查看更多>>摘要：Targeted protein degradation technology has gained substantial momentum over the past two decades as a revolutionary strategy for eliminating pathogenic proteins that are otherwise refractory to treatment.Among the various approaches developed to harness the body's innate protein homeostasis mechanisms for this purpose,lysosome targeting chimeras(LYTACs)that exploit the lysosomal degradation pathway by coupling the target proteins with lysosome-trafficking receptors represent the latest innovation.These chimeras are uniquely tailored to degrade proteins that are membrane-bound and extracellular,encompassing approximately 40％of all proteome.Several novel LYTAC formulas have been developed recently,providing valuable insights for the design and development of therapeutic degraders.This review delineates the recent progresses of LYTAC technology,its practical applications,and the factors that dictate target degradation efficiency.The potential and emerging trends of this technology are discussed as well.LYTAC technology offers a promising avenue for targeted protein degradation,potentially revolutionizing the therapeutic landscape for numerous diseases.
查看更多>>摘要：Non-communicable diseases(NCDs)are defined as a kind of diseases closely related to bad behaviors and lifestyles,e.g.,cardiovascular diseases,cancer,and diabetes.Driven by population growth and aging,NCDs have become the biggest disease burden in the world,and it is urgent to prevent and control these chronic diseases.Autophagy is an evolutionarily conserved process that degrade cellular senescent or malfunctioning organelles in lysosomes.Mounting evidence has demonstrated a major role of autophagy in the pathogenesis of cardiovascular diseases,cancer,and other major human diseases,suggesting that autophagy could be a candidate therapeutic target for NCDs.Natural products/phytochemicals are important resources for drugs against a wide variety of diseases.Recently,compounds from natural plants,such as resveratrol,curcumin,and ursolic acid,have been recognized as promising autophagy modulators.In this review,we address recent advances and the current status of the development of natural autophagy modulators in NCDs and provide an update of the latest in vitro and in vivo experiments that pave the way to clinical studies.Specifically,we focus on the relationship between natural autophagy modulators and NCDs,with an intent to identify natural autophagy modulators with therapeutic potential.
查看更多>>摘要：As a major contributor to neonatal death and neurological sequelae,hypoxic-ischemic encephalopathy(HIE)lacks a viable medication for treatment.Oxidative stress induced by hypoxic-ischemic brain damage(HIBD)predisposes neurons to ferroptosis due to the fact that neonates accumulate high levels of polyunsaturated fatty acids for their brain developmental needs but their antioxidant capacity is immature.Ferroptosis is a form of cell death caused by excessive accumulation of iron-dependent lipid peroxidation and is closely associated with mitochondria.Mitophagy is a type of mitochondrial quality control mechanism that degrades damaged mitochondria and maintains cellular homeostasis.In this study we employed mitophagy agonists and inhibitors to explore the mechanisms by which mitophagy exerted ferroptosis resistance in a neonatal rat HIE model.Seven-days-old neonatal rats were subjected to ligation of the right common carotid artery,followed by exposure to hypoxia for 2 h.The neonatal rats were treated with a mitophagy activator Tat-SPK2 peptide(0.5,1 mg/kg,i.p.)1 h before hypoxia,or in combination with mitochondrial division inhibitor-1(Mdivi-1,20 mg/kg,i.p.),and ferroptosis inhibitor Ferrostatin-1(Fer-1)(2 mg/kg,i.p.)at the end of the hypoxia period.The regulation of ferroptosis by mitophagy was also investigated in primary cortical neurons or PC1 2 cells in vitro subjected to 4 or 6 h of OGD followed by 24 h of reperfusion.We showed that HIBD induced mitochondrial damage,ROS overproduction,intracellular iron accumulation,lipid peroxidation and ferroptosis,which were significantly reduced by the pretreatment with Tat-SPK2 peptide,and aggravated by the treatment with Mdivi-1 or BNIP3 knockdown.Ferroptosis inhibitors Fer-1 and deferoxamine B(DFO)reversed the accumulation of iron and lipid peroxides caused by Mdivi-1,hence reducing ferroptosis triggered by HI.We demonstrated that Tat-SPK2 peptide-activated BNIP3-mediated mitophagy did not alleviate neuronal ferroptosis through the GPX4-GSH pathway.BNIP3-mediated mitophagy drove the P62-KEAP1-NRF2 pathway,which conferred ferroptosis resistance by maintaining iron and redox homeostasis via the regulation of FTH1,HO-1,and DHODH/FSP1-CoQ10-NADH.This study may provide a new perspective and a therapeutic drug for the treatment of neonatal HIE.
查看更多>>摘要：Esculetin(ESC)is a coumarin-derived phytochemical prevalent in traditional Chinese medicine that exhibits anti-acute ischemic stroke activities.Our previous studies demonstrate that CKLF1 is a potential anti-stroke target for coumarin-derived compound.In this study we investigated whether CKLF1 was involved in the neuroprotective effects of ESC against photothrombotic stroke in mice.The mice were treated with ESC(20,40 or 80 mg·kg-1·d-1,i.g.)for two weeks.The therapeutic effect of ESC was assessed using MRI,neurological function evaluation,and a range of behavioral tests on D1,3,7 and 14 of ESC administration.We showed that oral administration of ESC dose-dependently reduced the cerebral infarction volume within one week after stroke,improved behavioral performance,and alleviated neuropathological damage within two weeks.Functional MRI revealed that ESC significantly enhanced the abnormal low-frequency fluctuation(ALFF)value of the motor cortex and promoted functional connectivity between the supplementary motor area(SMA)and multiple brain regions.We demonstrated that ESC significantly reduced the protein levels of CKLF1 and CCR5,as well as the CKLF1/CCR5 protein complex in the peri-infarcted area.We showed that ESC(0.1-10 μM)dose-dependently blocked CKLF1-induced chemotactic movement of neutrophils in the Transwell assay,reducing the interaction of CKLF1/CCR5 on the surface of neutrophils,thereby reducing neutrophil infiltration,and decreasing the expression of ICAM-1,VCAM-1 and MMP-9 in the peri-infarct tissue.Knockout of CKLF1 reduced brain infarction volume and motor dysfunction after stroke but also negated the anti-stroke efficacy and neutrophil infiltration of ESC.These results suggest that the efficacy of ESC in promoting post-stroke neural repair depends on its inhibition on CKLF1-mediated neutrophil infiltration,which offering novel perspectives for elucidating the therapeutic properties of coumarins.
查看更多>>摘要：Alzheimer's disease(AD)is the most prevalent neurodegenerative disorder characterized by cognitive impairments.Despite the limited efficacy of current treatments for AD,the 1,2,4-oxadiazole structure has garnered significant attention in medicinal chemistry due to its potential impact on mGluR1 and its association with AD therapy.In this study,a series of novel 1,2,4-oxadiazole derivatives were designed,synthesized,and evaluated for the neuroprotective effects in human neuroblastoma(SH-SY5Y)cells.Among all the derivatives tested,FO-4-15(5f)existed the lowest cytotoxicity and the highest protective effect against H2O2.Based on these in vitro results,FO-4-15 was administered to 3×Tg mice and significantly improved the cognitive impairments of the AD mice.Pathological analysis showed that FO-4-15 significantly reduced Aβ accumulation,Tau hyper-phosphorylation,and synaptic impairments in the 3×Tg mice.Dysfunction of the CaMKⅡα/Fos signaling pathway in 3×Tg mice was found to be restored by FO-4-15 and the necessity of the CaMKⅡα/Fos for FO-4-15 was subsequently confirmed by the use of a CaMKⅡα inhibitor in vitro.Beyond that,mGluR1 was identified to be a potential target of FO-4-15,and the interaction of FO-4-15 and mGluR1 was displayed by Ca2+flow increase,molecular docking,and interaction energy analysis.The target of FO-4-15 was further confirmed in vitro by JNJ16259685,a nonselective inhibitor of mGluR1.These findings suggest that FO-4-15 may hold promise as a potential treatment for Alzheimer's disease.
查看更多>>摘要：Doxorubicin(DOX),a common chemotherapeutic agent in cancer therapy,is accompanied by pronounced cardiotoxicity.Ferroptosis has been implicated in the pathogenesis and therapeutics of DOX-induced cardiotoxicity(DIC).Asiatic acid(AA),a pentacyclic triterpene from the Chinese medicinal herb Centella asiatica,displays antioxidant,anti-inflammatory,and antiapoptotic activities.In this study,we investigated the beneficial effects of AA against DOX-induced ferroptosis and cardiotoxicity and the underlying mechanisms.A chronic DIC model was established by challenging mice with DOX(5 mg/kg,i.p.)once per week for 4 weeks.Concurrent with DOX insult,the mice were administered AA(25 mg·kg-1·d-1,i.g.).Cardiac function and mechanical properties of isolated cardiomyocytes were evaluated at the end of treatment.We showed that AA administration preserved cardiac function,significantly reduced cardiac injury,and improved cardiomyocyte contractile function in DIC mice.The beneficial effects of AA were causally linked to the inhibition of DOX-induced ferroptosis both in vivo and in vitro.We revealed that AA attenuated DOX-induced iron accumulation in HL-1 cells by increasing FPN-mediated iron export,in a Nrf2-dependent manner.AA upregulated Nrf2 expression and promoted Nrf2 nuclear translocation in DOX-treated HL-1 cells.Moreover,AA-offered benefits against DOX-induced cardiac dysfunction and ferroptosis were abolished by Nrf2 inhibitor ML385(30 mg.kg-1·d-1,i.p.)administrated 30 min before AA in DIC mice.Our data favor that AA promotes FPN-mediated iron export to inhibit iron overload and ferroptosis in DIC,suggesting its therapeutic potential in the treatment of DIC.
查看更多>>摘要：Abdominal aortic aneurysm(AAA)is a degenerative disease that caused mortality in people aged＞65.Senescence plays a critical role in AAA pathogenesis.Advances in AAA repair techniques have occurred,but a remaining priority is therapies to limit AAA growth and rupture.Our Previous study found cyclic nucleotide phosphodiesterase 1C(PDE1C)exacerbate AAA through aggravate vascular smooth muscle cells(VSMCs)senescence by downregulating Sirtuin1(SIRT1)expression and activity.Vinpocetine as a selective inhibitor of PDE1 and a clinical medication for cerebral vasodilation,it is unclear whether vinpocetine can rely on SIRT1 to alleviate AAA.This study showed that pre-treatment with vinpocetine remarkably prevented aneurysmal dilation and reduced aortic rupture in elastase-induced AAA mice.In addition,the elastin degradation,MMP(matrix metalloproteinase)activity,macrophage infiltration,ROS production,collagen fibers remodeling,and VSMCs senescence were decreased in AAA treated with vinpocetine.While these effects were unable to exert in VSMCs-specific SIRT1 knockout AAA mice.Accordingly,we revealed that vinpocetine suppressed migration,proliferation,and senescence in VSMCs.Moreover,vinpocetine reduced SIRT1 degradation by inhibiting lysosome-mediated autophagy.In conclusion,this study indicated that vinpocetine may be as a potential drug for therapy AAA through alleviate VSMCs senescence via the SIRT1-dependent pathway.
查看更多>>摘要：Pulmonary fibrosis(PF)is a chronic,progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation,extracellular matrix(ECM)deposition and inflammatory recruitment.PF has no curable medication yet.In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy.A murine PF model was established in mice by intratracheal instillation of bleomycin(BLM,5 mg/kg).We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A(PPM1A,also known as PP2Cα)was significantly downregulated in PF patients and BLM-induced PF mice.We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression.By screening the lab in-house compound library,we discovered otilonium bromide(OB,clinically used for treating irritable bowel syndrome)as a PPM1A enzymatic activator with an EC50 value of 4.23 μM.Treatment with OB(2.5,5 mg·kg-1·d-1,i.p.,for 20 days)significantly ameliorated PF-like pathology in mice.We constructed PF mice with PPM1 A-specific knockdown in the lung tissues,and determined that by targeting PPM1A,OB treatment suppressed ECM deposition through TGF-β/SMAD3 pathway in fibroblasts,repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells,and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts.Together,our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.
查看更多>>摘要：Liver fibrosis,one of the leading causes of morbidity and mortality worldwide,lacks effective therapy.The activation of hepatic stellate cells(HSCs)is the dominant event in hepatic fibrogenesis.Luteolin-7-diglucuronide(L7DG)is the major flavonoid extracted from Perilla frutescens and Verbena officinalis.Their beneficial effects in the treatment of liver diseases were well documented.In this study we investigated the anti-fibrotic activities of L7DG and the potential mechanisms.We established TGF-β1-activated mouse primary hepatic stellate cells(pHSCs)and human HSC line LX-2 as in vitro liver fibrosis models.Co-treatment with L7DG(5,20,50 μM)dose-dependently decreased TGF-β1-induced expression of fibrotic markers collagen 1,α-SMA and fibronectin.In liver fibrosis mouse models induced by CCl4 challenge alone or in combination with HFHC diet,administration of L7DG(40,150 mg·kg-1·d-1,i.g.,for 4 or 8 weeks)dose-dependently attenuated hepatic histopathological injury and collagen accumulation,decreased expression of fibrogenic genes.By conducting target prediction,molecular docking and enzyme activity detection,we identified L7DG as a potent inhibitor of protein tyrosine phosphatase 1B(PTP1B)with an IC50 value of 2.10 μM.Further studies revealed that L7DG inhibited PTP1B activity,up-regulated AMPK phosphorylation and subsequently inhibited HSC activation.This study demonstrates that the phytochemical L7DG may be a potential therapeutic candidate for the treatment of liver fibrosis.
查看更多>>摘要：Macrophage polarization is vital to mounting a host defense or repairing tissue in various liver diseases.Excessive activation of the NLR family pyrin domain containing 3(NLRP3)inflammasome is related to the orchestration of inflammation and alcohol-associated liver disease(ALD)pathology.Rab GTPases play critical roles in regulating vesicular transport.In this study we investigated the role of Rab11b in ALD,aiming to identify effective therapeutic targets.Here,we first demonstrated a decreased expression of Rab11b in macrophages from ALD mice.Knockdown of Rab11b by macrophage-specific adeno-associated virus can alleviate alcohol induced liver inflammation,injury and steatosis.We found that LPS and alcohol stimulation promoted Rab11b transferring from the nucleus to the cytoplasm in bone marrow-derived macrophages(BMDM)cells.Rab11b specifically activated the NLRP3 inflammasome in BMDMs and RAW264.7 cells to induce M1 macrophage polarization.Rab11b overexpression in BMDMs inhibited autophagic flux,leading to the suppression of LC3B-mediated NLRP3 degradation.We conclude that impaired Rab11b could alleviate alcohol-induced liver injury via autophagy-mediated NLRP3 degradation.
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