Mesenchymal stem cells-extracellular vesicles alleviate pulmonary fibrosis by regulating immunomodulators

BACKGROUND Pulmonary fibrosis(PF)is a chronic interstitial lung disease characterized by fibroblast proliferation and extracellular matrix formation,causing structural damage and lung failure.Stem cell therapy and mesenchymal stem cells-extracellular vesicles(MSC-EVs)offer new hope for PF treatment.AIM To investigate the therapeutic potential of MSC-EVs in alleviating fibrosis,oxidative stress,and immune inflammation in A549 cells and bleomycin(BLM)-induced mouse model.METHODS The effect of MSC-EVs on A549 cells was assessed by fibrosis markers[collagen I andα-smooth muscle actin(α-SMA),oxidative stress regulators[nuclear factor E2-related factor 2(Nrf2)and heme oxygenase-1(HO-1),and inflammatory regu-lators[nuclear factor-kappaB(NF-κB)p65,interleukin(IL)-1β,and IL-2].Similarly,they were assessed in the lungs of mice where PF was induced by BLM after MSC-EV transfection.MSC-EVs ion PF mice were detected by pathological staining and western blot.Single-cell RNA sequencing was performed to investigate the effects of the MSC-EVs on gene expression profiles of macrophages after modeling in mice.RESULTS Transforming growth factor(TGF)-β1 enhanced fibrosis in A549 cells,significantly increasing collagen I andα-SMA levels.Notably,treatment with MSC-EVs demonstrated a remarkable alleviation of these effects.Similarly,the expression of oxidative stress regulators,such as Nrf2 and HO-1,along with inflammatory regulators,including NF-κB p65 and IL-1β,were mitigated by MSC-EV treatment.Furthermore,in a parallel manner,MSC-EVs exhibited a downregulatory impact on collagen deposition,oxidative stress injuries,and inflammatory-related cytokines in the lungs of mice with PF.Additionally,the mRNA sequencing results suggested that BLM may induce PF in mice by upregulating pulmonary collagen fiber deposition and triggering an immune inflammatory response.The findings collectively highlight the potential therapeutic efficacy of MSC-EVs in ameliorating fibrotic processes,oxidative stress,and inflammatory responses associated with PF.CONCLUSION MSC-EVs could ameliorate fibrosis in vitro and in vivo by downregulating collagen deposition,oxidative stress,and immune-inflammatory responses.

The effect of Jiangan Xiaozhi Formula on oxidative stress and inflammatory factors in patients with non-alcoholic fatty liver disease

Objective:To investigate the effects of Jiangan Xiaozhi Formula(JGXZ)on oxidative stress and inflammatory factors in patients with non-alcoholic fatty liver disease(NAFLD).Methods:Between September 2022 and December 2023,our hospital admitted a total of 58 patients with NAFLD.These patients were split into two groups at random:one for experimentation and the other for control.There were 27 patients in the experimental group at the end,compared to 26 in the control group,reasonable exercise,weight management,lipid regulation,and oral polyene phosphatidylcholine capsules(PPC).The experimental group received JGXZ in addition to the above treatments for 12 consecutive weeks.Changes in Traditional Chinese Medicine(TCM)syndrome scores,blood lipids,liver function indicators,the levels of oxidative stress markers,such as malondialdehyde(MDA),glutathione peroxidase(GSH-Px),and superoxide dismutase(SOD),as well as serum inflammatory factors,such as interleukin-6(IL-6),interleukin-8(IL-8),and tumor necrosis factor-α(TNF-α),were measured both before and after treatment.Results:After treatment,both groups showed significant reductions in TCM syndrome scores(P<0.05)and improvements in blood lipids,liver function indicators,inflammatory factors,and oxidative stress markers(P<0.05).Improvements were noticeably better in the experimental group than in the control group.(P<0.05).Conclusion:JGXZ can significantly improve clinical symptoms,regulate blood lipids,and protect liver function in patients with NAFLD.Its mechanism may be related to inhibiting inflammatory responses and regulating the balance of the oxidation-antioxidation system.

Effects of Environmental Cadmium on Cadmium Accumulation, Oxidative Response, and Microelements Regulation in the Liver and Kidney of Hexagrammos otakii

The effects of cadmium(Cd)on metal accumulation,microelements contents,and antioxidant responses in Hexagram-mos otakii were studied.The fish were exposed to 0.2,2.5,or 10μg L−1 Cd for 12 or 24 days.Then,the concentration of Cd and mi-croelements(Ca,Fe,Zn,and Se)were determined in the liver and kidney.Moreover,the activities of antioxidant enzymes including superoxide dismutase(SOD),catalase(CAT),and glutathione-S-transferase(GST),and the content of malondialdehyde(MDA)in the liver and kidney were also measured.A continuous accumulation of Cd was observed throughout the experimental period.Cd accumulation was higher in liver than that in the kidney,while Ca and Fe contents were lower in liver than those in the kidney.Cd exposure resulted in a decrease of Ca and Fe concentrations in the kidney,while there was no effect on the liver.Zn and Se remained unaffected with exposure to Cd.Cd exposure induced severe oxidative stress in H.otakii,as indicated by significant induction of the activities of SOD,CAT,and GST,and a simultaneous increase of MDA content.These data show that antioxidant enzymes and mi-croelements contents can be used as potential biomarkers to monitor environmental health in fish.

Impact of the amount of PEG on prodrug nanoassemblies for efficient cancer therapy

PEGylation has been widely used to improve the pharmacokinetic properties of prodrug self-assembled nanoparticles(prodrug-SANPs).However,the impacts of the amount of PEG on the self-assemble stability,cellular uptake,pharmacokinetics,and antitumor efficacy of prodrug-SANPs are still unknown.Herein,selenoether bond bridged docetaxel dimeric prodrug was synthesized as the model prodrug.Five prodrug-SANPs were designed by using different mass ratios of prodrugs to PEG(W_(prodrug)/W_(DSPE-mPEG2000)=10:0,9:1,8:2,7:3 and 6:4),and defined as Pure drug NPs,9:1NPs,8:2NPs,7:3 NPs and 6:4 NPs,respectively.Interestingly,8:2 NPs formed the most compact nanostructure,thus improving the self-assemble stability and pharmacokinetics behavior.In addition,the difference of these prodrug-SANPs in cellular uptake was investigated,and the influence of PEG on cytotoxicity and antitumor efficacy was also clarified in details.The 8:2 NPs exhibited much better antitumor efficacy than other prodrug-SANPs and even commercial product.Our findings demonstrated the pivotal role of the amount of PEG on prodrug-SANPs.

Biochemistry of mammalian ferritins in the regulation of cellular iron homeostasis and oxidative responses

Ferritin,an iron-storage protein,regulates cellular iron metabolism and oxidative stress.The ferritin structure is characterized as a spherical cage,inside which large amounts of iron are deposited in a safe,compact and bioavailable form.All ferritins readily catalyze Fe(II)oxidation by peroxides at the ferroxidase center to prevent free Fe(II)from participating in oxygen free radical formation via Fenton chemistry.Thus,ferritin is generally recognized as a cytoprotective stratagem against intracellular oxidative damage.The expression of cytosolic ferritins is usually regulated by iron status and oxidative stress at both the transcriptional and post-transcriptional levels.The mechanism of ferritin-mediated iron recycling is far from clarified,though nuclear receptor co-activator 4(NCOA4)was recently identified as a cargo receptor for ferritin-based lysosomal degradation.Cytosolic ferritins are heteropolymers assembled by H-and L-chains in different proportions.The mitochondrial ferritins are homopolymers and distributed in restricted tissues.They play protective roles in mitochondria where heme-and Fe/S-enzymes are synthesized and high levels of ROS are produced.Genetic ferritin disorders are mainly related to the L-chain mutations,which generally cause severe movement diseases.This review is focused on the biochemistry and function of mammalian intracellular ferritin as the major iron-storage and anti-oxidation protein.

Reproductive toxicity of enrofloxacin in Caenorhabditis elegans involves oxidative stress-induced cell apoptosis

Fluoroquinolone antibiotics(FQs)that persist and bioaccumulate in the environment have aroused people’s great concern.Here,we studied the adverse effects of FQs in soil animals of Caenorhabditis elegans via food-chronically exposure.The result shows C.elegans exposed to FQs exhibited reproductive toxicity with small-brood size and low-egg hatchability.To study the underlying mechanism,we conduct a deep investigation of enrofloxacin(ENR),one of the most frequently detected FQs,on nematodes which is one of commonly used animal indicator of soil sustainability.The concentration-effect curves simulated by the Hill model showed that the half effect concentrations(EC50)of ENR were(494.3±272.9)μmol/kg and(107.4±30.9)μmol/kg for the brood size and the hatchability,respectively.Differential gene expression between the control and the ENR-exposure group enriched with the oxidative stress and cell apoptosis pathways.The results together with the enzyme activity in oxidative stress and the cell corpses suggested that ENR-induced reproductive toxicity was related to germ cell apoptosis under oxidative stress.The risk quotients of some soil and livestock samples were calculated based on the threshold value of EC10 for the egg hatchability(2.65μmol/kg).The results indicated that there was possible reproductive toxicity on the nematodes in certain agricultural soils for the FQs.This study suggested that chronic exposure to FQs at certain levels in environment would induce reproductive toxicity to the nematodes and might reduce the soil sustainability,alarming the environment risks of antibiotics abuse.

Bio-assembled smart nanocapsules for targeted delivery of KRAS shRNA and cancer cell bioimage

The five-year survival rate for pancreatic cancer is less than 5%. However, the current clinical multimodal therapy combined with first-line chemotherapy drugs only increases the patient’s median survival from 5.0 months to 7.2 months. Consequently, a new strategy of cancer treatments is urgently needed to overcome this high-fatality disease. Through a series of biometric analyses, we found that KRAS is highly expressed in the tumor of pancreatic cancer patients, and this high expression is closely related to the poor prognosis of patients. It shows that inhibiting the expression of KRAS has great potential in gene therapy for pancreatic cancer. Given those above, we have exploited the possibility of targeted delivery of KRAS shRNA with the intelligent and bio-responsive nanomedicine to detect the special oxidative stress microenvironment of cancer cells and realize efficient cancer theranostics. Our observations demonstrate that by designing the smart self-assembled nanocapsules of melanin with fluorescent nanoclusters we can readily achieve the bio-recognition and bioimaging of cancer cells in biological solution or serum.The self-assembled nanocapsules can make a significant bio-response to the oxidative stress microenvironment of cancer cells and generate fluorescent zinc oxide Nanoclusters in situ for targeted cell bioimaging. Moreover, it can also readily facilitate cancer cell suppression through the targeted delivery of KRAS shRNA and low-temperature hyperthermia. This raises the possibility to provide a promising theranostics platform and self-assembled nanomedicine for targeted cancer diagnostics and treatments through special oxidative stress-responsive effects of cancer cells.

Growth inhibition and oxidative damage of Microcystis aeruginosa induced by crude extract of Sagittaria trifolia tubers

Aquatic macrophytes are considered to be promising in controlling harmful cyanobacterial blooms. In this research, an aqueous extract of Sagittaria trifolia tubers was prepared to study its inhibitory effect on Microcystis aeruginosa in the laboratory. Several physiological indices of M. aeruginosa, in response to the environmental stress, were analyzed. Results showed that S. trifolia tuber aqueous extract significantly inhibited the growth of M. aeruginosa in a concentration-dependent way. The highest inhibition rate reached 90% after 6 day treatment. The Chlorophyll-a concentration of M. aeruginosa cells decreased from 343.1 to314.2 μg/L in the treatment group. The activities of superoxide dismutase and peroxidase and the content of reduced glutathione in M. aeruginosa cells initially increased as a response to the oxidative stress posed by S. trifolia tuber aqueous extract, but then decreased as time prolonged. The lipid peroxidation damage of the cyanobacterial cell membranes was reflected by the malondialdehyde level, which was notably higher in the treatment group compared with the controls. It was concluded that the oxidative damage of M. aeruginosa induced by S.trifolia tuber aqueous extract might be one of the mechanisms for the inhibitory effects.

Surviving the odds: From perception to survival of fungal phytopathogens under host-generated oxidative burst

Fungal phytopathogens pose a serious threat to global crop production.Only a handful of strategies are available to combat these fungal infections,and the increasing incidence of fungicide resistance is making the situation worse.Hence,the molecular understanding of plant–fungus interactions remains a primary focus of plant pathology.One of the hallmarks of host–pathogen interactions is the overproduction of reactive oxygen species(ROS)as a plant defense mechanism,collectively termed the oxidative burst.In general,high accumulation of ROS restricts the growth of pathogenic organisms by causing localized cell death around the site of infection.To survive the oxidative burst and achieve successful host colonization,fungal phytopathogens employ intricate mechanisms for ROS perception,ROS neutralization,and protection from ROS-mediated damage.Together,these countermeasures maintain the physiological redox homeostasis that is essential for cell viability.In addition to intracellular antioxidant systems,phytopathogenic fungi also deploy interesting effector-mediated mechanisms for extracellular ROS modulation.This aspect of plant–pathogen interactions is significantly under-studied and provides enormous scope for future research.These adaptive responses,broadly categorized into“escape”and“exploitation”mechanisms,are poorly understood.In this review,we discuss the oxidative stress response of filamentous fungi,their perception signaling,and recent insights that provide a comprehensive understanding of the distinct survival mechanisms of fungal pathogens in response to the host-generated oxidative burst.

Pregnane X receptor in drug-induced liver injury: Friend or foe?

The pregnane X receptor(PXR)is a ligand activated nuclear receptor that is highly expressed in the liver and regulates many cellular functions including drug metabolism,endobiotic metabolism,oxidative stress response,apoptosis,inflammation,cell proliferation and regeneration.PXR activation promotes drug-induced liver injury(DILI)through its ability to increase the expression of phaseⅠand phaseⅡdrug metabolizing enzymes.The PXR also increases lipid synthesis and fatty acid uptake into the liver,leading to lipid accumulation and steatosis.In recent years,PXR has been explored as an important target in DILI and liver diseases.This review will highlight the roles of PXR in modulating DILI.PXR polymorphisms that have been associated with DILI will also be discussed.