A novel mouse model of calcific aortic valve stenosis

Background:Calcific aortic valve stenosis(CAVS)is one of the most challenging heart diseases in clinical with rapidly increasing prevalence.However,study of the mecha-nism and treatment of CAVS is hampered by the lack of suitable,robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposi-tion.Here,we aim to establish a mouse model to mimic the development and features of CAVS.Methods:The model was established via aortic valve wire injury(AVWI)combined with vitamin D subcutaneous injected in wild type C57/BL6 mice.Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradi-ent.Histopathological specimens were collected and examined in respect of valve thickening,calcium deposition,collagen accumulation,osteogenic differentiation and inflammation.Results:Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time depend-ent manner and tended to be stable at 28 days.Compared with the sham group,sim-ple AVWI or the vitamin D group,the hybrid model group showed typical pathological features of CAVS,including hemodynamic alterations,increased aortic valve thicken-ing,calcium deposition,collagen accumulation at 28 days.In addition,osteogenic dif-ferentiation,fibrosis and inflammation,which play critical roles in the development of CAVS,were observed in the hybrid model.Conclusions:We established a novel mouse model of CAVS that could be induced efficiently,robustly and economically,and without genetic intervention.It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effec-tive pharmacological targets.

Mazabraud’s syndrome in female patients:Two case reports

BACKGROUND Mazabraud’s syndrome(MS)is a rare and slowly progressive benign disease characterized by the concurrent presence of fibrous dysplasia of bone and intramuscular myxoma,and is thought to be associated with mutations of the GNAS gene.To date,only about 100 cases of MS have been reported in the literature,but its standard treatment strategy remains unclear.CASE SUMMARY We report two cases of MS in young women who underwent different treatments based on their symptoms and disease manifestations.The first patient,aged 37,received internal fixation and intravenous bisphosphonate for a pathological fracture of the right femoral neck,excision of a right vastus medialis myxoma was subsequently performed for pain control,and asymptomatic psoas myxomas were monitored without surgery.Genetic testing confirmed a GNAS gene mutation in this patient.The second patient,aged 24,underwent right vastus intermedius muscle myxoma resection,and conservative treatment for fibrous dysplasia of the ilium.These patients were followed-up for 17 months and 3 years,respectively,and are now in a stable condition.CONCLUSION Various treatments have been selected for MS patients who suffer different symptoms.The main treatment for myxomas is surgical resection,while fibrous dysplasia is selectively treated if the patient experiences pathological fracture or severe pain.However,given the documented instances of malignant transformation of fibrous dysplasia in individuals with MS,close follow-up is necessary.

A polymyxin B loaded hypoxia-responsive liposome with improved biosafety for efficient eradication of bacterial biofilms

Biofilm-associated bacterial infection brings serious threats to global public health owing to serious antibiotic resistance.It is urgently needed to develop innovative strategies to combat biofilm-associated bacterial infections.Polymyxins stand out as the last line of defense against Gram-negative bacteria.However,serious nephrotoxicity of polymyxins severely limits their clinical utility.Herein,a hypoxia-responsive liposome is designed as the nanocarrier of polymyxin B(PMB)to combat biofilms developed by Gram-negative bacteria.A metronidazole modified lipid(hypoxia-responsive lipid(HRLipid))is synthesized to fabricate hypoxia-responsive liposomes(HRLip).PMB loaded hypoxia-responsive liposomes(HRL-PMB)is then prepared to mitigate the nephrotoxicity of PMB while preserving its excellent bactericidal activity.HRL-PMB shows very low hemolysis and cytotoxicity due to liposomal encapsulation of PMB.PMB can be readily released from HRL-PMB in response to hypoxic biofilm microenvironment,exerting its bactericidal activity to realize biofilm eradication.The excellent in vivo antibiofilm ability of HRL-PMB is confirmed by a Pseudomonas aeruginosa infected zebrafish model and a P.aeruginosa pneumonia infection model.Meanwhile,HRL-PMB can greatly reduce the nephrotoxicity of PMB after intravenous injection.The hypoxia-sensitive liposomes held great promise to improve the biosafety of highly toxic antibiotics while preserving their intrinsic bactericidal ability,which may provide an innovative strategy for combating biofilm-associated infections.

Genetic regulation of m^(6)A RNA methylation and its contribution in human complex diseases

N6-methyladenosine(m^(6)A)has been established as the most prevalent chemical modification in message RNA(mRNA),playing an essential role in determining the fate of RNA molecules.Dysregulation of m^(6)A has been revealed to lead to abnormal physiological conditions and cause various types of human diseases.Recent studies have delineated the genetic regulatory maps for m^(6)A methylation by mapping the quantitative trait loci of m^(6)A(m^(6)A-QTLs),thereby building up the regulatory circuits linking genetic variants,m^(6)A,and human complex traits.Here,we review the recent discoveries concerning the genetic regulatory maps of m^(6)A,describing the methodological and technical details of m^(6)A-QTL identification,and introducing the key findings of the cis-and trans-acting drivers of m^(6)A.We further delve into the tissue-and ethnicity-specificity of m^(6)A-QTL,the association with other molecular phenotypes in light of genetic regulation,the regulators underlying m^(6)A genetics,and importantly,the functional roles of m^(6)A in mediating human complex diseases.Lastly,we discuss potential research avenues that can accelerate the translation of m^(6)A genetics studies toward the development of therapies for human genetic diseases.

Exogeneous metal ions as therapeutic agents in cardiovascular disease and their delivery strategies

Metal ions participate in many metabolic processes in the human body,and their homeostasis is crucial for life.In cardiovascular diseases(CVDs),the equilibriums of metal ions are frequently interrupted,which are related to a variety of disturbances of physiological processes leading to abnormal cardiac functions.Exogenous supplement of metal ions has the potential to work as therapeutic strategies for the treatment of CVDs.Compared with other therapeutic drugs,metal ions possess broad availability,good stability and safety and diverse drug delivery strategies.The delivery strategies of metal ions are important to exert their ther-apeutic effects and reduce the potential toxic side effects for cardiovascular applications,which are also receiving increasing attention.Controllable local delivery strategies for metal ions based on various biomaterials are constantly being designed.In this review,we comprehensively summarized the positive roles of metal ions in the treatment of cVDs from three aspects:protecting cells from oxidative stress,inducing angiogenesis,and adjusting the functions of ion channels.In addition,we introduced the transferability of metal ions in vascular reconstruction and cardiac tissue repair,as well as the currently available engineered strategies for the precise delivery of metal ions,such as integrated with nanoparticles,hydrogels and scaffolds.