Monotropein induces autophagy through activation of the NRF2/PINK axis, thereby alleviating sepsis-induced colonic injury.

Sepsis is a systemic inflammatory disease that is caused by a dysregulated host response to infection and is a life-threatening organ dysfunction that affects many organs, which includes the colon. Mounting evidence suggests that sepsis-induced colonic damage is a major contributor to organ failure and cellular dysfunction. Monotropein (MON) is the major natural compound in the iris glycoside that is extracted from Morendae officinalis radix, which possesses the potent pharmacological activities of anti-inflammatory and antioxidant properties. This research evaluated whether MON is able to alleviate septic colonic injury in mice by cecal ligation and puncture. Colonic tissues were analyzed using histopathology, immunofluorescence, quantitative real-time polymerase chain reaction, and Western blot methods. It was initially discovered that MON reduced colonic damage in infected mice, in addition to inflammation, apoptosis, and oxidative stress in colonic tissues, while it activated autophagy, with the NRF2/keap1 and PINK1/Parkin pathways also being activated. Through the stimulation of NCM460 cells with lipopolysaccharides, an in vitro model of sepsis was created as a means of further elucidating the potential mechanisms of MON. In the in vitro model, it was found that MON could still activate the NRF2/keap1, PINK1/Parkin, and autophagy pathways. However, when MON was paired with the NRF2 inhibitor ML385, it counteracted MON-induced activation of PINK1/Parkin and autophagy, while also promoting inflammatory response and apoptosis in NCM460 cells. Therefore, the data implies that MON could play a therapeutic role through the activation of the NFR2/PINK pathway as a means of inducing autophagy to alleviate the oxidative stress in colonic tissues that is induced by sepsis, which will improve inflammation and apoptosis in colonic tissues.

Gypenoside XLIX attenuates sepsis-induced splenic injury through inhibiting inflammation and oxidative stress.

BACKGROUND: To investigate the effect of Gypenoside XLIX (Gyp-XLIX) on acute splenic injury (ASI) induced by cecal ligation and puncture (CLP) in septic mice, a study was conducted. METHODS: Sixty healthy mice were randomly divided into six groups: the NC group, the Sham group, the Sham + Gyp-XLIX group, the CLP group, the CLP + Gyp-XLIX group, and the CLP + Dexamethasone (DEX) group. The NC group did not undergo any operation, while the rest of the groups underwent CLP to establish the sepsis model. The Sham group only underwent open-abdominal suture surgery without cecum puncture. After the operation, the groups were immediately administered the drug for a total of 5 days. Various methods such as hematoxylin and eosin (HE) staining, biochemical kits, qRT-PCR, and reactive oxygen species (ROS) were used for analysis. RESULTS: The results demonstrated that Gyp-XLIX effectively mitigated the splenic histopathological damage, while reducing the malondialdehyde (MDA) lipid peroxidation index and enhancing the antioxidant activities of catalase (CAT), glutathione (GSH) and total antioxidant capacity (T-AOC). The utilization of Dihydroethidium (DHE) fluorescent probe revealed that Gyp-XLIX inhibited the acute splenic accumulation of ROS induced by CLP in septic mice. Further investigations revealed that Gyp-XLIX exhibited a down-regulatory effect on the protein levels of inflammatory mediators iNOS and COX-2, consequently leading to the suppression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1ß. Additionally, it up-regulated the expression of anti-inflammatory factor IL-10. CONCLUSION: In conclusion, Gyp-XLIX was significantly effective in attenuating CLP-induced acute splenic inflammation and oxidative stress in septic mice.

Quercetin attenuates environmental Avermectin-induced ROS accumulation and alleviates gill damage in carp through activation of the Nrf2 pathway.

Avermectin (AVM) is one of the most often used insecticides which is toxic to aquatic organisms, and cause oxidative-induced damages to the fish respiratory organ, the "gills". To better understand the mechanism by which an antioxidant reduces AVM-induced gill damage, we investigated the effects of Quercetin (Que) on AVM induction of oxidative stress to inhibit damages to the gills using common carp as a model organism. The Que is a fruit and vegetable rich flavonoid with antioxidant activity. In this study, four groups were created: the Control group, the Que group (400 mg/kg), the AVM group (2.404 µg/L), and the Que plus AVM group. The analytical methods were pathological structure examination, qPCR, Reactive Oxygen Species (ROS) and Western blot. The results showed that Que alleviated AVM-induced oxidative stress, inflammatory damage and apoptosis in the carp gills by activating the Nrf2 pathway. The mechanism was that Que alleviated the accumulation of ROS, reduced the balance between oxidation and antioxidant disrupted by AVM exposure, lowered the content of lipid peroxidation produced malondialdehyde (MDA), and increased the content of antioxidant enzymes including glutathione (GSH) and catalase (CAT). Nrf2 pathway was activated. Meanwhile, Que inhibited gill apoptosis in carp by decreasing the levels of Bax, Cytochrome C, Caspase9, Cleaved-Caspase3 and reduced Bcl2. This has important implications for future studies on Que and AVM. New suggestions are provided to reduce the threat of aquatic environmental pollution.

Quercetin attenuates avermectin-induced cardiac injury in carp through inflammation, oxidative stress, apoptosis and autophagy.

As an important antibiotic, avermectin (AVM) has been widely used in China, but its unreasonable application has caused serious harm to the water environment. In view of the various pharmacological effects of quercetin (QUE), such as anti-inflammatory and antioxidant, the scientific hypothesis that "QUE may cause carp poisoning by inhibiting AVM" was proposed in this study. However, its protective effect in AVM -induced heart damage has not been reported. QUE reduced the symptoms of AVM toxicity and decreased the levels of creatine kinase, lactate dehydrogenase, and creatine kinase in the serum of carp. By histological observation, QUE was found to significantly reduce cardiac fiber swelling in carp. A DHE fluorescence probe study showed that QUE was able to inhibit AVM -induced accumulation of reactive oxygen species (ROS) in carp myocardium. We found that QUE significantly increased the intracellular antioxidant enzymes CAT, T-AOC and GSH enzyme activity and reduced intracellular MDA content. In addition, QUE significantly increased il-10 and tgf-ß1 expression, and significantly down-regulated tnf-α, il-6, il-1ß and inos expression. Tunel assay showed that QUE attenuated AVM -induced apoptosis, significantly decreased the transcript levels of pro-apoptosis-related genes, and increased the expression of anti-apoptosis-related genes. We also detected the protein expression of LC3 in the AVM group and QUE + AVM group, and found that the expression of LC3 was significantly increased in both groups compared with the Control group, but after adding QUE, the expression of LC3 was significantly decreased compared with the AVM group. In addition, the transcript levels of p62 and atg5 were also detected by qPCR. QUE significantly increased the expression of p62 and decreased the expression of atg5, suggesting that QUE could attenuate AVM -induced cardiac autophagy in carp. This study will provide preliminary evidence of the principle of QUE attenuating AVM -induced myocardial injury in carp from four aspects, including oxidative stress, inflammatory response, apoptosis and autophagy, and provide a theoretical basis for its prevention and treatment.

Ameliorative Effect of Malvidin on Spleen Injury in LPS-Induced Sepsis.

Sepsis, one of the most destructive diseases in the world, is a syndrome of systemic inflammatory response caused by the invasion of pathogenic microorganisms such as bacteria into the body. Malvidin is one of the most widespread anthocyanins, and its significant antioxidant and anti-inflammatory activities have been widely reported. However, the effect of Malvidin on sepsis and related complications is still unclear. The present study aimed to determine the mechanisms of Malvidin's potential protection from lipopolysaccharide (LPS)-induced spleen injury model of sepsis. In the LPS-induced mouse spleen injury model of sepsis, pretreatment with Malvidin was performed to assess morphological damage in spleen tissue and to detect the expression of mRNA levels of serum necrosis factor α, interleukin 1ß and interleukin 6, and IL-10. Apoptosis was detected using the TUNEL technique, and the levels of oxidative stress-related oxidase and antioxidant enzymes were measured by kit to assess the effect of Malvidin on inflammation and oxidative stress associated with septic spleen injury. The results of this study indicated that Malvidin was be a potentially effective drug for the treatment of sepsis.

Mechanisms regarding respiratory toxicity triggered by accumulation of ROS in carp exposed to difenoconazole.

Difenoconazole is a widely used but difficult-to-degrade fungicide that can directly affect aquatic ecosystems. Here, two doses (0.488 mg/L, 1.953 mg/L) of difenoconazole were used to study the toxicity to the respiratory system of carp at an exposure time of 96 h. The results showed that difenoconazole exposure resulted in severe structural damage to carp gill tissue with extensive inflammatory cell infiltration. Mechanistically, difenoconazole exposure led to excessive accumulation of ROS in carp gill tissue, which induced an inflammatory response in the gill tissue. Meanwhile, the activities of SOD and CAT were reduced and the NRF2 signaling pathway was activated to regulate the imbalance between oxidation and antioxidation. In addition, difenoconazole exposure further activated the mitochondrial pathway of apoptosis by upregulating cytochrome C, BAX, cleaved-caspase 9, and downregulating Bcl-2. More interestingly, exposure to difenoconazole increased autophagosomes, but lysosomal dysfunction prevented the late stages of autophagy from proceeding smoothly, resulting in a protective autophagic response that is not properly initiated. In summary, difenoconazole exposure caused respiratory toxicity including inflammation response, oxidative stress, apoptosis, and autophagy in carp through the accumulation of ROS. The present study expanded our understanding of the toxic effects of difenoconazole on organisms and its possible threat to the aquatic environment.

Liensinine attenuates inflammation and oxidative stress in spleen tissue in an LPS-induced mouse sepsis model. / 莲心碱可减轻LPSè¯±å¯¼çš„å°é¼ è„“æ¯’ç—‡æ¨¡åž‹ä¸­è„¾è„ç»„ç»‡ç‚Žç—‡å’Œæ°§åŒ–åº”æ¿€ååº”.

Sepsis is a complex syndrome caused by multiple pathogens and involves multiple organ failure, particularly spleen dysfunction. In 2017, the worldwide incidence was 48.9 million sepsis cases and 11 million sepsis-related deaths were reported (Rudd et al., 2020). Inflammation, oxidative stress, and apoptosis are the most common pathologies seen in sepsis. Liensinine (LIE) is a bisbenzylisoquinoline-type alkaloid extracted from the seed embryo of Nelumbo nucifera. Lotus seed hearts have high content of LIE which mainly has antihypertensive and antiarrhythmic pharmacological effects. It can exert anti-carcinogenic activity by regulating cell, inflammation, and apoptosis signaling pathways (Manogaran et al., 2019). However, its protective effect from sepsis-induced spleen damage is unknown. In this research, we established a mouse sepsis model induced by lipopolysaccharide (LPS) and investigated the protective effects of LIE on sepsis spleen injury in terms of inflammatory response, oxidative stress, and apoptosis.

Crosstalk of oxidative stress, inflammation, apoptosis, and autophagy under reactive oxygen stress involved in difenoconazole-induced kidney damage in carp.

Difenoconazole is a commonly used triazole fungicide in agricultural production. Because of its slow degradation and easy accumulation in the environment, it seriously endangers both animal health and the ecological environment. Therefore, it is hoped that the effects on carp kidneys can be studied by simulating difenoconazole residues in the environment. The experiment was designed with two doses (0.488 mg/L, 1.953 mg/L) as exposure concentrations of difenoconazole for 4 d. Histopathological results showed that difenoconazole could cause severe damage to the kidney structure and extensive inflammatory cell infiltration in carp. Elevated levels of Creatinine, and BUN suggested the development of kidney damage. The DHE fluorescence probe's result suggested that difenoconazole might cause reactive oxygen species (ROS) to accumulate in the kidney of carp. Difenoconazole was found to increase MDA levels while decreasing the activities of CAT, SOD, and GSH-PX, according to biochemical indicators. In addition, difenoconazole could up-regulate the transcription levels of inflammatory factors tnf-α, il-6, il-1ß, and inos. At the same time, it inhibited the transcription level of il-10 and tgf-ß1. The TUNEL test clearly showed that difenoconazole induced apoptosis in the kidney and vastly raised the transcript levels of apoptosis-related genes p53, caspase9, caspase3, and bax while inhibiting the expression of Bcl-2, fas, capsase8. Additionally, TEM imaging showed that clearly autophagic lysosomes and autophagosomes were formed. Elevated levels of LC3II protein expression, increased transcript levels of the autophagy-related gene atg5 as well as decreased transcript levels of p62 represented the generation of autophagy. In conclusion, the study illustrated that oxidative stress, inflammation, apoptosis, and autophagy all played roles in difenoconazole-induced kidney injury in carp, which was closely linked to ROS production. This work provides a valuable reference for studying the toxicity of difenoconazole to aquatic organisms.