Ischemia-reperfusion injury:molecular mechanisms and therapeutic targets

Ischemia-reperfusion(I/R)injury paradoxically occurs during reperfusion following ischemia,exacerbating the initial tissue damage.The limited understanding of the intricate mechanisms underlying I/R injury hinders the development of effective therapeutic interventions.The Wnt signaling pathway exhibits extensive crosstalk with various other pathways,forming a network system of signaling pathways involved in I/R injury.This review article elucidates the underlying mechanisms involved in Wnt signaling,as well as the complex interplay between Wnt and other pathways,including Notch,phosphatidylinositol 3-kinase/protein kinase B,transforming growth factor-β,nuclear factor kappa,bone morphogenetic protein,N-methyl-D-aspartic acid receptor-Ca2+-Activin A,Hippo-Yes-associated protein,toll-like receptor 4/toll-interleukine-1 receptor domain-containing adapter-inducing interferon-β,and hepatocyte growth factor/mesenchymal-epithelial transition factor.In particular,we delve into their respective contributions to key pathological processes,including apoptosis,the inflammatory response,oxidative stress,extracellular matrix remodeling,angiogenesis,cell hypertrophy,fibrosis,ferroptosis,neurogenesis,and blood-brain barrier damage during I/R injury.Our comprehensive analysis of the mechanisms involved in Wnt signaling during I/R reveals that activation of the canonical Wnt pathway promotes organ recovery,while activation of the non-canonical Wnt pathways exacerbates injury.Moreover,we explore novel therapeutic approaches based on these mechanistic findings,incorporating evidence from animal experiments,current standards,and clinical trials.The objective of this review is to provide deeper insights into the roles of Wnt and its crosstalk signaling pathways in I/R-mediated processes and organ dysfunction,to facilitate the development of innovative therapeutic agents for I/R injury.

Erratum to:CD146 as a promising therapeutic target for retinal and choroidal neovascularization diseases

Erratum to:Sci China Life Sciences,Volume 65,Issue 6:1157-1170(2022),https://doi.org/10.1007/s11427-021-2020-0This paper contains four errors in Figure 4 and Figure 5.In Figure 4C,the image labeled as"1%O_(2)+IgG ctrl"is incorect.This image is another one for 1%O_(2) group.We provide a new image as follows for 1%O_(2)+IgG ctrl group.This new image does not affect the conclusion of this article.

CD146,a therapeutic target involved in cell plasticity

Since its identification as a marker for advanced melanoma in the 1980s,CD146 has been found to have multiple functions in both physiological and pathological processes,including embryonic development,tissue repair and regeneration,tumor progression,fibrosis disease,and inflammations.Subsequent research has revealed that CD146 is involved in various signaling pathways as a receptor or coreceptor in these processes.This correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis,prognosis,and targeted therapy.To better comprehend the versatile roles of CD146,we have summarized its research history and synthesized findings from numerous reports,proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development,regeneration,and various diseases.Targeting CD146 would consequently halt cell state shifting during the onset and progression of these related diseases.Therefore,the development of therapy targeting CD146 holds significant practical value.

Recent advances in drug delivery systems for targeting cancer stem cells

Cancer stem cells(CSCs)are a subpopulation of cancer cells with functions similar to those of normal stem cells.Although few in number,they are capable of self-renewal,unlimited proliferation,and multi-directional differentiation potential.In addition,CSCs have the ability to escape immune surveillance.Thus,they play an important role in the occurrence and development of tumors,and they are closely related to tumor invasion,metastasis,drug resistance,and recurrence after treatment.Therefore,specific targeting of CSCs may improve the efficiency of cancer therapy.A series of corresponding promising therapeutic strategies based on CSC targeting,such as the targeting of CSC niche,CSC signaling pathways,and CSC mitochondria,are currently under development.Given the rapid progression in this field and nanotechnology,drug delivery systems(DDSs)for CSC targeting are increasingly being developed.In this review,we summarize the advances in CSC-targeted DDSs.Furthermore,we highlight the latest developmental trends through the main line of CSC occurrence and development process;some considerations about the rationale,advantages,and limitations of different DDSs for CSCtargeted therapies were discussed.

FXYD6： a novel therapeutic target toward hepatocellular carcinoma

FXYD6, FXYD domain containing ion transport regulator 6, has been reported to affect the activity of Na＋/K＋-ATP- ase and be associated with mental diseases. Here, we demonstrate that FXYD6 is up-regulated in hepatocellular carcinoma （HCC） and enhances the migration and prolif- eration of HCC cells. Up-regulation of FXYD6 not only positively correlates with the increase of Na＋IK＋-ATPase but also coordinates with the activation of its downstream Src-ERK signaling pathway. More importantly, blocking FXYD6 by its functional antibody significantly inhibits the growth potential of the xenografted HCC tumors in mice, indicating that FXYD6 represents a potential therapeutic target toward HCC. Altogether, our results establish a critical role of FXYD6 in HCC progression and suggest that the therapy targeting FXYD6 can benefit the clinical treatment toward HCC patients.

Impaired tumor angiogenesis and VEGF- induced pathway in endothelial CD146 knockout mice

CD146 is a newly identified endothelial biomarker that has been implicated in angiogenesis. Though in vitro angio- genic function of CD146 has been extensively reported, in vivo evidence is still lacking. To address this issue, we generated endothelial-specific CD146 knockout （CD146 EC-Ko） mice using the Tg（Tek-cre） system. Surprisingly, these mice did not exhibit any apparent morphological defects in the development of normal retinal vasculature. To evaluate the role of CD146 in pathological angiogenesis, a xenograft tumor model was used. We found that both tumor volume and vascular density were significantly lower in CD146Ec-KO mice when compared to WT littermates. Additionally, the ability for sprouting, migration and tube formation in response to VEGF treatment was impaired in endothelial cells （ECs）of CD146Ec-Ko mice. Mechanistic studies further confirmed that VEGF- induced VEGFR-2 phosphorylation and AKT/p38 MAPKs/ NF-KB activation were inhibited in these CD146-null ECs, which might present the underlying cause for the observed inhibition of tumor angiogenesis in CD146Ec-Ko mice. These results suggest that CD146 plays a redundant role in physiological angiogenic processes, but becomes essential during pathological angiogenesis as observed in tumorigenesis.

CD146 as a promising therapeutic target for retinal and choroidal neovascularization diseases

Blood vessel dysfunction causes several retinal diseases,including diabetic retinopathy,familial exudative vitreoretinopathy,macular degeneration and choroidal neovascularization in pathological myopia.Vascular endothelial growth factor(VEGF)-neutralizing proteins provide benefits in most of those diseases,yet unsolved haemorrhage and frequent intraocular injections still bothered patients.Here,we identified endothelial CD146 as a new target for retinal diseases.CD146 expression was activated in two ocular pathological angiogenesis models,a laser-induced choroid neovascularization model and an oxygeninduced retinopathy model.The absence of CD146 impaired hypoxia-induced cell migration and angiogenesis both in cell lines and animal model.Preventive or therapeutic treatment with anti-CD146 antibody AA98 significantly inhibited hypoxia-induced aberrant retinal angiogenesis in two retinal disease models.Mechanistically,under hypoxia condition,CD146 was involved in the activation of NFκB,Erk and Akt signalling pathways,which are partially independent of VEGF.Consistently,anti-CD146therapy combined with anti-VEGF therapy showed enhanced impairment effect of hypoxia-induced angiogenesis in vitro and in vivo.Given the critical role of abnormal angiogenesis in retinal and choroidal diseases,our results provide novel insights into combinatorial therapy for neovascular fundus diseases.

Targeting the CD146/Galectin-9 axis protects the integrity of the blood-brain barrier in experimental cerebral malaria

Cerebral malaria(CM)is a life-threatening diffuse encephalopathy caused by Plasmodium falciparum,in which the destruction of the blood–brain barrier(BBB)is the main cause of death.However,increasing evidence has shown that antimalarial drugs,the current treatment for CM,do little to protect against CM-induced BBB damage.Therefore,a means to alleviate BBB dysfunction would be a promising adjuvant therapy for CM.The adhesion molecule CD146 has been reported to be expressed in both endothelial cells and proinflammatory immune cells and mediates neuroinflammation.Here,we demonstrate that CD146 expressed on BBB endothelial cells but not immune cells is a novel therapeutic target in a mouse model of experimental cerebral malaria(eCM).Endothelial CD146 is upregulated during eCM development and facilitates the sequestration of infected red blood cells(RBCs)and/or proinflammatory lymphocytes in CNS blood vessels,thereby promoting the disruption of BBB integrity.Mechanistic studies showed that the interaction of CD146 and Galectin-9 contributes to the aggregation of infected RBCs and lymphocytes.Deletion of endothelial CD146 or treatment with the anti-CD146 antibody AA98 prevents severe signs of eCM,such as limb paralysis,brain vascular leakage,and death.In addition,AA98 combined with the antiparasitic drug artemether improved the cognition and memory of mice with eCM.Taken together,our findings suggest that endothelial CD146 is a novel and promising target in combination with antiparasitic drugs for future CM therapies.

Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel

The extremely low bioavailability of oral paclitaxel(PTX)mainly due to the complicated gastrointestinal environment,the obstruction of intestinal mucus layer and epithelium barrier.Thus,it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously.In this work,a high-density PEGylation-based glycocholic acid-decorated micelles(PTX@GNPs)was constructed by a novel polymer,9-Fluorenylmethoxy carbonyl-poly ethylene glycocholic acid(Fmoc-PEG-GCA).The Fmoc motif in this polymer could encapsulate PTX viaπ-πstacking to form the core of micelles,and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG.Based on this versatile and flexible carriers,PTX@GNPs possess mucus trapping escape ability due to the flexible PEG,and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter.The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX,and exhibited similar antitumor efficacy to Taxol injection via intravenous route.In addition,oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX,which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.

狼疮性肾炎慢性化中肾脏固有细胞的间充质化研究进展

狼疮性肾炎(LN)的肾脏纤维化严重影响系统性红斑狼疮(SLE)患者的预后。肾脏固有细胞间充质化在LN纤维化进展中起关键作用。肾脏固有细胞间充质化早期可促进组织损伤的修复,但也是后期导致病变肾脏进入纤维化的一个关键途径。由于肾脏固有细胞间充质化是一个可逆的过程,所以这为早期抗纤维化治疗提供一个宝贵的时间窗。本文对LN中肾脏固有细胞间充质化的最新研究进展予以综述。

A subpopulation of CD146^(+) macrophages enhances antitumor immunity by activating the NLRP3 inflammasome

As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146+ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146+ TAMs. These data reveal a crucial antitumor role of CD146+ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.

A novel domain-duplicated SlitFAR3 gene involved in sex pheromone biosynthesis in Spodoptera litura

Fatty acyl reductases(FARs)are key enzymes that participate in sex pheromone biosynthesis by reducing fatty acids to fatty alcohols.Lepidoptera typically harbor numerous FAR gene family members.Although FAR genes are involved in the biosynthesis of sex pheromones in moths,the key FAR gene of Spodoptera litura remains unclear.In this work,we predicted 30 FAR genes from the S.litura genome and identified a domain duplication within gene SlitFAR3,which exhibited high and preferential expression in the sexually mature female pheromone glands(PGs)and a rhythmic expression pattern during the scotophase of sex pheromone production.The molecular docking of SlitFAR3,as predicted using a 3D model,revealed a co-factor NADPH binding cavity and 2 substrate binding cavities.Functional expression in yeast cells combined with comprehensive gas chromatography indicated that the SlitFAR3 gene could produce fatty alcohol products.This study is the first to focus on the special phenomenon of FAR domain duplication,which will advance our understanding of biosynthesis-related genes from the perspective of evolutionary biology.