Polystyrene microplastics induce myocardial inflammation and cell death via the TLR4/NF-κB pathway in carp.

Microplastics (MPs) have attracted widespread attention as an emerging environmental pollutant. Especially in aquatic ecosystems, the harm of MPs to aquatic animals has increasingly become a severe environmental problem. In this study, we constructed a carp polystyrene microplastics (PS-MPs) exposure model to explore the damage and mechanism of PS-MPs exposure to carp myocardial tissue. The results of H&E, TUNEL, and AO/EB staining showed that PS-MPs exposure could induce inflammation, apoptosis, and necrosis in carp myocardial tissue and cardiomyocytes. In addition, our study explored the targeting relationship between PS-MPs and TLR4 and found that PS-MPs exposure could significantly increase the expression of TLR4 pathway-related factors. As the concentration of PS-MPs increased, the NF-κB pathway and inflammation-related factors increased dose-dependent. In addition, myocardial injury induced by exposure to PS-MPs was predominantly apoptotic, accompanied by necrosis. In short, our data suggest that PS-MPs cause damage to myocardial tissue via the TLR4\NF-κB pathway. The above findings enrich the theory of toxicological studies on PS-MPs and provide an essential reference for aquaculture.

Polyethylene microplastics trigger cell apoptosis and inflammation via inducing oxidative stress and activation of the NLRP3 inflammasome in carp gills.

Microplastics cause varying degrees of damage to aquatic organisms. Exposure to microplastics contaminated water, the gills are among the first tissues, after the skin, to be affected by microplastics. As an essential immune organ, prolonged stimulation by microplastics disrupts immune function not only in the gills but throughout the body, yet the underlying mechanisms remain elusive. A model of gill injury from exposure to polyethylene (PE) microplastics was developed in this study. H&E staining revealed that polyethylene microplastics caused gill inflammation, vascular remodeling, and mucous cell proliferation. An increase in collagen indicates severe tissue damage. Additional analysis showed that polyethylene microplastics profoundly exacerbated oxidative stress in the gills. TUNEL assay demonstrated cell apoptosis induced by polyethylene microplastic. The mRNA levels were subsequently quantified using RT-PCR. The results showed that polyethylene microplastics increased the expression of the nuclear factor-κB (NF-κB) pathway (NF-κB p65, IKKα, IKKß) and apoptosis biomarkers (p53, caspase-3, caspase-9, and Bax). Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasomes, which is an influential component of innate immunity, were overactive. What's more, the pro-inflammatory factors (TNF-α, IFN-γ, IL-2, IL-6, IL-8, IL-1ß) that induce immune disorder also increased significantly, while the anti-inflammatory factors (IL-4, IL-10) decreased significantly. These results suggested that oxidative stress acted as an activation signal of apoptosis triggered by the NF-κB pathway and activating the NLRP3 inflammasome to promote inflammatory immune responses. The present study provided a different target for the prevention of toxin-induced gill injury under polyethylene microplastics.

Lithium intoxication induced pyroptosis via ROS/NF-κB/NLRP3 inflammasome regulatory networks in kidney of mice.

Humans and animals may be exposed to increasing contaminant lithium (Li) concentrations in the environment with the use and disposal of Li-containing products. Meanwhile, Li plays a key role in the treatment of human mental disorders, while the excessive accumulation of Li salts in the body can cause renal damage and nephrotic syndrome. In this study, the mechanism of renal inflammatory reaction induced by Li excessive intake was studied by establishing mice models in vitro and in vivo. The results of histopathology staining and TdT-mediated dUTP nick-end labeling assay showed that high Li condition (Lithium carbonate, 20 mg/kg/twice a day, i.e., for 30 consecutive days) caused inflammatory damage and apoptosis in kidney tissue cells. Western blot, qPCR, and immunohistochemical analysis were used to further study. In the vivo experiments, we found that Li reduced antioxidant enzyme capacity (glutathione peroxidase, total superoxide dismutase, total antioxidant capacity, and catalase) and induced the production of reactive oxygen species (ROS). Moreover, excessive Li activated nuclear factor kappa-B (NF-κB) signaling pathway and nucleotide-binding oligomerization domain-like receptors domains-containing protein 3 (NLRP3) inflammasome, resulting in activation of inflammatory factors tumor necrosis factor-α and IL-1ß in the kidney of mice. In the vitro study, ROS as an upstream signal phosphorylated IκBα and NF-κB, up-regulated the NLRP3 inflammasome, increased caspase3, 6, 7, and 9 to exaggerate inflammation response, finally inducing pyroptosis in renal cells.

Complex Coacervation in Asymmetric Solutions of Polycation and Polyanion.

We study coacervation upon mixing two aqueous solutions of polyelectrolytes (PEs) with opposite charge, by considering asymmetric effects of PE composition and charge valency. The phase behavior, interfacial structure, and coacervate composition are investigated by a classical density-functional theory. We find two types of coacervation that are different in their density. Supernatant phase in low-density coacervation (LDCA) fully consists of small ions, while in high-density coacervation (HDCA) it contains a considerable amount of PE chains. Asymmetric PE composition could generate an electric double layer at the interface of coacervate. For HDCA, ion density changes monotonically, while for LDCA it shows a global minimum at the double layer, giving a low tension value. Charged species of high charge valency enhance the existence of double layer. Our results explained the coacervate structure of low interfacial tension, which is important for experiments and industrial applications.

Uncovering the Therapeutic Potential of Phosphocreatine in Diabetic Retinopathy: Mitigating Mitochondrial Dysfunction and Apoptosis via JAK2/STAT3 Signaling Pathway.

Diabetic retinopathy (DR) stands as a prevalent complication of diabetes mellitus, causing damage to the delicate retinal capillaries and potentially leading to visual impairment. While the exact underlying cause of DR remains elusive, compelling research suggests that mitochondrial energy deficiency and the excessive generation of reactive oxygen species (ROS) play pivotal roles in its pathogenesis. Recognizing that controlling hyperglycemia alone fails to reverse the defects in retinal mitochondria induced by diabetes, current strategies seek to restore mitochondrial function as a means of safeguarding against DR. To address this pressing issue, a comprehensive study was undertaken to explore the potential of phosphocreatine (PCr) in bolstering mitochondrial bioenergetics and providing protection against DR via modulation of the JAK2/STAT3 signaling pathway. Employing rat mitochondria and RGC-5 cells, the investigation meticulously assessed the impact of PCr on ROS production, mitochondrial membrane potential, as well as the expression of crucial apoptotic and JAK2/STAT3 signaling pathway proteins, utilizing cutting-edge techniques such as high-resolution respirometry and western blotting. The remarkable outcomes revealed that PCr exerts a profound protective influence against DR by enhancing mitochondrial function and alleviating diabetes-associated symptoms and biochemical markers. Notably, PCr administration resulted in an upregulation of antiapoptotic proteins, concomitant with a downregulation of proapoptotic proteins and the JAK2/STAT3 signaling pathway. These significant findings firmly establish PCr as a potential therapeutic avenue for combating diabetic retinopathy. By augmenting mitochondrial function and exerting antiapoptotic effects via the JAK2/STAT3 signaling pathway, PCr demonstrates promising efficacy both in vivo and in vitro, particularly in counteracting the oxidative stress engendered by hyperglycemia. In summary, our study sheds light on the potential of PCr as an innovative therapeutic strategy for diabetic retinopathy. By bolstering mitochondrial function and exerting protective effects via the modulation of the JAK2/STAT3 signaling pathway, PCr holds immense promise in ameliorating the impact of DR in the face of oxidative stress induced by hyperglycemia.

TBBPA induces inflammation, apoptosis, and necrosis of skeletal muscle in mice through the ROS/Nrf2/TNF-α signaling pathway.

Tetrabromobisphenol A (TBBPA) is present in large quantities in the environment due to its widespread use. And TBBPA is capable of accumulating in animals, entering the ecological chain and causing widespread damage to organisms. TBBPA is capable of causing the onset of oxidative stress, which induces tissue damage and cell death, which in turn affects the physiological function of tissues. Skeletal muscle is a critical tissue for maintaining growth, movement, and health in the body. However, the mechanism of TBBPA-induced skeletal muscle injury remains unclear. In this study, we constructed mouse skeletal muscle models (10, 20, and 40 mg/kg TBBPA) and mouse myoblasts (C2C12) cell models (2,4, and 8 µg/L TBBPA) at different concentrations. The results of this experiment showed that under TBBPA treatment, the levels of reactive oxygen species (ROS) and Malondialdehyde (MDA) in mouse skeletal and C2C12 cells were increased significantly, but the activities of some antioxidant enzymes decreased. TBBPA can inhibit Nuclear factor E2-related factor 2 (Nrf2) entry into the nucleus, thus affecting the expression of the Nrf2 downstream factors. With the increase of TBBPA concentration, the expression levels of inflammatory factors were significantly increased, while the anti-apoptotic factors were significantly decreased. The expression of pro-apoptotic factors increased in a dose-dependent manner. Programmed necrosis-related factors were also significantly elevated. Our results suggest that TBBPA induces oxidative stress and inflammation, apoptosis, and necrosis in the skeletal muscle of mice by regulating Nrf2/ROS/TNF-α signaling pathway.

Polystyrene microplastics induce endoplasmic reticulum stress, apoptosis and inflammation by disrupting the gut microbiota in carp intestines.

Microplastics have been recognized as a widespread new pollutant in nature and have induced an increase in the occurrence of a variety of diseases in carp. An animal model of microplastic ingestion was successfully established in an aqueous environment. The gut microbiota was analysed using a metagenomic approach. The results showed a significant reduction in the relative abundances of Lactococcus garvieae, Bacteroides_paurosaccharolyticus, and Romboutsia_ilealis after PS-MPs treatment. The 16S Silva database was used to predict and analyse the known genes. Intestinal flora disorders related to infectious diseases, cancers, neurodegenerative diseases, endocrine and metabolic diseases, cardiovascular diseases, and other diseases were found. The intake of PS-MPs resulted in damage to carp intestinal tissue and apoptosis of intestinal epithelial cells. The levels of the inflammatory cytokines IL-1ß, IL-6, and TNF-α were significantly increased with the intake of PS-MPs. The gene and protein levels of GRP78, Caspase-3, Caspase-7, Caspase-9, Caspase-12, PERK, IRE1, and ATF6 were further examined in PS group. The occurrence of ERS and apoptosis in carp intestines was confirmed. These results suggest that the accumulation of PS-MPs in the aquatic environment can disturb the carp gut microbiota and induce ERS, apoptosis, and inflammation in the intestinal tissue.

Selenium Deficiency Leads to Inflammation, Autophagy, Endoplasmic Reticulum Stress, Apoptosis and Contraction Abnormalities via Affecting Intestinal Flora in Intestinal Smooth Muscle of Mice.

Selenium (Se) is a micronutrient that plays a predominant role in various physiological processes in humans and animals. Long-term lack of Se will lead to many metabolic diseases. Studies have found that chronic Se deficiency can cause chronic diarrhea. The gut flora is closely related to the health of the body. Changes in environmental factors can cause changes in the intestinal flora. Our study found that Se deficiency can disrupt intestinal flora. Through 16s high-throughput sequencing analysis of small intestinal contents of mice, we found that compared with CSe group, the abundance of Lactobacillus, Bifidobacterium, and Ileibacterium in the low selenium group was significantly increased, while Romboutsia abundance was significantly decreased. Histological analysis showed that compared with CSe group, the small intestine tissues of the LSe group had obvious pathological changes. We examined mRNA expression levels in the small intestine associated with inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junctions, and smooth muscle contraction. The mRNA levels of NF-κB, IκB, p38, IL-1ß, TNF-α, Beclin, ATG7, ATG5, LC3α, BaK, Pum, Caspase-3, RIP1, RIPK3, PERK, IRE1, elF2α, GRP78, CHOP2, ZO-1, ZO-2, Occludin, E-cadherin, CaM, MLC, MLCK, Rho, and RhoA in the LSe group were significantly increased. The mRNA levels of IL-10, p62 BcL-2 and BcL-w were significantly decreased in the LSe group compared with the CSe group. These results suggest that changes in the abundance of Lactobacillus, bifidobacterium, ileum, and Romboutsia may be associated with cellular inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junction, and abnormal smooth muscle contraction. Intestinal flora may play an important role in chronic diarrhea caused by selenium deficiency.

Enhancement of gemcitabine efficacy by K73-03 via epigenetically regulation of miR-421/SPINK1 in gemcitabine resistant pancreatic cancer cells.

BACKGROUND: Gemcitabine (GCB) is a first-line chemotherapeutic drug for pancreatic cancer (PCa). However, the resistance begins developing within weeks of chemotherapy. SPINK1 overexpression enhances resistance to chemotherapy. In a recent study, our laboratory established that the oleanolic acid (OA) derivative, K73-03, had a strong inhibitory effect on a SPINK1 overexpressed PCa cells. PURPOSE: In our current study, we studied the enhancement of GCB inhibitory effect by K73-03, a new novel OA derivative, alone or in combination with GCB on the GCB-resistant PCa cells by mitochondrial damage through regulation of the miR-421/SPINK1. METHODS: We detected the binding between miR-421 and SPINK1-3'-UTR in GCB-resistant PCa cells using Luciferase reporter assays. Cells viability, apoptosis, migration, and mitochondrial damage were investigated. RESULTS: The results demonstrated that the combination of K73-03 and GCB suppressed the growth of AsPC-1 and MIA PaCa-2 cells synergistically, with or without GCB resistance. Mechanistic findings showed that a combination of K73-03 and GCB silences SPINK1 epigenetically by miR-421 up-regulating, which leads to mitochondrial damage and inducing apoptosis in GCB-resistant PCa cells. CONCLUSION: We found an interesting finding that the 73-03 in combination with GCB can improve GCB efficacy and decrease PCa resistance, which induced apoptosis and mitochondrial damage through epigenetic inhibition of SPINK1 transcription by miR-421 up-regulation. This was the first study that used OA derivatives on GCB-resistant PCa cells, so this combined strategy warrants further investigation.

Near-Critical Phase Behavior in Polyelectrolyte Solutions: Effect of Charge Fluctuations.

The critical behaviors in polyelectrolyte (PE) solutions are studied by a renormalized Gaussian fluctuation theory. PEs are fully charged linear wormlike chains. The electrostatic interactions are considered in a continuum solvent while ignoring other interactions. The effects of temperature on the criticality are explored in a salt-free polyanion solution, and the effects of salt are explored in a symmetric mixed solution of polycation and polyanion. An unphysical phase coexistence (UPPC), in which a metastable dense phase coexists with an unstable dilute phase, always exists in the phase diagram. In the near-critical region, the UPPC could interfere with the real phase coexistence. The classical critical point is replaced by a "critical line", giving a flat top for the phase diagram. These behaviors are due to the effect of charge fluctuation in the near-critical region. Our results explain why the mean field approach overestimates the critical salt density by about 10% to experimental data in the study of coacervation between oppositely charged PEs.

Se Regulates the Contractile Ability of Uterine Smooth Musclevia Selenoprotein N, Selenoprotein T, and Selenoprotein Win Mice.

Selenium (Se) is an essential micronutrient that maintains normal physiological functions in humans and animals. Se plays a vital role in regulating smooth muscle contractions, and selenoprotein N (SelN), selenoprotein T (SelT), and selenoprotein W (SelW) are closely related to the release of Ca2+. The present study analyzed the effects and mechanisms of SelN, SelT, and SelW in uterine smooth muscle contractions in a mouse model fed Se. The mRNA and protein levels in the uterine smooth muscle of mice were detected by qPCR, Western blot, and immunohistochemical analysis. The results showed that Se played an indispensable role in uterine smooth muscle contractions. Increased Se concentration in food increased the release of Ca2+ to a certain extent, causing CaM expression, MLCK expression, and MLC phosphorylation, which can lead to uterine smooth muscle contractions. In contrast, Se deficiency reduced the release of Ca2+ to a certain degree, thereby reducing the contractile ability of uterine smooth muscle. In this study, genes related to SelN, SelT, and SelW expression in uterine smooth muscle cells were investigated. The results showed that the Se concentration had an effect on the expression of SelN, SelT, and SelW in uterine smooth muscle cells. Se influences the release of Ca2+ through SelN, SelT, and SelW, which changes the expression of MLCK and then affects uterine smooth muscle contractions. The three selenoproteins SelN, SelT, and SelW play a very important role in uterine smooth muscle contractions, and the absence of any of these proteins affects the contractility of the uterus.