We coadministered a FAP peptide vaccine with a CpG K3 oligonucleotide adjuvant to male C57/BL6J mice and confirmed an elevation in the anti-FAP antibody titer. After continuous angiotensin II and phenylephrine administration for 28 days, we evaluated the degree of cardiac fibrosis and the number of myofibroblasts in cardiac tissues. We found that cardiac fibrosis was significantly decreased in the FAP-vaccinated mice compared with the angiotensin II and phenylephrine control mice (3.45±1.11% versus 8.62±4.79%; P=4.59×10-3) and that the accumulation of FAP-positive cells was also significantly decreased, as indicated by FAP immunohistochemical staining (4077±1746 versus 7327±1741 cells/mm2; FAP vaccine versus angiotensin II and phenylephrine control; P=6.67×10-3). No systemic or organ-specific inflammation due to antibody-dependent cell cytotoxicity induced by the FAP vaccine was observed. Although the transient activation of myofibroblasts has an important role in maintaining the structural robustness in the process of tissue repair, the FAP vaccine showed no adverse effects in myocardial infarction and skin injury models. Our study demonstrates the FAP vaccine can be a therapeutic tool for cardiac fibrosis.

Design of a Magnetic Nanoplatform Based on CD26 Targeting and HSP90 Inhibition for Apoptosis and Ferroptosis-Mediated Elimination of Senescent Cells.

The accumulation of senescent cells, a hallmark of aging and age-related diseases, is also considered as a side effect of anticancer therapies, promoting drug resistance and leading to treatment failure. The use of senolytics, selective inducers of cell death in senescent cells, is a promising pharmacological antiaging and anticancer approach. However, more studies are needed to overcome the limitations of first-generation senolytics by the design of targeted senolytics and nanosenolytics and the validation of their usefulness in biological systems. In the present study, we have designed a nanoplatform composed of iron oxide nanoparticles functionalized with an antibody against a cell surface marker of senescent cells (CD26), and loaded with the senolytic drug HSP90 inhibitor 17-DMAG (MNP@CD26@17D). We have documented its action against oxidative stress-induced senescent human fibroblasts, WI-38 and BJ cells, and anticancer drug-induced senescent cutaneous squamous cell carcinoma A431 cells, demonstrating for the first time that CD26 is a valid marker of senescence in cancer cells. A dual response to MNP@CD26@17D stimulation in senescent cells was revealed, namely, apoptosis-based early response (2 h treatment) and ferroptosis-based late response (24 h treatment). MNP@CD26@17D-mediated ferroptosis might be executed by ferritinophagy as judged by elevated levels of the ferritinophagy marker NCOA4 and a decreased pool of ferritin. As 24 h treatment with MNP@CD26@17D did not induce hemolysis in human erythrocytes in vitro, this newly designed nanoplatform could be considered as an optimal multifunctional tool to target and eliminate senescent cells of skin origin, overcoming their apoptosis resistance.

Osthole induces accumulation of impaired autophagosome against pancreatic cancer cells

Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide, and few effective therapeutics are available. Osthole (OST), a natural coumarin, has been proven to be a potential anticancer compound. In this study, we found that OST significantly inhibited PC growth both in vitro and in vivo. Notably, the anti-PC effect of OST is mediated by excessive autophagosome accumulation and consequent apoptosis in PC cells. Mechanistically, OST increased the number of autophagosomes via two pathways. First, OST induced autophagy initiation by suppressing the Akt/mTOR signaling pathway. Second, OST induced autophagic arrest by blocking autophagosome-lysosome fusion. Consistently, inhibition of autophagy initiation restored PC cell growth, whereas autophagic flux inhibitors exacerbated the antitumor effect of OST in PC cells, suggesting a cytotoxic role of OST-induced autophagosome accumulation. In addition, we found that OST upregulates the expression of activating transcription factor 3 (ATF3), resulting in inactivation of the Akt/mTOR signaling pathway and autophagy initiation in PC cells. ATF3 overexpression increased the activation of autophagy, and inhibition of ATF3 expression decreased autophagy. Taken together, our study provides new insights into the OST-induced growth inhibitory effect on PC cells, suggesting a promising potential therapeutic role of OST for PC treatment.

Puzzle sine cosine optimization-based secure communication and brain tumor classification in IoT‐healthcare system

A brain tumor (BT) refers to an irregular accumulation of cells within the brain that proliferates uncontrollably, resulting in the formation of a mass. The accurate classification and early detection are important for effective treatment. In previous researches, the BT exhibited diverse features in terms of size, shape, and location. Moreover, the images used for segmentation, which suffered from image noise, low contrast, and shifting intensities within tissues. These issues are overcome by developing an effective method in this paper named Puzzle Sine Cosine Optimization enabled Deep Kronecker Network (PSCO-DKN) for classifying BT in the Internet of Things (IoT) healthcare system. Firstly, an IoT network is simulated, where the IoT device is used to capture the patient’s Magnetic Resonance Imaging (MRI) images. Further, the images are routed to the Base Station (BS) by employing PSCO. The routing is accomplished by contemplating several fitness parameters including delay, energy, and distance. At the BS, the process for BT classification is implemented as follows. Initially, the pre-processing is done by utilizing the median filter. Afterwards, the segmentation process is done by applying Spatial Attention U-Net (SA-Unet). After that, Statistical features and Shape Local Binary Texture (SLBT) are extracted. At last, BT classification is performed by utilizing the DKN, which is structurally optimized by using PSCO developed by the hybridization of Puzzle Optimization Algorithm (POA) and Sine Cosine Algorithm (SCA). Finally, PSCO-DKN attained superior outcomes of True Negative Rate (TNR) at 90.9 %, True Positive Rate (TPR) at 92.6 %, and accuracy at 87.7 %.

A chimeric peptide promotes immune surveillance of senescent cells in injury, fibrosis, tumorigenesis and aging.

The accumulation of senescent cells can lead to tissue degeneration, chronic inflammatory disease and age-related tumorigenesis. Interventions such as senolytics are currently limited by off-target toxicity, which could be circumvented by instead enhancing immune-mediated senescent cell clearance; however, immune surveillance of senescent cells is often impeded by immunosuppressive factors in the inflammatory microenvironment. Here, we employ a chimeric peptide as a 'matchmaker' to bind to the urokinase-type plasminogen activator receptor, a cell surface marker of senescent cells. This peptide modifies the cell surface with polyglutamic acid, promoting immune cell-mediated responses through glutamate recognition. By enhancing the recruitment of immune cells and directly coupling senescent cells and immune cells, we show that this chimeric peptide induces immune clearance of senescent cells and restores tissue homeostasis in conditions such as liver fibrosis, lung injury, cancer and natural aging in mice. This chimeric peptide introduces an immunological conversion strategy that rebalances the senescent immune microenvironment, offering a promising direction for aging immunotherapy.

Locus-specific differential expression of human satellite sequences in the nuclei of cancer cells and heat-shocked cells

ABSTRACT Human satellitess(HSats) are pericentric, tandemly repeating satellite DNA sequences in the human genome. While silent in normal cells, a subset of HSat2 noncoding RNA is expressed and accumulates in the nucleus of cancer cells. We developed a FISH-based approach for identification of the distribution of three subfamilies of HSat2 (A1, A2, B) sequences on individual human chromosomes. Further, using the HSat subfamily annotations in the T2T completed centromere satellite (CenSat) sequence, we isolated, defined and mapped differentially expressed sequence variants of nuclear-restricted HSat2 and HSat3 RNA from cancer cell lines and heat-shocked cells. We identified chromosome-specific and subfamily-specific expression of HSat2 and HSat3 and established a computational pipeline for differential expression analysis of tandemly repeated satellite sequences. Results suggest the differential expression of chromosome-specific HSat2 arrays in the human genome may underlie their accumulation in cancer cells and that specific HSat3 loci are upregulated upon heat shock.

Targeting EGFR Activation to Overcome Gemcitabine Resistance in Cholangiocarcinoma.

Chemotherapy resistance is an important problem in the treatment of patients with cholangiocarcinoma (CCA) who are not eligible for surgery. This study aimed to overcome gemcitabine (Gem) resistance in CCA by investigating and targeting Gem resistance-associated molecules. Three stable Gem-resistant CCA cell lines (CCA-GemR) were established by gradually exposing CCA cell lines to Gem. The cells were characterized in terms of growth, cross-resistance to chemotherapeutic drugs, cell cycle distribution, and colony formation. The molecular mechanisms related to Gem resistance were assessed using a phosphorylation array assay and protein expression was confirmed using western blotting analysis. The targeted molecules were subsequently analyzed using PanDrugs to identify potential targeted therapies. The drug was used to enhance Gem sensitivity. The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem. EGFR is a potential target molecule for reducing Gem resistance and enhancing its anti-tumor effects in patients with CCA.

Ablation of LKB1 gene changes the lipid profiles of goat intramuscular fat and enhances polyunsaturated fatty acids deposition

The content and composition of intramuscular fat (IMF) affect the cooked meat palatability such as tenderness and juiciness. Thus, elucidation of lipid deposition and its composition in goat IMF is necessary. Here, Jianzhou big-ear goats with higher IMF content is associated with lower mRNA level of LKB1 gene, compared with those of Chuannan black goats. Functionally, knockdown of LKB1 promoted intramuscular adipocyte lipid accumulation. Next, LC-MS/MS based pseudo target analysis found that 409 lipids existed in goat intramuscular adipocytes, of which polyunsaturated fatty acids accounted for most lipids. Compared with the control, 78 differential lipids were screened in the siLKB1 group, enriched in the triacylglycerols and fatty acids subclasses. The combined analysis between lipidomic and published transcriptomic data showed that siLKB1 enhanced polyunsaturated fatty acids synthesis through upregulation expression of HACD4. Finally, the promotion of lipid accumulation and polyunsaturated fatty acids synthesis in the LKB1 knockdown cells were partly rescued by ablation of HACD4. Collectively, these data provide a genetic target to produce PUFA enriched functional goat meat and expand new insights into improvement of meat quality.

ACSL4 is a target for β-hydroxybutyrate–induced increase in fatty acid content and lipid droplet accumulation in bovine mammary epithelial cells

ACSL4 is a target for β-hydroxybutyrate–induced increase in fatty acid content and lipid droplet accumulation in bovine mammary epithelial cells

Ovarian Cell Accumulation of Model PVC Nanoplastics Labelled With CdSe‐QDs Investigated by X‐Ray Fluorescence Microscopy

Ovarian Cell Accumulation of Model <scp>PVC</scp> Nanoplastics Labelled With <scp>CdSe</scp>‐<scp>QDs</scp> Investigated by X‐Ray Fluorescence Microscopy

Ameliorative potential of ellagic acid via PPARγ against hyperlipidemia: Insights from mice and zebrafish

Peroxisome proliferator-activated receptor γ (PPARγ) was a major transcription factor and performed an essential function in the regulation of lipid metabolism. Ellagic acid (EA) was a natural phytochemical extracted from berries and pomegranates, and research had demonstrated its ameliorative effects on lipid metabolism disorders. We intended to explore the interventional effect and mechanism of action of EA on hyperlipidemia. In vitro experiments revealed that EA could reduce lipid accumulation in HepG2 cells. EA was found to bind stably to PPARγ, suppressing its nuclear translocation as well as its luciferase activity. It could also down-regulate the expression of genes and proteins related to lipid metabolism upstream and downstream of PPARγ. To explore the impact of EA on hyperlipidemia in vivo from different levels and perspectives, we established hyperlipidemia mice and hyperlipidemia zebrafish models. Consistent with the in vitro results, in vivo experiments revealed that EA attenuated lipid accumulation in hyperlipidemia mice and reduced the levels of related inflammatory factors in their serum. EA also inhibited lipid accumulation by decreasing the expression of upstream and downstream lipid-associated genes of pparg in hyperlipidemia zebrafish. In conclusion, EA could effectively improve hyperlipidemia by regulating PPARγ.

The role of inhibitory immune checkpoint receptors in the pathogenesis of Alzheimer's disease.

There is mounting evidence that microglial cells have a key role in the pathogenesis of Alzheimer's disease (AD). In AD pathology, microglial cells not only are unable to remove β-amyloid (Aβ) plaques and invading pathogens but also are involved in synaptic pruning, chronic neuroinflammation, and neuronal degeneration. Microglial cells possess many different inhibitory immune checkpoint receptors, such as PD-1, LILRB2-4, Siglecs, and SIRPα receptors, which can be targeted by diverse cell membrane-bound and soluble ligand proteins to suppress the functions of microglia. Interestingly, in the brains of AD patients there are elevated levels of many of the inhibitory ligands acting via these inhibitory checkpoint receptors. For instance, Aβ oligomers, ApoE4, and fibronectin are able to stimulate the LILRB2-4 receptors. Increased deposition of sialoglycans, e.g., gangliosides, inhibits microglial function via Siglec receptors. AD pathology augments the accumulation of senescent cells, which are known to possess a high level of PD-L1 proteins, and thus, they can evade immune surveillance. A decrease in the expression of SIRPα receptor in microglia and its ligand CD47 in neurons enhances the phagocytic pruning of synapses in AD brains. Moreover, cerebral neurons contain inhibitory checkpoint receptors which can inhibit axonal growth, reduce synaptic plasticity, and impair learning and memory. It seems that inappropriate inhibitory immune checkpoint signaling impairs the functions of microglia and neurons thus promoting AD pathogenesis. KEY MESSAGES: Microglial cells have a major role in the pathogenesis of AD. A decline in immune activity of microglia promotes AD pathology. Microglial cells and neurons contain diverse inhibitory immune checkpoint receptors. The level of ligands for inhibitory checkpoint receptors is increased in AD pathology. Impaired signaling of inhibitory immune checkpoint receptors promotes AD pathology.

Identification of tanshinone I as a natural Cu(II) ionophore

The development of Cu(II) ionophores for targeted disruption of aberrant redox homeostasis in cancer cells has been considered an appealing strategy in the field of anticancer research. This study presents the first identification of tanshinone I (Ts1), a natural o-quinone, as a Cu(II) ionophore. Structure-activity relationship studies on tanshinones and mechanistic investigations reveal that the presence of Cu(II) effectively promotes the tautomerization of Ts1 from its diketo to keto-enol forms, thereby facilitating its sequential proton-loss Cu(II) chelation, and enabling it to function as a Cu(II) ionophore due to its structural features including the presence of an o-quinone moiety, a benzyl hydrogen, and a large conjugated system. The unique property allows Ts1 to preferentially induce copper accumulation in human hepatoma HepG2 cells over human umbilical vein endothelial cells, by releasing copper driven by reduced glutathione (GSH). This copper accumulation leads to a reduction in the GSH-to-oxidized glutathione ratio and the generation of reactive oxygen species, ultimately triggering apoptosis of HepG2 cells. The findings not only provide support for o-quinones as innovative types of anticancer Cu(II) ionophores, but also shed light on the previously unrecognized role of Ts1 as a potent Cu(II) ionophore for eradicating cancer cells by selectively disrupting their redox regulation programs, resembling a "Trojan horse".

Possibilities of gene, cellular and pharmacological approaches to correct age-related changes

Improvement of the human habitat has led to an increase in average life expectancy. Long life goes hand in hand with old age, which reduces the quality of human life and it is an acute social problem. Thus, the search for approaches that can improve the quality of life, the ability to live it without age-related diseases is an extremely urgent task. Aging of the body begins with the aging of cells, in which the activation of the aging process occurs through the induction of specific signaling pathways, which irreversibly divides the life of any cell into “before and after”. Aging cells are able to influence their microenvironment, secreting more inflammatory signaling molecules and inducing pathological changes in neighboring cells. The accumulation and long-term preservation of aged cells lead to deterioration of the condition of tissues and organs, and ultimately to a decrease in the quality of life and an increased risk of death. Among the most promising approaches to the correction of aging and age-related diseases are pharmacological, gene and cell therapy. Increasing the expression of aging suppressor genes, using certain populations of native and genetically modified cells, as well as senolytic drugs can help delay aging and associated diseases for a more distant future. This review examines currently studied approaches and achievements in the field of anti-aging therapy, in particular gene therapy using adeno-associated vectors and approaches based on cell therapy.