Angiogenesis in hepatocellular carcinoma:mechanisms and anti-angiogenic therapies

Hepatocellular carcinoma(HCC)is the fourth leading cause of cancer-associated death worldwide.Angiogenesis,the process of formation of new blood vessels,is required for cancer cells to obtain nutrients and oxygen.HCC is a typical hypervascular solid tumor with an aberrant vascular network and angiogenesis that contribute to its growth,progression,invasion,and metastasis.Current anti-angiogenic therapies target mainly tyrosine kinases,vascular endothelial growth factor receptor(VEGFR),and plateletderived growth factor receptor(PDGFR),and are considered effective strategies for HCC,particularly advanced HCC.However,because the survival benefits conferred by these anti-angiogenic therapies are modest,new anti-angiogenic targets must be identified.Several recent studies have determined the underlying molecular mechanisms,including pro-angiogenic factors secreted by HCC cells,the tumor microenvironment,and cancer stem cells.In this review,we summarize the roles of pro-angiogenic factors;the involvement of endothelial cells,hepatic stellate cells,tumor-associated macrophages,and tumor-associated neutrophils present in the tumor microenvironment;and the regulatory influence of cancer stem cells on angiogenesis in HCC.Furthermore,we discuss some of the clinically approved anti-angiogenic therapies and potential novel therapeutic targets for angiogenesis in HCC.A better understanding of the mechanisms underlying angiogenesis may lead to the development of more optimized anti-angiogenic treatment modalities for HCC.

The mechanism and therapy of aortic aneurysms

Aortic aneurysm is a chronic aortic disease affected by many factors.Although it is generally asymptomatic,it poses a significant threat to human life due to a high risk of rupture.Because of its strong concealment,it is difficult to diagnose the disease in the early stage.At present,there are no effective drugs for the treatment of aneurysms.Surgical intervention and endovascular treatment are the only therapies.Although current studies have discovered that inflammatory responses as well as the production and activation of various proteases promote aortic aneurysm,the specific mechanisms remain unclear.Researchers are further exploring the pathogenesis of aneurysms to find new targets for diagnosis and treatment.To better understand aortic aneurysm,this review elaborates on the discovery history of aortic aneurysm,main classification and clinical manifestations,related molecular mechanisms,clinical cohort studies and animal models,with the ultimate goal of providing insights into the treatment of this devastating disease.The underlying problem with aneurysm disease is weakening of the aortic wall,leading to progressive dilation.If not treated in time,the aortic aneurysm eventually ruptures.An aortic aneurysm is a local enlargement of an artery caused by a weakening of the aortic wall.The disease is usually asymptomatic but leads to high mortality due to the risk of artery rupture.

中国人群颅内动脉瘤不稳定性的标志物及风险分层模型

评估颅内动脉瘤的不稳定风险(破裂和生长风险)对于指导未破裂颅内动脉瘤(UIA)的治疗决策具有重要意义.本研究自2017年1月-2022年1月前瞻性地纳入了UIA患者,进行了2年的随访,并进一步分为发掘队列和验证队列,主要终点事件是UIA的不稳定事件,定义为在随访期内,动脉瘤出现破裂、大小生长或者形态学改变.基于758个UIA患者的发掘队列,联合影像特点和多组学分析,发现大小指数、形态不规则、油酸、花生四烯酸、白细胞介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)是UIA出现不稳定事件的危险因素.进一步分析显示,组织中和血清中油酸和花生四烯酸的表达水平有一致性趋势.运用机器学习算法,本研究构建了不稳定分类器,并能较好地识别发掘队列中的不稳定UIA(曲线下面积(AUC)为0.94).在含492个UIA患者的验证队列中,该分类器也能很好地识别不稳定UIA(AUC为0.89).基于大鼠颅内动脉瘤模型,发现干预油酸、IL-1β和TNF-α能预防UIA破裂.本研究基于中国人群揭示了UIA不稳定风险的标志物,并提供了一个风险分层模型,有望指导UIA的临床决策.

Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

Neurosteroids are synthesized in the nervous system from cholesterol or steroidal precursors imported from peripheral sources. These compounds are important allosteric modulators of γ-aminobutyric acid A receptors （GABAARs）, which play a vital role in pain modulation in the lateral thalamus, a main gate where somatosensory information enters the cerebral cortex. Using high-perfor mance liquid chromatography/tandem mass spectrometry, we found increased levels of neurosteroids （pregnenolone, progesterone, deoxycorticosterone, allopregnanolone, and tetrahydrodeoxycorticosterone） in the chronic stage of neuropathic pain （28 days after spared nerve injury） in rats.The expression of the translocator protein TSPO, the upstream steroidogenesis rate-limiting enzyme, increased at the same time. In vivo stereotaxic microinjection of neurosteroids or the TSPO activator AC-5216 into the lateral thalamus （AP -3.0 mm, ML 4-3.0 mm, DV 6.0 mm） alleviated the mechanical allodynia in neuropathic pain, while the TSPO inhibitor PK 11195 exacerbated it. The analgesic effects of AC-5216 and neurosteroids were sig- nificantly attenuated by the GABAAR antagonist bicuculline. These results suggested that elevated neurosteroids in the lateral thalamus play a protective role in the chronic stage of neuropathic pain.

FMO3-TMAO axis modulates the clinical outcome in chronic heart-failure patients with reduced ejection fraction:evidence from an Asian population

The association among plasma trimethylamine-N-oxide(TMAO),FMO3 polymorphisms,and chronic heart failure(CHF)remains to be elucidated.TMAO is a microbiota-dependent metabolite from dietary choline and carnitine.A prospective study was performed including 955 consecutively diagnosed CHF patients with reduced ejection fraction,with the longest follow-up of 7 years.The concentrations of plasma TMAO and its precursors,namely,choline and carnitine,were determined by liquid chromatography-mass spectrometry,and the FMO3 E158K polymorphisms(rs2266782)were genotyped.The top tertile of plasma TMAO was associated with a significant increment in hazard ratio(HR)for the composite outcome of cardiovascular death or heart transplantation(HR=1.47,95%CI=1.13-1.91,P=0.004)compared with the lowest tertile.After adjustments of the potential confounders,higher TMAO could still be used to predict the risk of the primary endpoint(adjusted HR=1.33,95%CI=1.01-1.74,P=0.039).This result was also obtained after further adjustment for carnitine(adjusted HR=1.33,95%CI=1.01-1.74,P=0.039).The FM03 rs2266782 polymorphism was associated with the plasma TMAO concentrations in our cohort,and lower TMAO levels were found in the AA-genotype.Thus,higher plasma TMAO levels indicated increased risk of the composite outcome of cardiovascular death or heart transplantation independent of potential confounders,and the FMO3 AA-genotype in rs2266782 was related to lower plasma TMAO levels.

Polarity-activated super-resolution imaging probe for the formation and morphology of amyloid fibrils

The formation of amyloid plaques usually occurs in the early-stage of Alzheimer’s disease(AD).Stimulated emission depletion(STED)imaging provided a powerful tool for visualizing amyloid structures on the nanometer scale.However,many commercial probes adopted in detecting amyloid fibrils are inapplicable to STED imaging,owing to their unmatched absorption and emission wavelengths,small Stokes'shift,easy photo-bleaching,etc.Herein,we demonstrated a polarity-activated STED probe based on an intramolecular charge transfer donor(D)-7c-acceptor(A)compound.The electron-rich carbazole group and the electron-poor pyridinium bromide group,linked by 7i-conjugated thiophen-bridge,ensure strong near infrared(NIR)emission with a Stokes'shift larger than 200 nm.The tiny change in polarity before and after binding with amyloid plaques leads to a transition from weakly emission charge-transfer(CT)state(Φ<0.04)to highly emissive locally-excited(LE)state(Φ=0.57),giving rise to a fluorescence Turn-On probe.Together with large Stokes'shift,good photostability and high depletion efficiency,the super-resolution imaging of the formation and morphology of amyloid fibrils in vitro based on this probe was realized with a lateral spatial resolution better than 33 nm at an extremely low depletion power.Moreover,the ex-vivo super-resolution imaging of(E)-1-butyl-4(2-(5-(9-ethyl-9Hcarbazol-3-yl)thiophen-2-yl)vinyl)pyridinium bromide(CTPB)probe in Aβ plaques in the brain slices of a Tg mouse was demonstrated.This research provides a demonstration of the super resolution imaging probe of amyloid fibrils based on polarity-response mechanism,providing a new approach to the development of future amyloid probes.

Trimethylamine-N-oxide is an important target for heart and brain diseases

Trimethylamine-N-oxide(TMAO)is a metabolite produced from dietary nutrients by the gut microbiome,which was first discovered in 2011 and used to predict the risk of car-diovascular disease[1].The precursors of TMAO,including phosphatidylcholine[1],choline[2],and L-carnitine[3],are commonly found in cheese,red meat,seafood,egg yolks,and other foods.To date,four different microbial enzyme systems have been identified that can convert precursor substances into trimethylamine(TMA),including choline-TMA lyase(cutC/D)[4],carnitine monooxygenase(cntA/B)[5],betaine reductase,and TMAO reductase[6].In addition,yeaW/X,which is homologous to cntA/B and can utilize a variety of substrates such as choline,betaine,carnitine andγ-butyr-obetaine,can also promote the synthesis of TMA.The coop-eration between yeaW/X and cutC/D was the most well studied[7].