Intratracheal administration of umbilical cord-derived mesenchymal stem cells attenuates hyperoxia-induced multi-organ injury via heme oxygenase-1 and JAK/STAT pathways

BACKGROUND Bronchopulmonary dysplasia(BPD)is not merely a chronic lung disease,but a systemic condition with multiple organs implications predominantly associated with hyperoxia exposure.Despite advances in current management strategies,limited progress has been made in reducing the BPD-related systemic damage.Meanwhile,although the protective effects of human umbilical cord-derived mesenchymal stem cells(hUC-MSCs)or their exosomes on hyperoxia-induced lung injury have been explored by many researchers,the underlying mechanism has not been addressed in detail,and few studies have focused on the therapeutic effect on systemic multiple organ injury.AIM To investigate whether hUC-MSC intratracheal administration could attenuate hyperoxia-induced lung,heart,and kidney injuries and the underlying regulatory mechanisms.METHODS Neonatal rats were exposed to hyperoxia(80%O_(2)),treated with hUC-MSCs intratracheal(iT)or intraperitoneal(iP)on postnatal day 7,and harvested on postnatal day 21.The tissue sections of the lung,heart,and kidney were analyzed morphometrically.Protein contents of the bronchoalveolar lavage fluid(BALF),myeloper oxidase(MPO)expression,and malondialdehyde(MDA)levels were examined.Pulmonary inflammatory cytokines were measured via enzyme-linked immunosorbent assay.A comparative transcriptomic analysis of differentially expressed genes(DEGs)in lung tissue was conducted via RNA-sequencing.Subsequently,we performed reverse transcription-quantitative polymerase chain reaction and western blot analysis to explore the expression of target mRNA and proteins related to inflammatory and oxidative responses.RESULTS iT hUC-MSCs administration improved pulmonary alveolarization and angiogenesis(P<0.01,P<0.01,P<0.001,and P<0.05 for mean linear intercept,septal counts,vascular medial thickness index,and microvessel density respectively).Meanwhile,treatment with hUC-MSCs iT ameliorated right ventricular hypertrophy(for Fulton’s index,P<0.01),and relieved reduced nephrogenic zone width(P<0.01)and glomerular diameter(P<0.001)in kidneys.Among the beneficial effects,a reduction of BALF protein,MPO,and MDA was observed in hUC-MSCs groups(P<0.01,P<0.001,and P<0.05 respectively).Increased pro-inflammatory cytokines tumor necrosis factor-alpha,interleukin(IL)-1β,and IL-6 expression observed in the hyperoxia group were significantly attenuated by hUC-MSCs administration(P<0.01,P<0.001,and P<0.05 respectively).In addition,we observed an increase in anti-inflammatory cytokine IL-10 expression in rats that received hUC-MSCs iT compared with rats reared in hyperoxia(P<0.05).Transcriptomic analysis showed that the DEGs in lung tissues induced by hyperoxia were enriched in pathways related to inflammatory responses,epithelial cell proliferation,and vasculature development.hUC-MSCs administration blunted these hyperoxia-induced dysregulated genes and resulted in a shift in the gene expression pattern toward the normoxia group.hUC-MSCs increased heme oxygenase-1(HO-1),JAK2,and STAT3 expression,and their phosphorylation in the lung,heart,and kidney(P<0.05).Remarkably,no significant difference was observed between the iT and iP administration.CONCLUSION iT hUC-MSCs administration ameliorates hyperoxia-induced lung,heart,and kidney injuries by activating HO-1 expression and JAK/STAT signaling.The therapeutic benefits of local iT and iP administration are equivalent.

Effects of Siwei Yuganzi decoction on LXRα and CYP7A1 in hyperlipidemic rats

Background:Hyperlipidemia(HLP)is a disorder in which lipids in the blood are disturbed due to abnormal lipid metabolism.Statins and fibrates lipid-regulating drugs prevent the generation of lipids and improves HLP,thereby reducing the likelihood of developing cardiovascular and cerebrovascular diseases.However,their adverse reactions and side effects limit a wide range of clinical applications.Tibetan medicine compound preparation Siwei Yuganzi decoction(SYD)is an adaptation of a classical prescription of the Tibetan medicine Sanguo decoction,that has been proved to have the effect of improving lipid metabolism;however,its possible mechanism remains unknown.Methods:Sixty specific-pathogen free grade Sprague Dawley rats were randomly divided into the blank control group,the HLP group,the Chinese patent medicine Xuezhikang positive control group,and the treatment groups with Tibetan SYD high-,middle-,and low-dosages respectively.Ten rats were assigned to each group.Every rat in these groups was fed with a high-fat emulsion to establish the hyperlipidemic animal model,except for those in the blank control group.Then the rats in the blank control and HLP groups were fed with 0.9%normal saline,those in Xuezhikang group were fed with Xuezhikang suspension at the dose of 0.11 g/kg/d,and those in SYD groups were fed with the SYD suspension at the dosage of 16.2 g/kg/d(high dosage),10.8 g/kg/d(middle dosage),and 5.4 g/kg/d(low dosage),respectively.After 8 weeks,the levels of serum total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C)were detected by the ELISA.The mRNA and protein expression levels of liver X receptorα(LXRα)and cholesterol 7α-hydroxylase 1(CYP7A1)were detected using RT-PCR,western blotting,and immunohistochemistry.Results:The serum levels of TC,TG,and LDL-C in the HLP group were higher than those in the blank control group(P<0.05),whereas the serum levels of HDL-C and the expression levels of both LXRαand CYP7A1 mRNA and proteins in the liver in the HLP group were lower than those in the control group(P<0.05).After the treatment of the Xuezhikang and SYD,the serum levels of TG,TC,and LDL-C significantly decreased(P<0.05),whereas the serum levels of HDL-C and the expression levels of both LXRαand CYP7A1 mRNA and proteins in the liver significantly increased compared with those in the HLP group(P<0.05).Furthermore,The serum levels of TC,TG,and LDL-C in the SYD group at high dosage were lower(P<0.05),the serum level of HDL-C was higher,and the expression levels of both LXRαand CYP7A1 mRNA and proteins in the liver tissue were higher than those in the Xuezhikang group(P<0.05).Conclusion:SYD can improve the serum levels of TC,TG,and LDL-C in the hyperlipidemic animal model via increasing the expression of both LXRαand CYP7A1 mRNA and proteins in the liver tissue.

Deep insight of unique phase transition behaviors and mechanism in Zr_(2)Co-H isotope system with ultra-low equilibrium pressure

Efficient capture,safe storage and release of tritium from the international thermonuclear experimental reactor(ITER) reaction exhaust gas is a perplexing problem,and the development of an efficient tritium-getter material with ultra-low hydrogenation equilibrium pressure is considered as a reliable way.In this work,Zr_(2)Co alloy was selected as a tritium-getter material and prepared through induction levitation melting.Fundamental performance test results show that Zr_(2)Co exhibits an ultra-low hydrogenation equilibrium pressure of 3.22 × 10^(-6) Pa at 25℃ and excellent hydriding kinetics under a low hydrogen pressure of 0.005 MPa.Interestingly,unique phase transition behaviors were presented in Zr_(2)Co-H system.Specifically,Zr_(2)CoH_(5) formed by Zr_(2)Co hydrogenated at room temperature is initially decomposed into ZrH_(2) and ZrCoH_(3) at200 ℃.With the temperature increasing to 350 ℃,ZrCoH_(3)is dehydrogenated to ZrCo,and then ZrCo further reacts with ZrH_(2) at 650 ℃ to reform Zr_(2)Co and hydrogen.Among the staged phase transition pathways during dehydrogenation,the decomposition of Zr_(2)CoH_(5) occurs preferentially,which is well accordance with both the smallest reaction energy barrier and the maximum reaction spontaneity that are determined respectively from kinetics activation energy and thermodynamics Gibbs free energy.Furthermore,first principles calculation results indicate that the stronger binding of hydrogen in interstitial environments of ZrCoH_(3)and ZrH_(2) triggers the hydrogen-stabilized phase transformation of Zr_(2)CoH_(5).The unique phase transition mechanisms in Zr_(2)Co-H system can shed light on the further exploration and regulation of analogous staged phase transition of hydrogen storage materials.

Development of Ti_(0.85)Zr_(0.17)(Cr-Mn-V)_(1.3)Fe_(0.7)-based Laves phase alloys for thermal hydrogen compression at mild operating temperatures

Metal hydride with proper hydrogen storage properties is the key component of hydride thermal hydrogen compressor.In this work,Ti_(0.85)Zr_(0.17)(Cr-Mn-V)_(1.3)Fe_(0.7)-based alloys were developed to achieve thermal hydrogen compression at mild operating temperatures of water bath.The results indicate the single C 14-type Laves phase as well as homogeneously distributed elements of all alloys.With increased Mn content in Ti_(0.85)Zr_(0.17)Cr_(1.2-x)Mn_xFe_(0.7)V_(0.1)(x=0,0.1,0.2,0.3)alloys.

Solvent-controlled regioselective arylation of indoles and mechanistic explorations

The ability to manipulate the site selectivity in C–H bond functionalization reactions is an important goal in modern chemistry.Herein,we report a new reaction strategy for the regioselective arylation of indoles at C2 or C3 positions,achieved by adjusting the solvent and with P(O)^(t) Bu_(2) as an auxiliary group.