Cell Function Research Articles

Ovarian Endometrioma Disrupts Oocyte-Cumulus Communication and Mitochondrial Function, With Melatonin Mitigating the Effects.

Ovarian endometrioma (OEM), a particularly severe form of endometriosis, is an oestrogen-dependent condition often associated with pain and infertility. The mechanisms by which OEM impairs fertility, particularly through its direct impact on oocyte-cumulus cell (CC) communication and related pathways, remain poorly understood. This study investigates the impact of OEM on oocyte-CC communication and explores melatonin's therapeutic potential. We used a mouse model of OEM and employed ovarian transcriptome and gene set enrichment analyses to identify disrupted gene pathways, alongside phalloidin staining for cytoskeletal analysis, gap junction coupling analysis for intercellular communication, and mitochondrial function assessments for cellular metabolism. Our results showed that OEM significantly impairs steroidogenesis and cumulus cell function, leading to increased apoptosis, disrupted transzonal projections (TZPs), and impaired antioxidant transfer to oocytes. This culminates in oxidative stress, mitochondrial dysfunction, and compromised ATP production. OEM oocytes also exhibited severe abnormalities, including DNA damage, maturation defects, spindle assembly disruptions, and increased aneuploidy. This study identifies disrupted TZPs as a key pathological feature in OEM and highlights melatonin's potential to restore intercellular communication, mitigate oxidative damage, and improve reproductive outcomes.

Two-layered immune escape in AML is overcome by Fcγ receptor activation and inhibition of PGE2 signaling in NK cells.

Loss of anticancer NK cell function in AML patients is associated with fatal disease progression and remains poorly understood. Here, we demonstrate that AML-blasts isolated from patients rapidly inhibit NK cell function and escape NK cell-mediated killing. Transcriptome analysis of NK cells exposed to AML-blasts revealed increased CREM expression and transcriptional activity, indicating enhanced cAMP signalling, confirmed by uniform production of the cAMP-inducing prostanoid PGE2 by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE2 induced a blockade of LCK-ERK signalling that is crucial for NK cell activation, indicating a two-layered escape of AML-blasts with low expression of NK cell-activating ligands and inhibition of NK cell signalling. To evaluate the therapeutic potential to target PGE2 inhibition, we combined Fcg-receptor-mediated activation with the prevention of inhibitory PGE2-signalling. This rescued NK cell function and restored the killing of AML-blasts. Thus, we identify the PGE2-LCK signalling axis as the key barrier for NK cell activation in two-layered immune escape of AML-blasts that can be targeted for immune therapy to reconstitute anti-cancer NK cell immunity in AML patients.

Study on the effects of Mogroside V in inhibiting NLRP3-mediated granulosa cell pyroptosis and insulin resistance to improve PCOS

ObjectivePolycystic Ovary Syndrome (PCOS) is a prevalent endocrinopathy in reproductive-aged women, contributing to 75% of infertility cases due to ovulatory dysfunction. The condition poses significant health and psychological challenges, making the study of its pathogenesis and treatment a research priority. This study investigates the effects of Mogroside V (MV) on PCOS, focusing on its anti-inflammatory and anti-insulin resistance properties.MethodsForty-five female Sprague–Dawley rats were divided into three groups: control, PCOS model, and MV treatment. The PCOS model was induced using a high-fat diet and letrozole. The MV treatment group was subsequently administered MV after the establishment of the PCOS model. The study monitored body mass, assessed estrous cycle changes, and measured serum hormone levels. Transcriptome sequencing and bioinformatics were used to identify differentially expressed genes related to inflammation and insulin resistance. Expression of pyroptosis and insulin resistance markers was analyzed using qRT-PCR, Western blot, and IHC. Additionally, an in vitro model assessed MV's impact on inflammation and insulin resistance.ResultsThe PCOS group exhibited elevated serum testosterone (T), luteinizing hormone (LH), insulin, and fasting glucose levels, along with increased insulin resistance (HOMA-IR) and decreased estradiol (E2), which were reversed by MV treatment. Transcriptome analysis identified significant gene expression changes between groups, particularly in pathways related to NLRP3 inflammation and insulin metabolism. MV treatment normalized the expression of ovarian pyroptosis factors (NLRP3, Caspase-1, GSDMD) and inflammatory cytokines (IL-1β, IL-18). In cellular models, MV increased E2 levels, reduced LDH release, and decreased the expression of insulin resistance and pyroptosis markers. Correlation analysis showed pyroptosis factors were positively correlated with HOMA-IR and IGF1, and negatively with IGF1R and E2 levels.ConclusionMV improves PCOS by reducing pyroptosis and insulin resistance, enhancing insulin sensitivity, and promoting estrogen synthesis, thereby restoring granulosa cell function and follicular development.

Reversing NK cell exhaustion: a novel strategy combining immune checkpoint blockade with drug sensitivity enhancement in the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common lethal cancers worldwide. Natural killer cells (NK cells) play a key role in liver immunosurveillance, but in the tumor microenvironment, NK cells are readily depleted, as evidenced by down-regulation of activating receptors, reduced cytokine secretion, and attenuated killing function. The up-regulation of inhibitory receptors, such as PD-1, TIM-3, and LAG-3, further exacerbates the depletion of NK cells. Combined blockade strategies targeting these immunosuppressive mechanisms, such as the combination of PD-1 inhibitors with other inhibitory pathways (eg. TIM-3 and LAG-3), have shown potential to reverse NK cell exhaustion in preclinical studies. This article explores the promise of these innovative strategies in HCC immunotherapy, providing new therapeutic directions for optimizing NK cell function and improving drug sensitivity.

Lovastatin and Resveratrol Synergistically Improve Wound Healing and Inhibit Bacterial Growth.

Wound healing is a complex physiological process, with scarring and infection caused by Staphylococcus aureus and Pseudomonas aeruginosa being the most common complications. The reutilization of known medications has received increased attention for their role in cell function as small molecules. Examples of these include lovastatin, a cholesterol-lowering agent, and resveratrol, which have multiple biological properties. Both molecules have been reported to improve wound healing and possess antibacterial properties, with conflicting results. The wound-healing capabilities of human mesenchymal stem cells were evaluated after exposure to lovastatin, resveratrol, and their combination through scratch test, migrations assay, and qPCR. Protein docking was performed to assess the lovastatin/resveratrol combination as potential wound-healing targets. AlamarBlue assay was used to determine cell viability. Additionally, the impact of lovastatin and resveratrol combination to inhibit the growth of S. aureus and P. aeruginosa was tested using broth microdilution test and checkerboard assay to determine synergism. The combination of lovastatin 0.1 μM and resveratrol 0.1 μM synergistically improved wound healing and demonstrated an additive effect against S. aureus and P. aeruginosa, presenting potential antibacterial applications.

Exploring the Impact of Ionic Additives on the Structure and Energetics of Dye-Sensitized NiO Interfaces: Insights from Electrochemistry and First-Principles Calculations.

The efficient functioning of dye-sensitized solar cells (DSSCs) is governed by the interplay of three essential components: the semiconductor, the dye, and the electrolyte. While the impact of the electrolyte composition on the device's performance has been extensively studied in n-type DSSCs, much less is known about p-type-based devices. Here, we investigate the effect of potential-determining ions on the energetics and stability of dye-sensitized NiO surfaces by using electrochemical, ab initio molecular dynamics simulations, and ab initio electronic structure calculations. The experimental results indicate that the presence of Li+ leads to a ca. 100 mV positive shift in the potential of NiO, which is in good agreement with what is theoretically predicted (ca. 180 mV). Moreover, both experiments and calculations pinpoint that the presence of Li+ at the interface weakens the bonds between C343 and NiO, resulting in an accelerated desorption of the dye from the substrate. Computational remodeling of C343@NiO interfaces in the presence and absence of lithium salts (LiF) confirms that the interfacial energetics are very sensitive to the dynamical structure of C343@NiO and to the presence of anionic/cationic species. Indeed, although the presence of lithium at the interface has only a minor impact on the potential difference between NiO and the dye, it significantly influences the electronic coupling between the two interfacial components. This, in turn, leads to variations in the interfacial hole transfer rates.

SERINC2-mediated serine metabolism promotes cervical cancer progression and drives T cell exhaustion.

Cervical cancer remains the most prevalent gynecological malignant disease. Reprogramming tumor immune metabolism stands out as a novel promising therapeutic target. Here, we identified serine incorporator 2 (SERINC2) as a critical gene which highly expressed in cervical cancer and negatively correlated with clinical outcomes. Through functional assays, SERINC2 was determined to play a pro-tumoral role both in vivo and in vitro. Besides, the growth of cervical cancer cells was found to be largely dependent on serine in a manner influenced by SERINC2. As a serine transport associated protein, SERINC2 knockdown significantly reduced cervical cancer cells' intracellular serine level and altered the serine-associated-lipid metabolism. Immune infiltration analysis revealed that SERINC2 was negatively associated with CD8+ T cell infiltration and function. More importantly, we demonstrated a competitive relation between cancer cells and immune cells brought about by SERINC2. Mechanistically, cancer cells SERINC2 preferentially competed for micro-environmental serine over CD8+ T cells and rendered T cell exhaustion. Overall, SERINC2 remodels cancer development and serine metabolism in the tumor immune microenvironment (TIME), establishing an immunosuppressive and pro-tumoral milieu.

A novel isolation method for chondrocytes differentiated from synovial fluid-derived mesenchymal stem cell

Mesenchymal stem cells (MSCs) in synovial fluid (SF) actively participate in the regeneration process of healthy joints and have been defined as a good source of chondrocyte cells, which can be obtained by in vitro differentiation of stem cells. This cell population derived from synovial fluid shares cellular characteristics with bone marrow and synovial membrane MSCs with respect to their differentiation potency. Current cell isolation protocols for cartilage therapy mainly focus on the isolation of chondrocytes or MSCs from biological samples. However, the isolation of chondrocytes after the in vitro differentiation from MSCs has not been described in the literature. In this context, we defined a novel method based on Ficoll-Paque density gradient centrifugation for high-throughput isolation of differentiated chondrocytes from human synovial fluid mesenchymal stem cells (hSF-MSCs) without the requirement for cell labeling. In this study, terminally differentiated chondrocytes were obtained after 21 days of chondrogenic differentiation from hSF-MSCs and were isolated using this novel protocol. The isolated chondrocytes were later analyzed for cell viability and functionality by staining with Alcian Blue and by gene expression analysis for chondrocyte markers. In conclusion, the novel chondrocyte isolation method described here is capable of achieving low-cost efficiency. According to the minimal process principles, we hope that this protocol will find use in both translational research and routine clinical applications involving the differentiation and isolation of chondrocytes in vitro.

The beneficial effects of curcumin on aging and age-related diseases: from oxidative stress to antioxidant mechanisms, brain health and apoptosis.

Aging and age-related disease are among the most common and challenging issues worldwide. During the aging process, the accumulation of oxidative stress, DNA damage, telomere dysfunction, and other related changes lead to cellular dysfunction and the development of diseases such as neurodegenerative and cardiovascular conditions. Curcumin is a widely-used dietary supplement against various diseases such as cancer, diabetes, cardiovascular diseases and aging. This agent mediates its effects through several mechanisms, including the reduction of reactive oxygen species (ROS) and oxidative stress-induced damage, as well as the modulation of subcellular signaling pathways such as AMPK, AKT/mTOR, and NF-κB. These pathways are involved in cellular senescence and inflammation, and their modulation can improve cell function and help prevent disease. In cancer, Curcumin can induce apoptosis in a variety of different tumor cell lines. Curcumin also activates redox reactions within cells inducing ROS production that leads to the upregulation of apoptosis receptors on the tumor cell membrane. Curcumin can also upregulate the expression and activity of p53 that inhibits tumor cell proliferation and increases apoptosis. Furthermore, curcumin has a potent inhibitory effect on the activity of nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (COX-2), which are involved in the overexpression of antiapoptosis genes such as Bcl-2. It can also attenuate the regulation of antiapoptosis phosphoinositide 3-kinases (PI3K) signaling and increase the expression of mitogen-activated protein kinases (MAPKs) to induce endogenous production of ROS. Therefore, herein, we aim to summarize how curcumin affect different epigenetic processes (such as apoptosis and oxidative stress) in order to change aging-related mechanisms. Furthermore, we discuss its roles in age-related diseases, such as Alzheimer, Parkinson, osteoporosis, and cardiovascular diseases.

Regulating white blood cell activity through the novel Universal Receptive System.

The understanding of the mechanisms that control key features of immune cells in various disease contexts remains limited, and few techniques are available for manipulating immune cells. Thus, discovering novel strategies for regulating immune cells is essential for gaining insight into their roles in health and disease. In this study, we investigated the potential of the recently described Universal Receptive System to regulate human immune cell functions. This was achieved for the first time by specifically targeting newly discovered surface-bound DNA and RNA-based receptors on leukocytes and generating "Leukocyte-Tells." This approach upregulated numerous genes related to immune cell signaling, migration, endocytosis, and phagocytosis pathways. The antimicrobial and anticancer activities of Leukocyte-Tells exceeded the activity of control leukocytes in vitro . In some settings, such as in antibiofilm experiments, the Leukocyte-Tells showed up to 1,000,000-fold higher activities than control leukocytes. Our findings reveal, for the first time, that the Universal Receptive System can orchestrate fundamental properties of immune cells, including enhanced antimicrobial and anti-tumor activities. This novel approach offers a new avenue for understanding the biology and regulation of white blood cells.

Trafficking in cancer: from gene deregulation to altered organelles and emerging biophysical properties.

Intracellular trafficking supports all cell functions maintaining the exchange of material between membrane-bound organelles and the plasma membrane during endocytosis, cargo sorting, and exocytosis/secretion. Several proteins of the intracellular trafficking machinery are deregulated in diseases, particularly cancer. This complex and deadly disease stays a heavy burden for society, despite years of intense research activity. Here, we give an overview about trafficking proteins and highlight that in addition to their molecular functions, they contribute to the emergence of intracellular organelle landscapes. We review recent evidence of organelle landscape alterations in cancer. We argue that focusing on organelles, which represent the higher-order, cumulative behavior of trafficking regulators, could help to better understand, describe and fight cancer. In particular, we propose adopting a physical framework to describe the organelle landscape, with the goal of identifying the key parameters that are crucial for a stable and non-random organelle organization characteristic of healthy cells. By understanding these parameters, we may gain insights into the mechanisms that lead to a pathological organelle spatial organization, which could help explain the plasticity of cancer cells.

Trimetazidine: Activating AMPK Signal to Ameliorate Coronary Microcirculation Dysfunction after Myocardial Infarction.

Myocardial ischemia-reperfusion (I/R) injury and coronary microcirculation dysfunction (CMD) are observed in patients with myocardial infarction after vascular recanalization. The antianginal drug trimetazidine has been demonstrated to exert a protective effect in myocardial ischemia-reperfusion injury. This study aimed to investigate the role of trimetazidine in endothelial cell dysfunction caused by myocardial I/R injury and thus improve coronary microcirculation. The myocardial I/R mouse model was established, and trimetazidine was administered for 7 days before myocardial I/R model establishment. Echocardiography, 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (H&E) staining, and thioflavin S staining were applied to assess myocardial injury and microvascular function. Additionally, the oxygen-glucose deprivation/reperfusion (OGD/R) model was developed in endothelial cells to simulate myocardial I/R injury in vitro. Griess reaction method, immunofluorescence, and western blotting (WB) were employed to detect the expressions of nitric oxide (NO), platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial (VE)-cadherin, zonula occludens protein 1 (ZO-1), occludin, vascular endothelial growth factor (VEGF) and adenosine monophosphate (AMP)-activated protein kinase (AMPK) signaling-related proteins in endothelial cells and mouse cardiomyocytes. AMPK pathway inhibitor compound C was used for further mechanism validation. Our research demonstrated that trimetazidine can alleviate myocardial pathological injury and cardiac function injury during myocardial I/R. Trimetazidine was observed to improve microvascular reflux phenomenon and microvascular function and barrier injury in myocardial I/R and OGD/R models. Additionally, the expressions of AMPK signal-related proteins were found to be inhibited in myocardial I/R and OGD/R models, which were then activated in mice administered trimetazidine. However, the effects of trimetazidine on endothelial cell function and barrier damage were attenuated after co-treatment with compound C and trimetazidine. Trimetazidine ameliorated myocardial I/R-induced CMD by activating AMPK signaling.

Vascular Cell Adhesion Molecule 1 and E-Selectin as Potential Cardiovascular Risk Biomarkers in Psoriasis.

Vascular cell adhesion molecule-1 (VCAM-1) and E-selectin are involved in different inflammatory diseases and may be potential cardiovascular risk biomarkers in psoriasis. They play an important role in regulating the recruitment and adhesion to endothelial cells during inflammation, affecting various conditions like vasculitis, atherosclerosis, and cardiovascular diseases. Positive outcomes have been observed when using Tumor Necrosis Factor Alpha (TNF-α) inhibitors and biological therapies that target selectins to control the functioning of endothelial cells and reduce inflammation in psoriasis and related conditions. Moreover, the effects of systemic treatments and ultraviolet B (UVB) phototherapy on VCAM-1 and E-selectin levels in psoriasis patients highlights the potential to impact the severity of psoriasis and activation of endothelial cells. In addition, various factors such as age, sex, metabolic syndrome, hyperglycemia, migraines, and tobacco smoking have been found to affect levels of VCAM-1 and E-selectin. This sheds light on understanding the complex relationship between endothelial activation and the development of diseases. Studies show the potential of using the levels of VCAM-1 and E-selectin as indicators of systemic treatment effectiveness and the progression of the disease. In summary, this review highlights the importance of VCAM-1 and E-selectin as potential biomarkers for assessing inflammation, disease severity and cardiovascular risk in individuals with psoriasis. The shared mechanisms of psoriasis and atherosclerosis, along with the effect of treatments on endothelial activation markers, provide significant insights for further research and approaches to manage inflammatory diseases in the future.

Post-Translational Modifications of Proteins Orchestrate All Hallmarks of Cancer.

Post-translational modifications (PTMs) of proteins dynamically build the buffering and adapting interface between oncogenic mutations and environmental stressors, on the one hand, and cancer cell structure, functioning, and behavior. Aberrant PTMs can be considered as enabling characteristics of cancer as long as they orchestrate all malignant modifications and variability in the proteome of cancer cells, cancer-associated cells, and tumor microenvironment (TME). On the other hand, PTMs of proteins can enhance anticancer mechanisms in the tumoral ecosystem or sustain the beneficial effects of oncologic therapies through degradation or inactivation of carcinogenic proteins or/and activation of tumor-suppressor proteins. In this review, we summarized and analyzed a wide spectrum of PTMs of proteins involved in all regulatory mechanisms that drive tumorigenesis, genetic instability, epigenetic reprogramming, all events of the metastatic cascade, cytoskeleton and extracellular matrix (ECM) remodeling, angiogenesis, immune response, tumor-associated microbiome, and metabolism rewiring as the most important hallmarks of cancer. All cancer hallmarks develop due to PTMs of proteins, which modulate gene transcription, intracellular and extracellular signaling, protein size, activity, stability and localization, trafficking, secretion, intracellular protein degradation or half-life, and protein-protein interactions (PPIs). PTMs associated with cancer can be exploited to better understand the underlying molecular mechanisms of this heterogeneous and chameleonic disease, find new biomarkers of cancer progression and prognosis, personalize oncotherapies, and discover new targets for drug development.

Sodium tanshinone IIA sulfonate alleviates fetal growth restriction by mediating aquaporin-3 expression in placental trophoblast cells.

Fetal growth restriction (FGR) is characterized by the inability of the fetus to achieve its growth potential due to pathological factors, most commonly impaired placental trophoblast cell function. Currently, effective prevention and treatment methods of FGR are limited. We aimed to explore the pathogenesis of FGR and provide potential strategies for mitigating its occurrence. The case-control study compared AQP3 expression in placental trophoblast cells of pregnant women with FGR and those with normal pregnancies. Then mouse FGR models were induced via cadmium exposure, and placental trophoblast cells (JEG-3) were similarly treated. The study assessed the effects of Sodium tanshinone IIA sulfonate (STS) and the role of the PI3K/Akt pathway in improving AQP3 expression and trophoblast cell function. Placental trophoblast cells in FGR cases exhibited significantly reduced AQP3 expression. AQP3-knockdown cells displayed dysfunction. Cadmium exposure in mice and JEG-3 cells led to decreased AQP3 expression and trophoblast cell dysfunction, both of which were ameliorated by STS. Fetal mouse weight increased with STS treatment. STS upregulated AQP3 expression and improved trophoblast cell function in AQP3-knockdown cells. Inhibiting the PI3K/Akt pathway diminished STS's beneficial effects. ThereforeSTS may enhance AQP3 expression in placental trophoblast cells affected by FGR through the activation of the PI3K/Akt pathway, ultimately bolstering placental trophoblast cell function and alleviating FGR. As above, STS appears to be a potential therapeutic agent for alleviating FGR.

Longitudinal association between DNA methylation and type 2 diabetes: findings from the KORA F4/FF4 study

BackgroundType 2 diabetes (T2D) has been linked to changes in DNA methylation levels, which can, in turn, alter transcriptional activity. However, most studies for epigenome-wide associations between T2D and DNA methylation comes from cross-sectional design. Few large-scale investigations have explored these associations longitudinally over multiple time-points.MethodsIn this longitudinal study, we examined data from the Cooperative Health Research in the Region of Augsburg (KORA) F4 and FF4 studies, conducted approximately seven years apart. Leucocyte DNA methylation was assessed using the Illumina EPIC and 450K arrays. Linear mixed-effects models were employed to identify significant associations between methylation sites and diabetes status, as well as with fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), homoeostasis model assessment of beta cell function (HOMA-B), and homoeostasis model assessment of insulin resistance (HOMA-IR). Interaction effects between diabetes status and follow-up time were also examined. Additionally, we explored CpG sites associated with persistent prediabetes or T2D, as well as the progression from normal glucose tolerance (NGT) to prediabetes or T2D. Finally, we assessed the associations between the identified CpG sites and their corresponding gene expression levels.ResultsA total of 3,501 observations from 2,556 participants, with methylation measured at least once across two visits, were included in the analyses. We identified 64 sites associated with T2D including 15 novel sites as well as known associations like those with the thioredoxin-interacting protein (TXNIP) and ATP-binding cassette sub-family G member 1 (ABCG1) genes. Of these, eight CpG sites exhibited different rates of annual methylation change between the NGT and T2D groups, and seven CpG sites were linked to the progression from NGT to prediabetes or T2D, including those annotated to mannosidase alpha class 2a member 2 (MAN2A2) and carnitine palmitoyl transferase 1 A (CPT1A). Longitudinal analysis revealed significant associations between methylation and FPG at 128 sites, HbA1c at 41 sites, and HOMA-IR at 57 sites. Additionally, we identified 104 CpG-transcript pairs in whole blood, comprising 40 unique CpG sites and 96 unique gene transcripts.ConclusionsOur study identified novel differentially methylated loci linked to T2D as well as to changes in diabetes status through a longitudinal approach. We report CpG sites with different rates of annual methylation change and demonstrate that DNA methylation associated with T2D is linked to following transcriptional differences. These findings provide new insights into the molecular mechanisms of diabetes development.Graphical abstract

The CD4/CD8 ratio is associated with T lymphocyte functions in long-term virally suppressed patients with HIV

ObjectiveLong-term management of people living with HIV (PLWHs) often relies on CD4+ T cell counts for assessing immune recovery, yet a single metric offers limited information. This study aimed to explore the association between the CD4/CD8 ratio and T lymphocyte activities in PLWHs.Methods125 PLWHs and 31 HIV-uninfected controls (UCs) were enrolled and categorized into four groups based on their CD4/CD8 ratios: extremely low ratio (ELR) group: 0.4 < CD4/CD8; low ratio (LR) group: 0.4 ≤ CD4/CD8<0.7; medium ratio (MR) group: 0.7 ≤ CD4/CD8<1; high ratio (HR) group: CD4/CD8 ≥ 1. The activation and proliferation phenotypes, mitochondrial functions, and inflammatory indexes of CD4+ T cells and CD8+ T cells were measured, and correlations between the CD4/CD8 ratio and T cell functions were analyzed.ResultsT cell activation and proliferation were significantly elevated in the ELR group compared to UCs. However, the ELR group had a larger proportion of T cells with lipid peroxidation, mitochondrial lipid reactive oxygen species (ROS), and mitochondrial membrane potential (MMP) abnormalities compared to the other groups. As the CD4/CD8 ratio increased, mitochondrial lipid peroxidation damage decreased and MMP was restored. Additionally, the ELR group had more inflammatory markers in CD4+ T cells. Correlation analysis revealed that the CD4/CD8 ratio was associated with multiple T cell functions, and its correlation coefficient with mitochondrial function was higher than that of CD4+ T cell count.ConclusionThe CD4/CD8 ratio is closely related to T lymphocyte functions and is significantly superior to the CD4+ T cell count in reflecting the mitochondrial lipid peroxidation level and mitochondrial functions within T lymphocytes.

Parthenolide improves sepsis-induced coagulopathy by inhibiting mitochondrial-mediated apoptosis in vascular endothelial cells through BRD4/BCL-xL pathway

BackgroundSepsis is a systemic inflammatory syndrome that can cause coagulation abnormalities, leading to damage in multiple organs. Vascular endothelial cells (VECs) are crucial in the development of sepsis-induced coagulopathy (SIC). The role of Parthenolide (PTL) in regulating SIC by protecting VECs remains unclear.MethodsThe study utilized septic rats and lipopolysaccharide (LPS)-stimulated VECs to simulate a SIC model and observe the therapeutic effects of PTL. Additionally, nanotechnology was employed to produce Nano-PTL (N-PTL), to observe whether it has advantages over PTL in treating SIC.ResultsPTL has been shown to mitigate lung injury in septic rats, significantly reduce tumor necrosis factor-α (TNF-α) levels, and increase survival rates. PTL treatment also enhances coagulation function, augments vascular endothelial cell (VEC) function, reduces mitochondrial fragmentation, and increases both mitochondrial oxygen consumption rate (OCR) and mitochondrial membrane potential (MMP), while inhibiting reactive oxygen species (ROS) production. By increasing BRD4/BCL-xL levels, PTL can prevent mitochondrial-mediated apoptosis in VECs, improve VEC function, and consequently ameliorate SIC. Additionally, nanotechnology-synthesized N-PTL further enhances the protective effects on VECs and coagulation function.ConclusionsThis study clarifies the therapeutic effects and mechanisms of PTL on SIC, offering new strategies and directions for the treatment of sepsis.

Cannabis vaping elicits transcriptomic and metabolomic changes in inflammatory, oxidative stress and cancer pathways in human bronchial epithelial cells.

The increasing shift from cannabis smoking to cannabis vaping is largely driven by the perception that vaping to form an aerosol represents a safer alternative to smoking and is a form of consumption appealing to youth. Herein, we compared the chemical composition and receptor-mediated activity of cannabis smoke extract (CaSE) to cannabis vaping extract (CaVE) along with the biological response in human bronchial epithelial cells. Chemical analysis using HPLC and GC/MS revealed that cannabis vaping aerosol contained fewer toxicants than smoke; CaSE and CaVE contained teratogens, carcinogens, and respiratory toxicants. A bioluminescence resonance energy transfer (BRET)-based biosensor detected the receptor-mediated activity of the extracts, primarily driven by Δ9-THC concentration. RNA- sequencing showed both CaSE and CaVE induced similar transcriptional responses, significantly upregulating genes within pathways related to inflammation, cancer, and cellular stress. This was paralleled by downregulation of pathways related to lipid synthesis and metabolism similarly from both CaSE and CaVE. Targeted metabolomics revealed significant changes in metabolites involved in lipid and membrane metabolism, energy production, nucleotide/DNA/RNA pathways, and oxidative stress response, suggesting potential impairment of lung epithelial cell repair and function. Additionally, the upregulation of 5-hydroxymethylcytosine (5hmC) indicates epigenetic changes potentially contributing to inflammation, oxidative stress, and an increased risk of cancer. These findings challenge the notion that cannabis vaping is risk-free, highlighting an urgent need for comprehensive research into its respiratory health effects. This comparison of cannabis consumption methods offers insights that could inform public health policies and raise consumer awareness regarding the potential risks of inhaling cannabis aerosol.

The Multifaceted Roles of MicroRNA-181 in Stem Cell Differentiation and Cancer Stem Cell Plasticity.

Stem cells are undifferentiated or partially differentiated cells with an extraordinary ability to self-renew and differentiate into various cell types during growth and development. The epithelial-mesenchymal transition (EMT), a critical developmental process, enhances stem cell-like properties in cells, and is associated with both normal stem cell function and the formation of cancer stem cells. Cell stemness and the EMT often coexist and are interconnected in various contexts. Cancer stem cells are a critical tumor cell population that drives tumorigenesis, cancer progression, drug resistance, and metastasis. Stem cell differentiation and the generation of cancer stem cells are regulated by numerous molecules, including microRNAs (miRNAs). These miRNAs, particularly through the modulation of EMT-associated factors, play major roles in controlling the stemness of cancer stem cells. This review presents an up-to-date summary of the regulatory roles of miR-181 in human stem cell differentiation and cancer cell stemness. We outline studies from the current literature and summarize the miR-181-controlled signaling pathways responsible for driving human stem cell differentiation or the emergence of cancer stem cells. Given its critical role in regulating cell stemness, miR-181 is a promising target for influencing human cell fate. Modulation of miR-181 expression has been found to be altered in cancer stem cells' biological behaviors and to significantly improve cancer treatment outcomes. Additionally, we discuss challenges in miRNA-based therapies and targeted delivery with nanotechnology-based systems.