Excessive Production Research Articles

EGCG Alleviates Skeletal Muscle Oxidative Damage in Heat-Stressed Pigs via Keap1/PGAM5 Complex-Mediated Mitophagy.

The heat stress (HS) induced by high temperatures can result in oxidative damage to muscles, thereby compromising both muscle growth and immune function within the organism. Mitophagy serves as a pivotal pathway in alleviating excessive ROS production and subsequent oxidative damage. However, the potential role of epigallocatechin-3-gallate (EGCG), a natural antioxidant found in tea, in mitophagy under HS remains unexplored. Here, we present evidence of EGCG mitigating the oxidative-redox imbalance in porcine skeletal muscles induced by HS involving the antioxidant enzyme system mediated by the Keap1/Nrf2 pathway and mitophagy mediated by the PINK1/Parkin pathway. Importantly, we identified phosphate mutase 5 (PGAM5) for the first time as a key protein modulated by EGCG under HS conditions, regulating mitophagy. Inhibition of PGAM5 significantly attenuated the activation of mitophagy by EGCG. Molecular docking and dynamics simulations further suggested that EGCG directly binds to Keap1, disrupting the Keap1-PGAM5 protein interaction and thus promoting the release of PGAM5 and subsequently activating mitophagy. In summary, this study represents the first discovery of EGCG directly targeting Keap1/PGAM5-mediated mitophagy, which serves as a potential functional supplement for regulating the antioxidant capacity in pigs.

Mechanisms and Therapeutic Potential of Multiple Forms of Cell Death in Myocardial Ischemia–Reperfusion Injury

Programmed cell death, especially programmed necrosis such as necroptosis, ferroptosis, and pyroptosis, has attracted significant attention recently. Traditionally, necrosis was thought to occur accidentally without signaling pathways, but recent discoveries have revealed that molecular pathways regulate certain forms of necrosis, similar to apoptosis. Accumulating evidence indicates that programmed necrosis is involved in the development of various diseases, including myocardial ischemia–reperfusion injury (MIRI). MIRI occurs when blood flow and oxygen return to an ischemic area, causing excessive production of reactive oxygen species. While this reperfusion is critical for treating myocardial infarction, it inevitably causes cellular damage via oxidative stress. Furthermore, this cellular damage triggers multiple forms of cardiomyocyte death, which is the primary cause of inflammation, cardiac tissue remodeling, and ensuing heart failure. Therefore, understanding the molecular mechanisms of various forms of cell death in MIRI is crucial for therapeutic target discovery. Developing therapeutic strategies to inhibit multiple cell death pathways simultaneously could provide effective protection against MIRI. In this paper, we review the fundamental molecular pathways and MIRI-specific mechanisms of apoptosis, necroptosis, ferroptosis, and pyroptosis. Additionally, we suggest that the simultaneous suppression of multiple cell death pathways could be an effective therapy and identify potential therapeutic targets for implementing this strategy.

Cascade-Activatable Nanoprodrug System Augments Sonochemotherapy of Bladder Cancer.

Sonochemotherapy (SCT) has emerged as a powerful modality for cancer treatment by triggering excessive production of reactive oxygen species (ROS) and controlled release of chemotherapeutic agents under ultrasound. However, achieving spatiotemporally controlled release of chemotherapeutic agents during ROS generation is still an enormous challenge. In this work, we developed a cascade-activated nanoprodrug (CAN) system that utilizes a reversible covalent Schiff base mixed with a hypoxia-activatable camptothecin (CPT) prodrug. Briefly, the designed fluorinated CAN system is self-assembled into nanoparticles under aqueous conditions, which could penetrate deep tumors to offer sufficient oxygen for ultrasound-triggered ROS production. Consequently, the nanoparticles substantially exacerbated the hypoxia of the tumor microenvironment (TME) by elevating oxygen consumption. The aggravated hypoxia in turn served as a positive amplifier to boost the tumor-specific CPT release of Azo-CPT prodrug, which made up for the insufficient treatment efficacy of sonodynamic therapy (SDT). On this basis, we observed a substantial reduction, approximately 3.5-fold, in the half-maximal inhibitory concentration (IC50) of the CAN system compared to that of free CPT in bladder cancer cell lines (T24). Furthermore, the CAN system demonstrated potent antitumor efficacy with reduced side effects, resulting in regression and eradication of T24 tumors in various mouse models. In summary, the CAN system can be easily extended by incorporating different chemotherapeutic agents, showing great potential to revolutionize the clinical management paradigm of bladder cancer.

Phosphocholine inhibits proliferation and reduces stemness of endometrial cancer cells by downregulating mTOR-c-Myc signaling

BackgroundEndometrial cancer (EC) represents a serious health concern among women globally. Excessive activation of the protooncogene c-Myc (c-Myc) is associated with the proliferation and stemness of EC cells. Phosphocholine (PC), which is synthesized by choline kinase alpha (CHKA) catalysis, is upregulated in EC tumor tissues. The present study aimed to investigate the effect of PC accumulation on EC cells and clarify the relationship between PC accumulation and c-Myc activity in EC.MethodsThe c-Myc and CHKA expression in EC tumor tissues were examined using immunohistochemistry. Cell Counting Kit-8 assay, colony formation assay, flow cytometry, western blotting, BrdU staining, and tumorsphere formation assay were used to assess the effect of PC accumulation on EC cells. The mechanism by which PC accumulation inhibits c-Myc was evaluated using RNA-sequencing. Patient-derived organoid (PDO) models were utilised to explore the preclinical efficacy of PC against EC cells.ResultsPC accumulation suppressed EC cell proliferation and stemness by inhibiting the activation of the mammalian target of rapamycin (mTOR)-c-Myc signaling. PC accumulation promoted excessive reactive oxygen species production, which reduced the expression of GTPase HRAS. This, in turn, inhibited the mTOR-c-Myc axis and induced EC cell apoptosis. Finally, PC impeded proliferation and downregulated the expression of the mTOR–MYC signaling in EC PDO models.ConclusionsPC accumulation impairs the proliferation ability and stem cell characteristics of EC cells by inhibiting the activated mTOR-c-Myc axis, potentially offering a promising strategy to enhance the efficacy of EC clinical therapy through the promotion of PC accumulation in tumor cells.

Comparative Descriptive: Level Of Knowledge and Acne Self-Medication Patterns Between Health and Non-Health Students in Medan City

Acne is a skin health problem caused by the excessive production of oil (sebum), which appears on the face, neck, chest, and back; if not treated properly, it will leave scars. The aim of this study is to compare descriptively the level of knowledge and patterns on self-medication acne between health and non-health students in Medan, Indonesia. This quantitative descriptive collected data through a survey via a Google form. The study’s respondents were 206 students from 4 universities in Medan, North Sumatra, Indonesia. The sampling technique was probability sampling with Simple Random Sampling. The results of the present study show that the level of knowledge of self-medication for acne of health and non-health students was getting a score of 75.6% and 73.3%, respectively. The pattern of self-medication of health students tended to be better than non-health students because as many as 47.5% of health students did self-medication, while non-health students, 35.4% because they did not know the right way to care for their skin. The conclusion of this study is that the level of knowledge on acne self-medication in health and non-health students was almost similar, but on the pattern of self-medication, the health student was better than the non-health student.

Современные представления о моногенных аутовоспалительных заболеваниях

Autoinflammatory diseases (AIDs) are a group of rare disorders characterized by recurrent episodes of inflammation with neither infectious nor autoimmune nor neoplastic trigger. The AIDs pathogenesis is based on mutations in genes that lead to uncontrolled and excessive production of proinflammatory cytokines. Authors represent current views on the pathogenesis, clinical manifestations, diagnosis and treatment of the most studied monogenic AIDs. New therapeutic approaches based on targeted blockade of key inflammatory mediators are described as well.

EFEKTIVITAS EKSTRAK DAUN SIRIH MERAH TERHADAP JUMLAH KOLONI BAKTERI PADA REMAJA PEREMPUAN YANG MENGALAMI KEPUTIHAN

Leukorrhea, or vaginal discharge, is a common issue faced by adolescent girls during puberty. The Indonesian Adolescent Reproductive Health Survey reports that 31.8% of young women experience this condition, indicating their increased vulnerability to vaginal infections. Bacterial growth is a primary cause of leukorrhea, particularly in adolescent girls whose thin vaginal mucosa provides a favorable environment for bacterial proliferation, resulting in excessive fluid production and discomfort. Red betel leaf extract, containing natural antiseptics and antibiotics, offers an effective treatment for leukorrhea. The research sought to examine how extract from Piper crocatum (red betel leaf) impacts the growth of bacteria responsible for leukorrhea in young female adolescents. The research employed the Total Plate Count method to measure aerobic bacterial colony numbers in the participants' leukorrhea samples The research employed a quasi-experimental methodology, utilizing a single group pre-post test design and sequential sampling. Results demonstrated a notable impact of red betel leaf extract on the quantity of bacterial colonies in teenage girls. The statistical evaluation produced a p-value below 0.05 (specifically, 0.02), validating the extract's effectiveness. The research concludes that red betel leaf extract, a readily available natural remedy, can serve as an effective therapy to reduce bacterial colonies responsible for leukorrhea in adolescent girls. This herbal treatment's accessibility makes it a practical option for community use.

In Situ Transformable Nanoparticle Effectively Suppresses Bladder Cancer by Damaging Mitochondria and Blocking Mitochondrial Autophagy Flux.

Tumor therapeutic strategies based on mitochondrial damage have become an emerging trend. However, the low drug delivery efficiency caused by lysosomal sequestration and the activation of protective mitochondrial autophagy severely restricts the therapeutic efficacy. Herein, an in situ transformable nanoparticle named KCKT is developed to promote lysosomal escape and directly damage mitochondria while blocking mitochondrial autophagy. KCKT exhibits acid responsiveness for precise self-assembly into nanofibers within the lysosomes of cancer cells. The massive accumulation of nanofibers and excessive production of reactive oxygen species (ROS) under sonodynamic therapy synergistically induce lysosomal damage. This facilitates the escape of nanofibers from lysosomal sequestration, thereby enhancing drug delivery. Subsequently, the escaped nanofibers specifically aggregate around the mitochondria for long-term retention and generate ROS under ultrasound irradiation to induce mitochondrial damage. Notably, due to lysosomal dysfunction, damaged mitochondria cannot be cleared by autophagy, further aggravating oxidative damage. These results reveal that KCKT effectively improves drug delivery and mitochondria-targeted therapy efficiency by blocking protective autophagy. These findings hold significant potential for advancing the field of mitochondria-targeted therapy.

Photothermal Nanozyme‐Encapsulating Microneedles for Synergistic Treatment of Infected Wounds

AbstractPhotothermal therapy (PTT) is widely used in wound healing because it produces heat under near‐infrared irradiation, eliminating bacterial infections. However, excessive production of reactive oxygen species (ROS) occurs during PTT, which causes oxidative stress damage. In this study, a nanozyme, PDA‐MnO2 (PM), is synthesized and encapsulated in the needle tip layer of a bi‐layer GelMA microneedle patch (PbMP), which has excellent mechanical properties and can easily penetrate the skin. In a study involving an SD rat wound model infected with S. aureus, the PbMP significantly accelerated the healing process of bacterially challenged wounds, resulting in better blood vessel growth, cell proliferation, and collagen biosynthesis than other wound dressings. The experiment shows that the PM nanoparticles in PbMP improve photothermal conversion efficiency and activate SOD and CAT, resulting in an efficient cascade enzyme reaction system to eliminate ROS during the PTT process. This study describes a highly effective nanozyme hydrogel microneedle platform with photothermal synergistic antibacterial effects on wound healing.

Glutathione's Role in Liver Metabolism and Hangover Symptom Relief: Dysregulation of Protein S-Glutathionylation and Antioxidant Enzymes.

Hangovers from alcohol consumption cause symptoms like headaches, nausea, and fatigue, disrupting daily activities and overall well-being. Over time, they can also lead to inflammation and oxidative stress. Effective hangover relief alleviates symptoms, prevents dehydration, and replenishes energy needed for daily tasks. Natural foods considered high in antioxidants and antiinflammatory properties may aid in the hepatic breakdown of alcohol. The study aims to investigate the impact of glutathione or its enriched yeast extract, which is recognized for its antioxidant characteristics, on alcohol metabolism and alleviating hangovers in a rat model exposed to binge drinking. In this study, glutathione and its enriched yeast extract controlled hangover behaviour patterns, including locomotor activity. Additionally, it enhanced the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) following ethanol ingestion (3 g/kg). Further, the incorporation of glutathione led to an increase in the expression of antioxidant enzymes, such as SOD and catalase, by activating the nuclear erythroid 2-related factor 2 (Nrf2) signaling pathway. This activation reduced the excessive production of reactive oxygen species (ROS) and malondialdehyde. Next, glutathione modulated the activity of cytochrome P450 2E1 (CYP2E1) and the protein expressions of Bax and Bcl2. Besides, in vitro and in vivo investigations with glutathione demonstrated a regulating effect on the pan-s-glutathionylation and its associated protein expression, glutaredoxin 1 (Grx1), glutathione-S-transferase Pi (GST-π), and glutathione reductase (GR). Together, these findings suggest that glutathione or its enriched yeast extract as a beneficial dietary supplement for alleviating hangover symptoms by enhancing alcohol metabolism and its associated Nrf2/Keap1 signalings.

Recent Advances in the Application of Foodborne Substances in Hyperuricemia.

Hyperuricemia (HUA) is a purine metabolism disorder characterized by the excessive production or inadequate excretion of uric acid. Current pharmacological strategies targeting uric acid reduction have potential adverse effects. Following the concept of "homology of medicine and food", food ingredients are increasingly being explored to prevent HUA and gout, with xanthine oxidase (XOD) emerging as a crucial therapeutic target in managing HUA. Recent scientific investigations have determined that uric acid-lowering substances come from various food sources, such as seafood, dairy products, and agricultural products. These bioactive substances have attracted wide attention because of their effective antihyperuricemia and XOD inhibitory ability. In this study, the pathogenesis, many side effects of uric acid-lowering drugs, and some components of uric acid-lowering drugs are mainly described, with emphasis on the source, composition, preparation technology, and mechanism of uric acid-lowering peptides.

Fructose-mediated AGE-RAGE axis: approaches for mild modulation.

Fructose is a valuable and healthy nutrient when consumed at normal levels (≤50 g/day). However, long-term consumption of excessive fructose and elevated endogenous production can have detrimental health impacts. Fructose-initiated nonenzymatic glycation (fructation) is considered as one of the most likely mechanisms leading to the generation of reactive species and the propagation of nonenzymatic processes. In the later stages of glycation, poorly degraded advanced glycation products (AGEs) are irreversibly produced and accumulated in the organism in an age- and disease-dependent manner. Fructose, along with various glycation products-especially AGEs-are present in relatively high concentrations in our daily diet. Both endogenous and exogenous AGEs exhibit a wide range of biological effects, mechanisms of which can be associated with following: (1) AGEs are efficient sources of reactive species in vivo, and therefore can propagate nonenzymatic vicious cycles and amplify glycation; and (2) AGEs contribute to upregulation of the specific receptor for AGEs (RAGE), amplifying RAGE-mediated signaling related to inflammation, metabolic disorders, chronic diseases, and aging. Therefore, downregulation of the AGE-RAGE axis appears to be a promising approach for attenuating disease conditions associated with RAGE-mediated inflammation. Importantly, RAGE is not specific only to AGEs; it can bind multiple ligands, initiating a complex RAGE signaling network that is not fully understood. Maintaining an appropriate balance between various RAGE isoforms with different functions is also crucial. In this context, mild approaches related to lifestyle-such as diet optimization, consuming functional foods, intake of probiotics, and regular moderate physical activity-are valuable due to their beneficial effects and their ability to mildly modulate the fructose-mediated AGE-RAGE axis.

Dihydromyricetin Suppresses Lipopolysaccharide-Induced Intestinal Injury Through Reducing Reactive Oxygen Species Generation and NOD-Like Receptor Pyrin Domain Containing 3 Inflammasome Activation.

As an integral component of the gram-negative bacterial cellular envelope, excess production of lipopolysaccharide (LPS) regularly precipitates causing intestinal damage and barrier dysfunction in avian species. Dihydromyricetin (DHM), a naturally occurring constituent in rattan tea, exhibits protective characteristics against various tissue injuries. However, the intervention mechanism of DHM on intestinal injury induced by LPS in chickens has not been determined. Consequently, this study aimed to elucidate the mechanisms through which DHM mitigates LPS-induced intestinal damage in chickens through the reactive oxygen species (ROS)-NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome. Primary intestinal epithelial cells (IECs) were isolated and cultured from 14-day-old specific pathogen free (SPF) chicken embryos, and DHM ranging from 20 to 320 μmol/L increased cell survival rates. Additionally, DHM at 20 and 40 μmol/L demonstrated reduction in oxidative stress and ROS accumulation, mirroring the impact of ROS inhibitor (2.5 mmol/L NAC). DHM efficiently regulated ROS production, thereby augmenting ZO-1, occludin and claudin-1 expression to enhance barrier function; upregulating bcl-2 expression and downregulating bax and caspase-3 expression to regulate apoptosis and suppressing inflammation in IECs. Suppression of ROS subsequently attenuates NLRP3 inflammasome activation, leading to a remarkable downregulation of IL-1β, IL-18 and lactate dehydrogenase (LDH) secretion, consistent with direct inactivation of NLRP3 inflammasome (10 μmol/L MCC950). Notably, DHM diminished IL-1β and IL-18 levels and LDH activity via suppression of ROS-regulated NLRP3 and caspase-1 expression and activation. In summary, DHM prevents LPS-induced intestinal impairment by modulating ROS generation and NLRP3 inflammasome activation.

Nitric oxide fumigation maintains cantaloupe fruit quality by regulating the production of reactive oxygen species

Cantaloupe (Cucumis melo L.) is a major crop cultivated in Northwest China. However, with the extension of storage periods, cantaloupes are increasingly prone to post-ripening senescence, quality deterioration, rot, and other phenomena, which in turn seriously limit shelf life. During postharvest storage, the quality of cantaloupes is affected by a large increase in ROS in the fruit. Herein, the effects of exogenous NO fumigation treatment on the quality of Xizhoumi NO.17 cantaloupe were investigated, with a focus on ROS generation and removal. NO fumigation treatment effectively reduced the rate of cantaloupe decay, inhibited fruit water loss and better maintained fruit firmness and relative conductivity. NO treatment induced O2·– and H2O2 production during early storage (within 24 h), whereas their accumulation decreased during later storage. NOX activity and expression of related genes in the treatment group were higher than those in the control group during the early storage but lower during later storage. NO fumigation also induced the antioxidant capacity of enzymatic and non-enzymatic systems in cantaloupe and helped to inhibit the accumulation of ROS. Taken together, NO fumigation triggers H2O2 production via the NOX/SOD system, activating the antioxidant response of cantaloupe to overcome excessive ROS production in the late stage of storage, thus maintaining fruit quality.

Potential role of bacterial extracellular vesicles in the pathophysiology of systemic lupus erythematosus

Systemic Lupus Erythematosus (SLE) is a rare autoimmune disorder influenced by various factors, including infections. Following bacterial or viral infections, there is an increase in IFN-I production, primarily by plasmacytoid dendritic cells (pDCs). Overproduction of IFN-I has been shown to drive the progression of SLE. Recent findings indicate that the gene expression signature of IFN-I in lupus nephritis patients does not co-occur with pDCs as expected; instead, it is localized in glomerular regions with anastomosing capillaries, suggesting a potential source from the blood. T cells, natural killer cells, and myeloid lineage cells may also secrete IFN in the bloodstream. Bacterial presence in the bloodstream challenges the concept of blood sterility, raising the possibility that cell-free microbial components, such as bacterial extracellular vesicles (BEVs), could trigger excessive IFN production through systemic circulation. While existing studies suggest a role for BEVs in human SLE, experimental evidence has yet to establish a direct association between the entire BEV nanoparticle and the disease. Research has primarily focused on (1) mammalian EVs and (2) purified eDNA and other specific cargoes as contributors to SLE progression. It remains unproven whether these bacterial molecules exert their effects while associated with vesicular membranes, i.e., BEVs. We hypothesize that BEVs, which carry diverse cargoes including nucleic acids, may enter systemic circulation, induce cellular responses leading to IFN overproduction, and exacerbate SLE severity. Clinical studies could investigate the association of BEVs with SLE progression by monitoring their presence and quantity in blood samples and correlating these factors with disease outcomes. Furthermore, understanding the involvement of BEVs may aid in identifying SLE biomarkers, inform infection prevention strategies, and inspire the development of BEV-neutralizing agents.

Chitosan/siRNA nanoparticles targeting PARP-1 attenuate Neuroinflammation and apoptosis in hyperglycemia-induced oxidative stress in Neuro2a cells

Hyperglycemia induces an excessive production of superoxide by the mitochondria's electron-transport chain triggers several pathways of injury contributing to the development of diabetic complications. This increase in oxidative and nitrosative stress triggers the activation of PARP-1, a nuclear enzyme, through mechanisms such as DNA damage. siRNA-chitosan nanoparticles were formed based on electrostatic interaction, their particle size, zeta potential, STEM, and cellular uptake were characterized. Neuro2a cells were treated with low glucose (LG) and high glucose (HG) for 24 and 48 h. Neuro2a cells were pre-treated with negative siRNA, naked siRNA, siRNA-Lipofectamine™300, and ChNPs-5. qRT-PCR was used to analyze the expression of regulatory, inflammatory, and apoptotic biomarkers. The siRNA-chitosan complex at the weight ratio 1:3000 were approximately uniform spheres with particle size 150.5 nm and a positive zeta potential of about +41.5 mV. The uptake of FITC-labeled nanoparticles into Neuro2a cells was visualized using fluorescence microscopy with no significant cytotoxicity compared to the control cells. High glucose stimulation of Neuro2a cells increased PARP1 expression, and with siRNA-ChNP (1:3000) treatment, significant inhibition of PARP1 expression is observed that consequently reversed the expression of regulatory genes like SIRT1, FOXO1, FOXO3, and p53. PARP-1 inhibition reduced HG-induced inflammatory response, including NF-kB, IL6, IL1β, TNFα, iNOS, and TGF-β expression, and HG-induced apoptosis response, such as Cas-3, Cas-9, BAK, BAX, and AIF expression. This study highlights the crucial role of siRNA delivery via ChNPs and PARP-1 inhibition in hyperglycemia-induced oxidative stress in Neuro2a cells and PARP-1 inhibition may be a feasible strategy for the treatment of hyperglycemia-induced oxidative stress.

An overview of the relationship between inflammation and cognitive function in humans, molecular pathways and the impact of nutraceuticals

Inflammation has been associated with cognitive decline, whether in the peripheral or central nervous systems. The primary mechanism involves the response of microglia, an immune cell in the brain, which generates pro-inflammatory mediators such as cytokines, chemokines, and adhesion molecules. The excessive production of pro-inflammatory mediators may accelerate the damage to neurons, contributing to the development of neurodegenerative diseases such as Alzheimer’s disease, mild cognitive impairment, and vascular dementia, as well as a general decline in cognitive function. Various studies have supported the correlation between elevated pro-inflammatory mediators and a decline in cognitive function, particularly in aging and age-related neurodegenerative diseases. Moreover, this association has also been observed in other inflammatory-related conditions, including post-operative cognitive impairment, diabetes, stroke, obesity, and cancer. However, the interaction between inflammatory processes and cognitive function in humans remains unclear and varies according to different health conditions. Therefore, this review aims to consolidate and evaluate the available evidence from original studies as well as meta-analyses in order to provide a greater understanding of the inflammatory process in connection with cognitive function in humans. Furthermore, relevant biological cellular processes, putative inflammatory biomarkers, and the role of nutraceuticals on the interaction between cognitive performance and inflammatory status are outlined.

Automatic kidney disease prediction using deep learning techniques

The kidneys play an energetic role in eliminating excess products and fluids from the body, by a complex mechanism which is crucial for upholding a stable balance of body chemicals. Chronic kidney disease (CKD) is considered by an unhurried weakening in renal function that may eventually result in kidney injury or failure. The difficulty of diagnosing the illness rises as it worsens. However, using data from normal medical visits to evaluate the various phases of CKD could help with early detection and prompt care. Researchers suggest a classification strategy for CKD along with optimization strategies used in the learning process. The incorporation of artificial intelligence offers promise because it may often astonish with its skills and enable seemingly difficult undertakings. Modern machine learning techniques have been developed to detect renal illness in light of this. In the current study, a new deep learning model for CKD initial recognition and prediction is introduced. The main objective of the project is to build a strong deep neural network (DNN) and estimate its result outcomes in comparison to other leading-edge machine learning techniques. The outcomes demonstrate that the proposed strategy outperforms current approaches and has promise as a useful tool for CKD detection.

Manganese nanosheets loaded with selenium and gemcitabine activate the tumor microenvironment to enhance anti-tumor immunity

Breast cancer is among the most common malignant tumors globally. Despite advances in immunotherapy and targeted therapies, chemotherapy remains the primary clinical treatment. Gemcitabine, a cytosine nucleoside analog, is widely used for various solid tumors; however, its effectiveness is often limited by drug resistance and adverse side effects. In this study, we developed a novel drug delivery system, Mn/Se-Gem, designed to target tumor cells overexpressing CD44 and facilitate the controlled release of gemcitabine. This system exploits gemcitabine’s pH sensitivity and HA-mediated CD44 targeting to induce DNA damage. Simultaneously, it neutralizes the acidic tumor microenvironment and releases nano-selenium and manganese ions, which promote the excessive production of reactive oxygen species (ROS), leading to mitochondrial damage and enhanced apoptosis of cancer cells. Furthermore, Mn (II) activates the cGAS-STING pathway, increasing susceptibility to ROS-induced DNA double-strand breaks, promoting macrophage maturation, inhibiting M2 polarization, and enhancing the cytotoxic function of T lymphocytes against tumor cells. In summary, this combination of chemotherapy and immunotherapy presents a promising strategy for the treatment of breast cancer.

PTPN22 and the pathogenesis of ulcerative colitis: Insights into T cell differentiation and the JAK/STAT signaling pathway

70 % of the ulcerative colitis (UC) linked gene loci are associated with other autoimmune or immunodeficient diseases. The phosphatase activity of PTPN22 can regulate the development of T cells and contribute to regulate the level of inflammation in autoimmune diseases. We produced PTPN22-CS thymus-specific transgenic mice, which suppressed PTPN22 enzyme activity in the thymocytes. Overexpressed PTPN22-CS facilitated the development of the thymocytes towards CD4+T cells and resulted in an increased proportion of the Th1 and Treg cells in the UC mesenteric lymph nodes. PTPN22-CS promoted the activation of the JAK/STAT signaling pathway in the Th1 and Treg cells that localized in the colon, resulting in an excessive production of inflammatory mediators such as IL-2 and IFN-γ. Consequently, PTPN22-CS contributes to the inflammatory response of ulcerative colitis. In summary, the tyrosine phosphatase activity of PTPN22 plays a role in modulating UC by regulating T cell differentiation and modulating the JAK/STAT signaling pathway, thereby influencing the inflammatory response in colonic. These findings provide new insight into the association between PTPN22 and the pathogenesis of UC.