Cellular Protective Mechanisms Research Articles

A Machine Learning Approach to Gene Expression in Hypertrophic Cardiomyopathy

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is a common heart disorder characterized by the thickening of the heart muscle, particularly in the left ventricle, which increases the risk of cardiac complications. This study aims to analyze the expression of apoptosis-regulating genes (CASP8, CASP9, CASP3, BAX, and BCL2) in blood samples from HCM patients, to better understand their potential as biomarkers for disease progression. Methods: Quantitative real-time PCR (qPCR) was used to evaluate gene expression in blood samples from 93 HCM patients. The correlation between apoptosis-regulating genes was conducted and clinical parameters were integrated for feature importance and clustering analysis. Results: Most patients exhibited significant downregulation of CASP8, CASP9, and CASP3. In contrast, BAX expression was elevated in 71 out of 93 patients, while BCL2 was increased in 55 out of 93 patients. Correlation analysis revealed weak negative correlations between the BAX/BCL2 ratio and CASP gene expression. Conclusions: These findings suggest that reduced expression of apoptotic genes may indicate a protective cellular mechanism, which could serve as a biomarker for disease progression. Further studies are needed to investigate the potential for therapeutic modulation of these pathways to improve patient outcomes.

Harnessing L-Cysteine to enhance lyophilization tolerance in Lactiplantibacillus plantarum: Insights into cellular protection mechanisms

Enhancing the viability of lyophilized microbial strains by modulating their physiological metabolism is an important focus of microbiological research. Certain amino acids have been shown to influence the physiology of microbial strains; however, their effect on strain survival during lyophilization remains largely unexplored. In this study, we employed five different amino acids to investigate the potential correlation between amino acid supplementation and the viability of Lactiplantibacillus plantarum during lyophilization. We discovered that the addition of 0.05 g/L L-cysteine could significantly improve the post-lyophilization viability of all four L. plantarum strains after culture. Subsequently, the mechanisms underlying this enhancement were elucidated using L. plantarum LIP-1 as a type strain. The results showed that L. plantarum metabolised L-cysteine to produce glutathione, which in turn decreased the levels of reactive oxygen species, enhanced hydroxyl radical scavenging, inhibited the oxidation of unsaturated fatty acids, and maintained cell membrane fluidity. As a result, cell membrane damage was attenuated, ultimately improving the lyophilization resistance of L. plantarum.

The role of genetic and epigenetic factors on the development of cognitive deficits in patients with severe trauma after repeated anesthesia (literature review)

Introduction. When a severe combined injury occurs in a patient, various biochemical, humoral, cellular and pathophysiological mechanisms of protection against death occur. Immediately after receiving an injury, the patient is hospitalized in a hospital for medical care, where every effort is made to stabilize the condition, resorting to the appointment of various instrumental and laboratory tests. The development and course of traumatic illness, and treatment outcomes in patients with similar injuries are sometimes dramatically different. Based on this, it was suggested that there is a genetic basis for the regularity of the disease, as well as that exogenous factors themselves can affect certain molecular genetic markers, primarily telomere length.The objective was to summarize the current literature data on the study of changes in telomere length, as well as the influence of exogenous and endogenous factors on their shortening. To determine the prospects of studying the effect of polymorphic alleles of various genes on the development of a pathological condition in a certain cohort, namely the development of cognitive dysfunction in patients with severe trauma after repeated anesthesia.Materials and methods. The literature search and analysis was performed in the medical information systems PubMed and eLibrary, using the keywords «telomere», «trauma», «cognitive», and «anesthesia».Results. Since 1950, data on the study of human telomeres began to be published abroad. Between 2002 and the present, 39 articles were published on PubMed when searching for the keywords «anesthesia» and «telomeres»; by keywords «cognitive», «trauma», «telomeres» – 27. Most articles are devoted to the effect of childhood trauma on changes in telomere length, as well as the assessment of short telomeres in patients with various cognitive deficits. However, there are no articles devoted to studying the effect of repeated anesthesia, as an exogenous factor, on the genetic apparatus of a patient with severe combined trauma.Conclusion. The literature highlights the influence of various exogenous factors on the shortening of telomere length, especially in the context of childhood trauma, cognitive impairment in various observed groups. The section related to the effects of anesthesia and their number, the consequences for the genetic apparatus of a particular person, is open for study.

Physiological and Transcriptomic Analyses Provide Insights into Nitrite Stress Responses of the Swimming Crab Portunus trituberculatus.

Nitrite is a common environmental pollutant in intensive aquaculture systems. In this study, physiological and transcriptomic analyses were performed to investigate nitrite stress responses in the swimming crab Portunus trituberculatus, an important aquaculture species in China. The results revealed that nitrite can affect neurotransmitter signaling via the expression of neurotransmitter receptors such as octopamine receptor (OAR) and 5-hydroxytryptamine receptor (5-HTR), and depress ecdysteroid signaling by downregulating ecdysteroid receptor (EcR) as well as its downstream transcription factors in hepatopancreas. In addition, nitrite suppressed the expression of hemocyanins, the oxygen-transporting protein, which at least partly contributed to tissue hypoxia, resulting in a switchover of energy metabolism from aerobic to anaerobic pathway. To meet the energy demand, glycogens and lipids were mobilized and transported to the hemolymph, and the catabolism of amino acids and fatty acids was enhanced to provide energy for hepatopancreas. β-oxidation of fatty acids, the major process by which fatty acids are oxidized to generate energy, seems to occur mainly not in mitochondria but in peroxisomes. Although the cellular protective mechanisms, including antioxidant defense, heat shock response (HSR), unfolded protein response (UPR), and autophagy, were activated, nitrite-induced cellular stress overwhelmed the repairing capacity and caused significant increase in the levels of apoptosis. These results indicated that nitrite stress influences neurotransmitter and endocrine signaling, disturbs energy metabolism, damages cellular components, and induces apoptosis in P. trituberculatus. The findings of this study provide new insights into nitrite stress response in the swimming crab and provide valuable information for aquaculture management of this species.

Role of Dapagliflozin in Ischemic Preconditioning in Patients with Symptomatic Coronary Artery Disease-DAPA-IP Study Protocol.

Background: Ischemic preconditioning (IP) is a powerful cellular protection mechanism. The cellular pathways underlying IP are extremely complex and involve the participation of cell triggers, intracellular signaling pathways, and end-effectors. Experimental studies have shown that sodium-glucose transport protein 2 (SGLT2) inhibitors promote activation of 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), the main regulator of adenosine 5'-triphosphate homeostasis and energy metabolism in the body. Despite its cardioprotective profile demonstrated by numerous clinical trials, the results of studies on the action of SGLT2 inhibitors in IP are scarce. This study will investigate the effects of dapagliflozin on IP in patients with coronary artery disease (CAD). Methods: The study will include 50 patients with multivessel CAD, ischemia documented by stress testing, and preserved left ventricular ejection fraction (LVEF). Patients will undergo four exercise tests, the first two with a time interval of 30 min between them after washout of cardiovascular or hypoglycemic medications and the last two after 7 days of dapagliflozin 10 mg once a day, also with a time interval of 30 min between them. Discussion: The role of SGLT2 inhibitors on IP is not clearly established. Several clinical trials have shown that SGLT2 inhibitors reduce the occurrence cardiovascular events, notably heart failure. However, such studies have not shown beneficial metabolic effects of SGLT2 inhibitors, such as reducing myocardial infarction or stroke. On the other hand, experimental studies with animal models have shown the beneficial effects of SGLT2 inhibitors on IP, a mechanism that confers cardiac and vascular protection from subsequent ischemia-reperfusion (IR) injury. This is the first clinical study to evaluate the effects of SGLT2 inhibitors on IP, which could result in an important advance in the treatment of patients with stable CAD.

Overlooked volcanic effect during transmission of antibiotic resistance genes induced by copper and zinc

Adding heavy metals such as copper and zinc to animal feeds is common practice to promote growth, but meanwhile has side consequence of enhancing spread of antibiotic resistance genes (ARGs) in soil. This presents a global challenge to food security and human health. We in this study investigated the transmission of typical ARGs, i. e. β-lactamase genes (β-RGs), in dairy farm environments where dietary Cu and Zn were present in a wide range of concentration. The β-RGs were demonstrated to be highly prevalent across environmental media, with a relative abundance of 94.55%, dominated by mechanisms of antibiotic deactivation (93.75%) and cellular protection (6.25%). More importantly, we first found the transmission of ARGs to be highly dependent on the overlooked volcanic effect, i. e. low-concentration Cu (12–22 mg/kg) and Zn (45–80 mg/kg) acted as micronutrients necessary for microbial growth but facilitated ARGs transfer, whereas higher-concentration Cu (22–39 mg/kg) and Zn (80–153 mg/kg) became toxic to microbial communities and gene expression patterns. Notably, the specific microbial phyla Proteobacteria (2.28–82.94%), Bacteroidetes (0.02–56.48%) and Actinobacteria (1.62–12.92%) exhibited resistance at low concentration of Cu and Zn, which enhanced the transmission of β-RGs. However, this process was inhibited at higher concentration due to inactivation of microbes by Cu and Zn. The increase in resistance was first observed in class Gammaproteobacteria (2.02–88.51%) and Alphaproteobacteria (0.68–10.1%) with increased Cu and Zn concentration. This resulted in heightened transfer of ARGs by tnpA-07 (80.35%) due to protection of thicker cell membrane by chelation with Cu and Zn. This study not only offers mechanistic insights into the volcanic effect of dietary metals on dissemination of ARGs, but also has important implications for safe management of agricultural settings.

The Effects of ML385 on Head and Neck Squamous Cell Carcinoma: Implications for NRF2 Inhibition as a Therapeutic Strategy.

Head and neck squamous cell carcinoma (HNSCC) affects squamous cells in the head and neck region and is currently ranked as the sixth most common cancer worldwide. NF-E2-related factor 2 (NRF2) plays a crucial role in cellular protection and defence mechanisms and NRF2 over-expression has been linked to various cancers; however, its role in the response of HNSCC cells remains elusive. We investigated the effects of ML385, a selective NRF2 inhibitor, on HNSCC to understand the underlying molecular mechanisms, and to assess the potential of ML385 as a therapeutic agent. We treated HNSCC cell lines with ML385 and observed a significant reduction in the expression of NRF2 and its downstream target, heme oxygenase-1 (HO-1), using Western blotting. We evaluated its effects on various cellular processes, including cell proliferation, cloning, migration, and wound healing, in HNSCC cell lines. ML385 treatment substantially reduced NRF2 expression, promoting a decrease in the investigated cellular activities. Additionally, we examined changes in the expression of cell-cycle-related proteins and found that ML385 induced cell cycle arrest at the G1/S phase in HNSCC cell lines. Our findings suggest that ML385 can regulate cell cycle progression, inhibit HNSCC growth, and have potential as a therapeutic agent for HNSCC.

The effect of Fernblock® in preventing blue-light-induced oxidative stress and cellular damage in retinal pigment epithelial cells is associated with NRF2 induction

Blue light exposure of the ocular apparatus is currently rising. This has motivated a growing concern about potential deleterious effects on different eye structures. To address this, ARPE-19 cells were used as a model of the retinal pigment epithelium and subjected to cumulative expositions of blue light. The most relevant cellular events previously associated with blue-light-induced damage were assessed, including alterations in cell morphology, viability, cell proliferation, oxidative stress, inflammation, and the induction of DNA repair cellular mechanisms. Consistent with previous reports, our results provide evidence of cellular alterations resulting from repeated exposure to blue light irradiation. In this context, we explored the potential protective properties of the vegetal extract from Polypodium leucotomos, Fernblock® (FB), using the widely known treatment with lutein as a reference for comparison. The only changes observed as a result of the sole treatment with either FB or lutein were a slight but significant increase in γH2AX+ cells and the raise in the nuclear levels of NRF2. Overall, our findings indicate that the treatment with FB (similarly to lutein) prior to blue light irradiation can alleviate blue-light-induced deleterious effects in RPE cells, specifically preventing the drop in both cell viability and percentage of EdU+ cells, as well as the increase in ROS generation, percentage of γH2AX+ nuclei (more efficiently with FB), and TNF-α secretion (the latter restored only by FB to similar levels to those of the control). On the contrary, the induction in the P21 expression upon blue light irradiation was not prevented neither by FB nor by lutein. Notably, the nuclear translocation of NRF2 induced by blue light was similar to that observed in cells pre-treated with FB, while lutein pre-treatment resulted in nuclear NRF2 levels similar to control cells, suggesting key differences in the mechanism of cellular protection exerted by these compounds. These results may represent the foundation ground for the use of FB as a new ingredient in the development of alternative prophylactic strategies for blue-light-associated diseases, a currently rising medical interest.

Number of Erythrocytes in Male Mice (Mus musculus) Exposed to Cigarette Smoke After Treatment with Ethanol Extract of Red Pomegranate Peel (Punica ganatu)

Plant extracts have the potential to serve as natural therapeutic agents that can counteract the negative effects of various toxins, including those found in cigarette smoke. One such plant with this potential is the red pomegranate (Punica granatum). This study aims to determine the effect of administering Red Pomegranate (Punica ganatum) peel extract on the number of erythrocytes and hemoglobin levels in white mice exposed to cigarette smoke. This type of research is experimental laboratory post test only group design. Mice were divided into 4 treatment groups, namely: P0, control group, test animals treated with distilled water; treatment groups P1, P2 and P3, which were treated with neem leaf ethanol extract at a dose of 10 each; 20; 40 mg/head/day and mice were exposed to cigarette smoke. The research results showed that the higher the extract given, the higher the HB and erythrocyte levels. From this research it can be concluded that administration of Red Pomegranate rind extract can increase the number of erythrocytes and hemoglobin levels but it is not significant (p>0.05). The contribution of this research provides important data on the interaction between toxins (in this case, cigarette smoke) and protective agents (red pomegranate peel ethanol extract). This information is valuable in the fields of toxicology and pharmacology for understanding cellular protection mechanisms and potential new treatments.

Exploring the molecular mechanisms of melatonin-induced tolerance to salt-alkali stress in Populus cathayana × canadansis 'Xinlin 1′

Melatonin is widely recognized as involved in a wide range of plant growth and development functions. Research has primarily focused on herbaceous plants, with few findings on the function of melatonin in supporting tree growth. In this study, it was demonstrated that melatonin, as an endogenous hormone, considerably contributed towards the increased tolerance of poplar to salt-alkali stress. Transcriptome and metabolome analysis revealed that melatonin may enhance the cellular protection and antioxidant mechanisms of poplar and improve salt-alkali tolerance by regulating genes and metabolites involved in photosynthesis, antioxidant enzyme systems, plant hormone signal transduction pathways, and in the flavonoid as well as the melatonin biosynthesis pathway. The results of this study not only aid our increased understanding of the potential roles of melatonin in salt-alkali stress but also shed light on the potential mechanisms of the economically important woody model plant, poplar, involved in resisting abiotic stress.

The Potential Use of Dimethyltryptamine against Ischemia-reperfusion Injury of the Brain

Ischemia-Reperfusion Injury (IRI) is the outcome of two intertwined pathological processes resulting from the shortage of blood flow to tissues and the subsequent restoration of circulation to a previously ischemic area. IRI (sometimes just one side of the dyad) remains one of the most challenging problems in several branches of emergency medicine. Mitochondrial and endoplasmic reticulum dysfunction is a crucial pathological factor involved in the development of IRI. The sigma-1 receptor (Sig1-R) is an intracellular chaperone molecule located between the mitochondria and endoplasmic reticulum with an apparent physiological role in regulating signaling between these cell organelles and serves as a safety mechanism against cellular stress. Therefore, amelioration of IRI is reasonably expected by the activation of the Sig1-R chaperone. Indeed, under cellular stress, Sig1-R agonists improve mitochondrial respiration and optimize endoplasmic reticulum function by sustaining high-energy phosphate synthesis. The discovery that N, N-dimethyltryptamine (DMT) is an endogenous agonist of the Sig1-R may shed light on yet undiscovered physiological mechanisms and therapeutic potentials of this controversial hallucinogenic compound. In this article, the authors briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes involved in IRI and summarize the results of their in vitro and in vivo DMT studies aiming at mitigating IRI. The authors conclude that the effect of DMT may involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different components and types of IRIs emerging in local and generalized brain ischemia after stroke or cardiac arrest.

Abstract B072: Claudin-4 modulates autophagy via cell-cell junctions as a cellular protective mechanism before genomic instability in ovarian cancer

Abstract Objectives: Claudin-4 is a protein upregulated in most high-grade serous carcinomas of the ovary, fallopian tube, and peritoneum (HGSC) and its overexpression is associated with cancer therapy resistance; nevertheless, disruption of the claudin-4 function is associated with increased genomic instability and sensibility of tumor cells to cancer therapeutics. The typical role of claudin-4 is on cell-cell junction regulation; however, this protein also participates in migration, mitosis, DNA repair. Furthermore, a key cellular process that regulates genomic instability is autophagy which has been linked to therapy resistance; however, the association of claudin-4, autophagy, and genomic instability is not known. Therefore, the goal of this work was to evaluate the claudin-4 participation in autophagy to regulate genomic instability. Methods: We used authenticated and routinely checked for mycoplasma HGSC cells (OVCA429, OVCAR3, OVCAR8) to evaluate the elimination (CRISPRi) and overexpression (lentivirus transduction) of claudin-4; complementary, we disrupted the function of claudin-4 using a claudin mimic peptide (CMP). We used immunofluorescence, live-cell imaging, and confocal microscopy to characterize markers of genome instability (micronuclei; Dapi) and its association with cell junctions (F-actin; LifeAct), and cell growth (cell cycle, propidium iodide and flow cytometry, FC). In addition, those cell lines were engineered to express (mCherry-GFP-LC3) to evaluate autophagy by FC under different conditions (chloroquine, autophagy inhibitor; rapamycin, autophagy activator, etc.); complementary assays included immunoblotting for LC3 A/B, and the up-stream regulators of autophagy, SLC1A5/Lat1. Finally, we evaluated the blocking of claudin-4 with CMP and compered such effect with a PARPi (niraparib) in a PDX-human system mice (unpaired t and One-way ANOVA with Tukey's multiple comparisons tests; p< 0.05). Results: By modifying the claudin-4 function with CMP and CRISPRi, we determined this protein regulates cellular cytoskeletal connections and mitosis. Disruption of this axis leads to aberrant cell junctions, abnormal mitotic progression, and autophagic activity. Particularly, cell-cell connections become unstable which affects mitosis progression and drives genomic instability. In addition, genomic instability was associated with downregulation of the plasma membrane modulators of autophagy, SLC1A5/SLC7A5. Consequently, autophagy activity increased and associated with engulfment of cytoplasm-localized damaged DNA; thus, functioning to clear damaged genetic material. In addition, we found that targeting claudin-4 with CMP is as effective as niraparib treatment in disrupting the ovarian tumor progression, and a combinatorial therapy enhances the anti-tumor efficacy compared to the single agent. Conclusions: Claudin-4 promotes a protective cellular mechanism that links cell-cell junctions to genome integrity. Citation Format: Fabian R. Villagomez, Julie Lang, Patricia Webb, Margaret Neville, Elizabeth R. Woodruff, Benjamin G. Bitler. Claudin-4 modulates autophagy via cell-cell junctions as a cellular protective mechanism before genomic instability in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B072.

Engineering RNA polymerase to construct biotechnological host strains of cyanobacteria.

Application of cyanobacteria for bioproduction, bioremediation and biotransformation is being increasingly explored. Photoautotrophs are carbon-negative by default, offering a direct pathway to reducing emissions in production systems. More robust and versatile host strains are needed for constructing production strains that would function as efficient and carbon-neutral cyanofactories. We have tested if the engineering of sigma factors, regulatory units of the bacterial RNA polymerase, could be used to generate better host strains of the model cyanobacterium Synechocystis sp. PCC 6803. Overexpressing the stress-responsive sigB gene under the strong psbA2 promoter (SigB-oe) led to improved tolerance against heat, oxidative stress and toxic end-products. By targeting transcription initiation in the SigB-oe strain, we could simultaneously activate a wide spectrum of cellular protective mechanisms, including carotenoids, the HspA heat shock protein, and highly activated non-photochemical quenching. Yellow fluorescent protein was used to test the capacity of the SigB-oe strain to produce heterologous proteins. In standard conditions, the SigB-oe strain reached a similar production as the control strain, but when cultures were challenged with oxidative stress, the production capacity of SigB-oe surpassed the control strain. We also tested the production of growth-rate-controlled host strains via manipulation of RNA polymerase, but post-transcriptional regulation prevented excessive overexpression of the primary sigma factor SigA, and overproduction of the growth-restricting SigC factor was lethal. Thus, more research is needed before cyanobacteria growth can be manipulated by engineering RNA polymerase.

An Update of Kaempferol Protection against Brain Damage Induced by Ischemia-Reperfusion and by 3-Nitropropionic Acid.

Kaempferol, a flavonoid present in many food products, has chemical and cellular antioxidant properties that are beneficial for protection against the oxidative stress caused by reactive oxygen and nitrogen species. Kaempferol administration to model experimental animals can provide extensive protection against brain damage of the striatum and proximal cortical areas induced by transient brain cerebral ischemic stroke and by 3-nitropropionic acid. This article is an updated review of the molecular and cellular mechanisms of protection by kaempferol administration against brain damage induced by these insults, integrated with an overview of the contributions of the work performed in our laboratories during the past years. Kaempferol administration at doses that prevent neurological dysfunctions inhibit the critical molecular events that underlie the initial and delayed brain damage induced by ischemic stroke and by 3-nitropropionic acid. It is highlighted that the protection afforded by kaempferol against the initial mitochondrial dysfunction can largely account for its protection against the reported delayed spreading of brain damage, which can develop from many hours to several days. This allows us to conclude that kaempferol administration can be beneficial not only in preventive treatments, but also in post-insult therapeutic treatments.

Docosahexanoic Acid Attenuates Palmitate-Induced Apoptosis by Autophagy Upregulation via GPR120/mTOR Axis in Insulin-Secreting Cells.

Polyunsaturated fatty acids (PUFAs) reportedly have protective effects on pancreatic β-cells; however, the underlying mechanisms are unknown. To investigate the cellular mechanism of PUFA-induced cell protection, mouse insulinoma 6 (MIN6) cells were cultured with palmitic acid (PA) and/or docosahexaenoic acid (DHA), and alterations in cellular signaling and apoptosis were examined. DHA treatment remarkably repressed caspase-3 cleavage and terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL)-positive red dot signals in PA-treated MIN6 cells, with upregulation of autophagy, an increase in microtubule- associated protein 1-light chain 3 (LC3)-II, autophagy-related 5 (Atg5), and decreased p62. Upstream factors involved in autophagy regulation (Beclin-1, unc51 like autophagy activating kinase 1 [ULK1], phosphorylated mammalian target of rapamycin [mTOR], and protein kinase B) were also altered by DHA treatment. DHA specifically induced phosphorylation on S2448 in mTOR; however, phosphorylation on S2481 decreased. The role of G protein-coupled receptor 120 (GPR120) in the effect of DHA was demonstrated using a GPR120 agonist and antagonist. Additional treatment with AH7614, a GPR120 antagonist, significantly attenuated DHA-induced autophagy and protection. Taken together, DHA-induced autophagy activation with protection against PA-induced apoptosis mediated by the GPR120/mTOR axis. These findings indicate that DHA has therapeutic effects on PA-induced pancreatic β-cells, and that the cellular mechanism of β-cell protection by DHA may be a new research target with potential pharmacotherapeutic implications in β-cell protection.

8-Oxoadenine: A «New» Player of the Oxidative Stress in Mammals?

Numerous studies have shown that oxidative modifications of guanine (7,8-dihydro-8-oxoguanine, 8-oxoG) can affect cellular functions. 7,8-Dihydro-8-oxoadenine (8-oxoA) is another abundant paradigmatic ambiguous nucleobase but findings reported on the mutagenicity of 8-oxoA in bacterial and eukaryotic cells are incomplete and contradictory. Although several genotoxic studies have demonstrated the mutagenic potential of 8-oxoA in eukaryotic cells, very little biochemical and bioinformatics data about the mechanism of 8-oxoA-induced mutagenesis are available. In this review, we discuss dual coding properties of 8-oxoA, summarize historical and recent genotoxicity and biochemical studies, and address the main protective cellular mechanisms of response to 8-oxoA. We also discuss the available structural data for 8-oxoA bypass by different DNA polymerases as well as the mechanisms of 8-oxoA recognition by DNA repair enzymes.

All‐in‐Human Target Discovery in Alzheimer’s Disease and Resilient Brains

AbstractBackgroundAlzheimer’s disease (AD) is characterized by neuropathological hallmarks including amyloid plaques and tau tangles and neurodegeneration in the frontal cortex. While there is a strong association of tau pathology with neurodegeneration and cognitive decline, around 30% of amyloid plaque‐carrying seniors remain cognitively healthy. We hypothesize that protective cellular mechanisms upstream of tau phosphorylation and neurodegeneration may underlie this resilience.MethodWe applied high resolution spatial transcriptomics and single nuclei RNA sequencing on postmortem frontal lobes from 10 demented and 10 non‐demented individuals with comparable degrees of amyloid pathology. We integrated the generated transcriptomics data with proteomics, genomics and drug action databases and interpret cellular transcriptome responses to pathology in the context of human specific protein‐protein interaction networks.ResultUsing spatial and single nuclei transcriptomics, we identify specific transcriptomic signatures and regulatory networks in cellular microenvironments around amyloid plaques and pTau pathology niches. Our results suggest that specific neuronal and glial subpopulations carry enriched vulnerability towards amyloid plaque and pTau depositions. We further find that certain cell death signaling pathways related to neurodegeneration are overrepresented in the context of pTau pathology. Finally, our multi‐omics database integration approach has led to the identification of potential drug targets for therapeutics addressing cellular mechanisms of neuroprotection.ConclusionSpatial transcriptomics from human brain tissue is a powerful approach to reveal cellular mechanisms of pathogenic lesions and enables us to identify neuroprotective mechanisms that may prevent the development of tauopathy and ultimately neuronal loss. The combination of single cell and spatial transcriptomics together with protein‐protein interaction networks provides a promising approach for the identification of novel therapeutic targets for AD.

Analysis of Resistance Gene Diversity in the Intestinal Microbiome of Broilers from Two Types of Broiler Farms in Hebei Province, China.

The crucial reservoir of antibiotic resistance genes (ARGs) within the chicken intestinal microbiome poses a serious threat to both animal and human health. In China, the overuse of antibiotics has significantly contributed to the proliferation of ARGs in the chicken intestinal microbiome, which is a serious concern. However, there has been relatively little research on the diversity of resistance genes in the chicken intestinal microbiome since the implementation of the National Pilot Work Program for Action to Reduce the Use of Veterinary Antimicrobial Drugs in China. The objective of this study was to analyze the diversity of antibiotic resistance genes carried by the chicken intestinal microbiome in both standard farms (SFs), which implement antibiotic reduction and passed national acceptance, and nonstandard farms (NSFs), which do not implement antibiotic reductions, in Hebei Province. Fresh fecal samples of broiler chickens were collected from SFs (n = 4) and NSF (n = 1) and analyzed using high-throughput qPCR technology. Our findings revealed that all five farms exhibited a wide range of highly abundant ARGs, with a total of 201 ARGs and 7 MGEs detected in all fecal samples. The dominant ARGs identified conferred resistance to aminoglycosides, macrolide-lincosamide-streptomycin B (MLSB), and tetracycline antibiotics. Cellular protection mechanisms were found to be the primary resistance mechanism for these ARGs. The analysis of the co-occurrence network demonstrated a significant positive correlation between the abundance of MGEs and ARGs. The SF samples showed a significantly lower relative abundance of certain ARGs than the NSF samples (p < 0.05). The results of this study show that the abundance of ARGs demonstrated a downward trend after the implementation of the National Pilot Work Program for Action to Reduce the Usage of Veterinary Antimicrobial Drugs in Hebei Province, China.

Heat Shock Factor 1 Inhibition: A Novel Anti-Cancer Strategy with Promise for Precision Oncology.

Heat shock factor 1 (HSF1) is a transcription factor crucial for regulating heat shock response (HSR), one of the significant cellular protective mechanisms. When cells are exposed to proteotoxic stress, HSF1 induces the expression of heat shock proteins (HSPs) to act as chaperones, correcting the protein-folding process and maintaining proteostasis. In addition to its role in HSR, HSF1 is overexpressed in multiple cancer cells, where its activation promotes malignancy and leads to poor prognosis. The mechanisms of HSF1-induced tumorigenesis are complex and involve diverse signaling pathways, dependent on cancer type. With its important roles in tumorigenesis and tumor progression, targeting HSF1 offers a novel cancer treatment strategy. In this article, we examine the basic function of HSF1 and its regulatory mechanisms, focus on the mechanisms involved in HSF1's roles in different cancer types, and examine current HSF1 inhibitors as novel therapeutics to treat cancers.

Involvement of the heat shock response (HSR) regulatory pathway in cadmium-elicited cerebral damage.

The heat shock response (HSR) is a cellular protective mechanism that is characterized by the induction of heat shock transcription factors (HSFs) and heat shock proteins (HSPs) in response to diverse cellular and environmental stressors, including cadmium (Cd). However, little is known about the relationship between the damaging effects of Cd and the HSR pathway in the chicken cerebrum following Cd exposure. To explore whether Cd exposure elicits cerebral damage and triggers the HSR pathway, chicks were exposed to Cd in the daily diet at different concentrations (35, 70, or 140mg/kg feed) for 90days, while a control group was fed the standard diet without Cd. Histopathological examination of cerebral tissue from Cd-exposed chickens showed neuronal damage, as evidenced by swelling and degeneration of neurons, loss of neurons, and capillary damage. Cd exposure significantly increased mRNA expression of HSF1, HSF2, and HSF3, and mRNA and protein expression of three major stress-inducible HSPs (HSP60, HSP70, and HSP90). Moreover, Cd exposure differentially modulated mRNA expression of small HSP (sHSPs), most notably reducing expression of HSP27 (HSPB1). Furthermore, Cd exposure increased TUNEL-positive neuronal apoptotic cells and up-regulated protein expression of caspase-1, caspase-8, caspase-3, and p53, leading to apoptosis. Taken together, these data demonstrate that activation of the HSR and apoptotic pathways by Cd exposure is involved in Cd-elicited cerebral damage in the chicken. Synopsis for the graphical abstract Cadmium (Cd)-induced neuronal damage triggers the heat shock response (HSR) by activating heat shock transcription factors (HSFs) and subsequent induction of major heat shock proteins (notably, HSP60, HSP70, and HSP90). Moreover, Cd exposure activates caspase-1, caspase-8, caspase-3, and p53 protein, thereby resulting in neuronal apoptosis in the chicken brain.