Drosophila models used to simulate human ATP1A1 gene mutations that cause Charcot-Marie-Tooth type 2 disease and refractory seizures

Certain amino acids changes in the human Na^(+)/K^(+)-ATPase pump,ATPase Na^(+)/K^(+)transporting subunit alpha 1(ATP1A1),cause Charcot-Marie-Tooth disease type 2(CMT2)disease and refractory seizures.To develop in vivo models to study the role of Na^(+)/K^(+)-ATPase in these diseases,we modified the Drosophila gene homolog,Atpα,to mimic the human ATP1A1 gene mutations that cause CMT2.Mutations located within the helical linker region of human ATP1A1(I592T,A597T,P600T,and D601F)were simultaneously introduced into endogenous Drosophila Atpαby CRISPR/Cas9-mediated genome editing,generating the Atpα^(TTTF)model.In addition,the same strategy was used to generate the corresponding single point mutations in flies(Atpα^(I571T),Atpα^(A576T),Atpα^(P579T),and Atpα^(D580F)).Moreover,a deletion mutation(Atpα^(mut))that causes premature termination of translation was generated as a positive control.Of these alleles,we found two that could be maintained as homozygotes(Atpα^(I571T)and Atpα^(P579T)).Three alleles(Atpα^(A576T),Atpα^(P579)and Atpα^(D580F))can form heterozygotes with the Atpαmut allele.We found that the Atpαallele carrying these CMT2-associated mutations showed differential phenotypes in Drosophila.Flies heterozygous for Atpα^(TTTF)mutations have motor performance defects,a reduced lifespan,seizures,and an abnormal neuronal morphology.These Drosophila models will provide a new platform for studying the function and regulation of the sodium-potassium pump.

X-linked Charcot-Marie-Tooth disease after SARS-CoV-2 vaccination mimicked stroke-like episodes: A case report

BACKGROUND Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) vaccinations have been administered worldwide, with occasional reports of associated neurological complications. Specifically, the impact of vaccinations on individuals with Xlinked Charcot-Marie-Tooth disease type 1(CMTX1) is unclear. Patients with CMTX1 can have stroke-like episodes with posterior reversible encephalopathy syndrome on magnetic resonance imaging(MRI), although this is rare.CASE SUMMARY A 39-year-old man was admitted with episodic aphasia and dysphagia for 2 d. He received SARS-CoV-2 vaccination 39 d before admission. Physical examination showed pes cavus and reduced tendon reflexes. Brain MRI showed bilateral, symmetrical, restricted diffusion with T2 hyperintensities in the cerebral hemispheres. Nerve conduction studies revealed peripheral nerve damage. He was diagnosed with Charcot-Marie-Tooth disease, and a hemizygous mutation in the GJB1 gene on the X chromosome, known to be pathogenic for CMTX1, was identified. Initially, we suspected transient ischemic attack or demyelinating leukoencephalopathy. We initiated treatment with antithrombotic therapy and immunotherapy. At 1.5 mo after discharge, brain MRI showed complete resolution of lesions, with no recurrence.CONCLUSION SARS-CoV-2 vaccination could be a predisposing factor for CMTX1 and trigger a sudden presentation.

The MORC2 p.S87L mutation reduces proliferation of pluripotent stem cells derived from a patient with the spinal muscular atrophy-like phenotype by inhibiting proliferation-related signaling pathways

Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal muscular atrophy-like clinical phenotype.The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies.Epithelial cells were isolated from urine samples from a spinal muscular atrophy(SMA)-like patient[MORC2 p.S87L),a CMT2Z patient[MORC2 p.Q400R),and a healthy control and induced to generate pluripotent stem cells,which were then differentiated into motor neuron precursor cells.Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAP K/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells.Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control.G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient.MORC2 p.S87Lspecific antisense oligonucleotides(p.S87L-ASO-targeting)showed significant efficacy in improving cell prolife ration and activating the PI3K/Akt and MAP K/ERK pathways in induced pluripotent stem cells.Howeve r,p.S87L-ASO-ta rgeting did not rescue prolife ration of motor neuron precursor cells.These findings suggest that downregulation of the PI3K/Akt and MAP K/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype.p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction.

Mechanism of stilbene glycosides on apoptosis of SH-SY5Y cells via regulating PI3K/AKT signaling pathway

Objective:To investigate the effects of stilbene glycoside(TSG)on okadaic acid-induced apoptosis in human neuroblastoma cells(SH-SY5Y)via the PI3K/AKT pathway.Methods:The optimal concentration of OA was screened by CCK-8 assay,and SH-SY5Y cells were divided into control group,model group,TSG group,LY294002 group and LY294002+TSG group.The proliferation and apoptosis in each group were detected by CCK-8 and TUNEL assays;Western blotting method and real-time fluorescence quantitative polymerase chain reaction was used to detect the expression of PI3K,P-PI3K(Y607),AKT,P-AKT(Ser473),Bcl-2 and Bax proteins.The relative protein expression was represented by P-PI3K(Y607)/PI3K,P-AKT(Ser473)/AKT and Bcl-2/Bax gray ratio.Results:CCK-8 screened the optimal concentration of OA as 40 nmol/L.Compared with the control group,the model group increased relative cell viability,decreased apoptosis rate,the pathway and apoptotic proteins expression levels of P-PI3K(Y607)/PI3K,P-AKT(Ser473)/AKT and Bcl-2/Bax were decreased,and the mRNA expression levels of PI3K,AKT and Bcl-2 were decreased.Bax mRNA expression level increased(P<0.05);Compared with model group,TSG group increased relative cell viability,decreased apoptosis rate,increased protein expression levels of P-PI3K(Y607)/PI3K,P-AKT(Ser473)/AKT,Bcl-2/Bax,and increased mRNA expression levels of PI3K,AKT,and Bcl-2.Bax mRNA expression decreased(P<0.05),LY294002 group decreased relative cell viability,increased apoptosis rate,P-PI3K(Y607)/PI3K protein expression levels were significantly decreased(P<0.05),P-AKT(Ser473)/AKT and Bcl-2/Bax protein expression levels were significantly decreased,but there was no statistical significance,PI3K,AKT and Bcl-2 mRNA expression levels were decreased,and Bax mRNA expression levels were increased(all P<0.05);Compared with LY294002 group,LY294002+TSG group increased relative cell viability,decreased apoptosis rate,and the protein expression levels of P-PI3K(Y607)/PI3K,P-AKT(Ser473)/AKT and Bcl-2/Bax were increased.The mRNA expression levels of PI3K,AKT,Bcl-2 were increased,Bax was decreased(all P<0.05).Conclusion:Stilbene glycoside may alleviate okadaic acid-induced apoptosis in SH-SY5Y cells by interfering with the PI3K/AKT signaling pathway,which in turn regulates the expression of apoptotic factors such as Bcl-2 and Bax.

肉苁蓉对帕金森病模型大鼠PI3K、Akt、Bcl-2、Bax蛋白表达的影响

目的:观察肉苁蓉对帕金森病(PD)模型大鼠行为学及中脑黑质-纹状体组织PI3K、Akt、Bcl-2、Bax蛋白表达的影响,探讨其对神经细胞的保护作用机制。方法:将48只健康SD雄性大鼠随机分为正常组、溶剂对照组、模型组、肉苁蓉低、中、高剂量组6组,采用颈背部皮下注射鱼藤酮葵花油乳化液建立PD大鼠模型,给予肉苁蓉水煎剂后,第3、7、14天分别进行行为学步幅试验;第14天行为学检测后,处死大鼠,提取黑质-纹状体蛋白,Western Blot检测PI3K、Akt、Bcl-2、Bax蛋白的表达。结果:肉苁蓉干预14天后,与模型组比较,中、高剂量组步幅明显增大(P <0. 01),低、中、高剂量组PI3K、Bcl-2蛋白表达、Bcl-2/Bax值明显升高(P <0. 01或P <0. 05),中剂量组Akt蛋白表达明显升高(P <0. 01),低、中、高剂量组Bax表达明显降低(P <0. 01)。结论:肉苁蓉能改善帕金森病模型大鼠的行为障碍,其对多巴胺神经细胞的保护作用可能是通过影响PI3K/Akt信号通路,上调Bcl-2表达,下调Bax表达,升高Bcl-2/Bax值,进而抑制神经细胞的凋亡实现的。

中药二至丸对老年痴呆模型小鼠脑组织Na^+-K^+-ATPase、Ca^(2+)-ATPase活性及学习记忆的影响

目的:观察中药二至丸对老年痴呆(alzhe im er d isease AD)模型小鼠脑组织Na+-K+-ATPase、Ca2+-ATPase活性及学习记忆的影响。方法:颈背部皮下注射D-半乳糖建立亚急性老年痴呆模型,测定脑组织中Na+-K+-ATPase、Ca2+-ATPase活性、采用跳台法测定小鼠的学习记忆能力。结果:中药二至丸能明显提高Na+-K+-ATPase、Ca2+-ATPase活性、缩短小鼠学习潜伏期,延长记忆潜伏期、减少错误次数。结论:中药二至丸能改善老年痴呆模型小鼠的学习记忆能力,提高ATP酶的活性,维持脑组织的正常功能。

外伤性牙髓炎中6-K-PGF_(1α)和TXB_2的检测及意义

目的 :探讨前列环素与血栓素A2 及其比值即PGI2 /TXA2 在外伤性牙髓病发生、发展中的作用及在治疗中的意义。方法 :采用放射免疫检测技术对 11例正常牙髓及 2 2例于外伤后不同时间出现不可复性牙髓病症状的外伤牙髓组织中的 6 -K -PGF1浕(PGI2 的稳定代谢产物 )、TXB2 (TXA2 的稳定代谢产物 )的水平进行测定 ,并计算二者比值 6 -K -PGF1浕/TXB2 即K/T值。结果 :牙齿受外伤后虽然经历不同时间 ,但当牙髓发生不可逆性病变时 ,其 6 -K -PGF1浕、ＴＸＢ2 水平及比值在外伤牙各组间均无显著性差异 ,且其 6 -K -PGF1浕、ＴＸＢ2 水平均显著高于正常组 ,K/T值均显著低于正常组。结论 :PGI2 、TXA2 水平及其比值与外伤性牙髓病的发生。

11,12-表氧化二十碳三烯酸对COPD大鼠气道平滑肌细胞钙激活性钾通道的作用

目的观察COPD大鼠气道平滑肌细胞(ASMCs)的钙激活性钾通道(KCa)的活性变化,以及11,12表-氧化二十碳三烯酸(11,12-EETs)对气道平滑肌细胞KCa的作用。方法40只雄性SD大鼠随机分为正常对照组和COPD组,每组20只。在相对密闭舱内吸入纸烟建立COPD动物模型,采用急性酶分离法分离大鼠ASMCs,应用膜片钳技术,分离出KCa电流,测定KCa开放概率(Po)、平均开放时间(To)和平均关闭时间(Tc)。比较COPD组和正常对照组KCa上述活性指标的变化,以及应用3μmol/L的11,12-EETs对COPD组ASMCs细胞进行灌流后KCa活性的变化。结果与正常对照组比较,COPD组ASMCs的KCa通道Po明显降低(0.084±0.028比0.198±0.029,P<0.01),To显著缩短[(0.732±0.058)m s比(1.648±0.152)m s,P<0.01],Tc显著延长[(12.259±2.612)m s比(6.753±1.237)m s,P<0.01]。而用11,12-EETs灌流ASMCs细胞后可明显激活KCa活性,Po增加(0.227±0.059比0.084±0.028,P<0.01),To延长[(2.068±0.064)m s比(0.732±0.058)m s,P<0.01],Tc缩短[(4.273±0.978)m s比(12.259±2.612)m s,P<0.01]。结论COPD大鼠ASMCs细胞KCa通道活性降低可能在COPD发病机制中起着一定作用,11,12-EETs可以直接激活COPD大鼠ASMCs细胞KCa活性,提高膜电位稳定性,从而松弛COPD大鼠气道平滑肌。

TM6SF2 E167K Variant, a Novel Genetic Susceptibility Variant, Contributing to Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease(NAFLD)is one of the most common causes of liver dysfunction worldwide,and its prevalence is highly associated with genetic susceptibility.The transmembrane 6 superfamily member 2(TM6SF2)E167K variant represents a general genetic determinant of hepatic triglyceride content and lobular inflammation,and its presence appears to be directly involved in the pathogenesis and development of NAFLD.Although this variant appears to be a novel powerful modifier in the development of NAFLD,whether it is associated with an increased risk of NAFLD-refated liver fibrosis and hepatocellular carcinoma(HCC)remains to be determined.The aim of this review is to describe the functions of the TM6SF2 E167K variant and its association with NAFLD,with particular emphasis on the underlying mechanisms of its role in the development and progression of NAFLD.Additionally,the links between the TM6SF2 E167K variant and NAFLD-related liver fibrosis and HCC will be discussed.

Hepatocellular Carcinoma: Known and Emerging Risk Factors

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with a high mortality rate. While chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections represent the leading risk factors worldwide, the spreading of metabolic disorders, such as diabetes, obesity and non-alcoholic fatty liver disease (NAFLD) justifies the increasing attention on their oncogenic mechanisms. This review discusses about the main pathogenic mechanisms implicated in occurrence of HCC in presence of viral and metabolic diseases. Additionally, it points to the importance of clinical surveillance for those patients considered at risk of HCC and highlights the strategical role of serum markers, such as alfa-fetoprotein (αFP) and Protein Induced by Vitamin K Absence or Antagonist II (PIVKA-II), which, in association to a strictly instrumental follow-up, contribute to the early detection of hepatic nodules with a better prognosis for affected patients.

Intermediate conductance, Ca^2＋-activated K^＋ channels： a novel target for chronic renal diseases

Renal failure is a medical condition in which the kidneys are not working properly. There are two types of kidney failure： 1） acute kidney failure, which is sudden and often reversible with adequate treatment; and 2） chronic renal failure, which develops slowly and often is not reversible. The last stage of chronic renal failure is fatal without dialysis or kidney transplant. The treatment for chronic renal failure is focusing on slowing the progression of kidney damage. Several reports have described a promising approach to slow the loss of renal function through inhibition of the basolateral membrane, Ca^2＋-activated K^＋ （KCa3.1） channel with a selective and nontoxic blocker TRAM-34. This review summarizes pathophysiological studies that describe the role of KCa3.1 in kidney diseases.

野菊花对大骨节病大鼠TNF-α、IL-6、NO、NOS的影响

目的:观察野菊花对大骨节病大鼠肿瘤坏死因子α(TNF-α)、白介素6(IL-6)、一氧化氮(NO)、一氧化氮合成酶(NOS)的影响。方法:将50只SPF级SD大鼠分为5组,分别为空白组,模型组,野菊花高、中、低剂量组。将大鼠T-2毒素灌胃4周造成大骨节病模型,造模的同时给予相应药物灌胃治疗。给药1个月后所有动物统一处死,取血清、膝关节检测。结果:与空白对照组比较,模型组大鼠血清血清IL-6及TNF-α的含量、NO、NOS指数均升高,2组比较差异有统计学意义(P<0.05);与模型组比较,野菊花高、中、低剂量组TNF-α、IL-6、NO、NOS指数均降低,差异有统计学意义(P<0.05)。从大鼠膝关节软骨病理切片HE染色来看:与空白对照组比较,模型组大鼠软骨细胞破坏明显,染毒成功;与模型组比较,野菊花高、中、低剂量组大鼠软骨细胞有明显的修复。结论:野菊花对大骨节病大鼠有一定的治疗作用。

肌注维生素K_3、654-2对提高胆道疾病超声诊断的研究

对正常人４０例、胆道疾患４７例施行肌注维生素Ｋ３或６５４－２后超声观察肝外胆管内径变化及下段病变显示率。结果表明，正常人４０例无明显变化。胆道疾患２３例肌注维生素Ｋ３１６ｍｇ后肝外胆管内径均值从１１．６ｍｍ增宽达１３．１ｍｍ，平均增宽１．５ｍｍ；２４例肌注６５４－２１０ｍｇ后肝外胆管内径均值从１２．６ｍｍ增宽达１３．９ｍｍ，平均增宽１．３ｍｍ；同时肝外胆管内透声均改善，下段病变显示率从５７％提高至８５％。本方法为提高胆道疾病的诊断率提供了无创伤的手段。

风心瓣膜病变患者红细胞膜钠、钙泵活性和脂质过氧化的变化

用酶解法和Ｈ２Ｏ２分解法分别测定２８例风心瓣膜病变患者红细胞膜钠泵（Ｎａ＋、Ｋ＋－ＡＴＰ酶）、钙泵（Ｃａ２＋、Ｍｇ２＋－ＡＴＰ酶）活性和膜过氧化氢酶（ＣＡＴ）活性，并用硫代巴比妥酸比色法测定患者红细胞膜脂质过氧化物（ＬＰＯ）含量。患者红细胞膜Ｎａ＋、Ｋ＋－ＡＴＰ酶活性和Ｃａ２＋、Ｍｇ２＋－ＡＴＰ酶活性分别显著低于正常人３４．７５％（Ｐ＜０．０１）和２６．７７％（Ｐ＜０．０１）；ＣＡＴ活性显著低于正常人２０．０７％（Ｐ＜０．０１）；而患者ＬＰＯ含量却显著高于正常人９７．５０％（Ｐ＜０．０１）。结果提示风心病患者瓣膜病变与质膜钠、钙泵活性变化以及膜脂质过氧化作用有关。

Screening for SH3TC2, PMP2, and BSCL2 Variants in a Cohort of Chinese Patients with Charcot-Marie-Tooth

Background： SH3TC2, PMP2, and BSCL2 genes are related to autosomal recessive （AR） Charcot-Marie-Tooth （CMT） disease type 1, autosomal dominant （AD）-CMTI, and AD-CMT2, respectively. Pathogenic variants in these three genes were not well documented in Chinese CMT patients. Therefore, this study aims to detect SH3TC2, PMP2, and BSCL2 pathogenic variants in a cohort of 315 unrelated Chinese CMT families. Methods： A total of 315 probands from 315 unrelated Chinese CMT families were recruited from the Department of Neurology of Third Xiangya Hospital and Xiangya Hospital. We screened for SH3TC2 pathogenic variants in 84 AR or sporadic CMT probands, PMP2 pathogenic variants in 39 AD or sporadic CMTI probands, and BSCL2 pathogenic variants in 50 AD or sporadic CMT2 probands, using polymerase chain reaction and Sanger sequencing. All these patients were out of 315 unrelated Chinese CMT families and genetically undiagnosed after exclusion of pathogenic variants of PMP22, MFN2, MPZ, GJB 1, GDAP1, HSPB1, HSPB8, EGR2, NEFL. and RABT. Candidate variants were analyzed based on the standards and guidelines of American College of Medical Genetics and Genomics （ACMG）. Clinical features were reevaluated. Results： We identified three novel heterozygous variants such as p.L95V （c.283C〉G）, p.L 1048P （c.3143T〉C）, and p.V 1105 M （c.3313G〉A） of SH3TC2 gene and no pathogenic variants of PMP2 and BSCL2 genes. Although evaluation in silico and screening in the healthy control revealed that the three SH3TC2 variants were likely pathogenic, no second allele variants were discovered. According to the standards and guidelines of ACMG, the heterozygous SH3TC2 variants such as p.L95V, p.LI048P, and p.V1105M were considered to be of uncertain significance. Conclusions： SH3TC2, PMP2, and BSCL2 pathogenic variants might be rare in Chinese CMT patients. Further studies to confirm our findings are needed.

Novel nervous and multi-system regenerative therapeutic strategies for diabetes mellitus with mTOR

Throughout the globe,diabetes mellitus（DM） is increasing in incidence with limited therapies presently available to prevent or resolve the significant complications of this disorder.DM impacts multiple organs and affects all components of the central and peripheral nervous systems that can range from dementia to diabetic neuropathy.The mechanistic target of rapamycin（m TOR） is a promising agent for the development of novel regenerative strategies for the treatment of DM.m TOR and its related signaling pathways impact multiple metabolic parameters that include cellular metabolic homeostasis,insulin resistance,insulin secretion,stem cell proliferation and differentiation,pancreatic β-cell function,and programmed cell death with apoptosis and autophagy.m TOR is central element for the protein complexes m TOR Complex 1（m TORC1） and m TOR Complex 2（m TORC2） and is a critical component for a number of signaling pathways that involve phosphoinositide 3-kinase（PI 3-K）,protein kinase B（Akt）,AMP activated protein kinase（AMPK）,silent mating type information regulation 2 homolog 1（Saccharomyces cerevisiae）（SIRT1）,Wnt1 inducible signaling pathway protein 1（WISP1）,and growth factors.As a result,m TOR represents an exciting target to offer new clinical avenues for the treatment of DM and the complications of this disease.Future studies directed to elucidate the delicate balance m TOR holds over cellular metabolism and the impact of its broad signaling pathways should foster the translation of these targets into effective clinical regimens for DM.

A Novel Dimeric Dipeptide Mimetic of the Nerve Growth Factor Exhibits Pharmacological Effects upon Systemic Administration and Has No Side Effects Accompanying the Neurotrophin Treatment

The development of small molecule nerve growth factor (NGF) mimetics is a promising approach to overcome limitations in the use of the neurotrophin as a drug, which are poor pharmacokinetics and undesirable side effects. We designed dimeric dipeptide called GK-2 (bis(N-succinyl-L-glutamyl-L-lysine)hexametylendiamide) on the base of beta-turn sequence of NGF loop4 which most exposed to solvent and hence can play the major role in the interaction of NGF with the receptor. It was shown, that GK-2 stimulates phosphorylation of TrkA receptor, selectively activates PI3K/Akt signaling cascade that is important for cell survival, and does not activate MAPK/Erk pathway, associated not only with cell survival but also with cell differentiation. According to these data, GK-2 in vitro prevented H2O2- or MPTP- or glutamate-induced neuronal cell death at nanomolar concentrations, but did not provoke neurite outgrowth in PC12 cells. In vivo GK-2 exhibits therapeutic effects in models of Parkinson’s disease, Alzheimer’s disease, brain ischemia and diabetes mellitus. GK-2 shows activity in doses 0.01 - 5 mg/kg intraperitoneally and retains the activity after oral administration in dose 10 mg/kg. GK-2 has no side effects accompanying NGF treatment namely hyperalgesia and weight loss. Thus, the designed dimeric substituted dipeptide provides promising drug candidate and a molecular tool for investigating the possibility of divergence in NGF therapeutic and adverse effects.

钾-氯离子协同转运蛋白2在神经系统疾病中的研究进展

钾-氯离子协同转运蛋白2（KCC2）大量表达于哺乳动物成熟神经元中。众多研究表明KCC2与多种神经系统疾病的发生机制密切相关，从而广受关注。本文将综述KCC2在神经系统疾病中的最新研究进展。

KCa3.1离子通道及相关疾病研究进展

KCa3.1即中电导钙激活钾通道(intermediate-conductance Ca2+-activated K+channel),通过调节细胞膜电位和钙信号参与红细胞容积调节、淋巴细胞活化、巨噬细胞迁移、丝裂原刺激的血管平滑肌细胞和成纤维细胞增殖等过程,并在多种疾病的发生、发展中发挥作用。本文对KCa3.1的病理、生理作用及其在炎症及自身免疫性疾病、动脉粥样硬化等疾病中作用的研究进展作一综述。

Nasal delivery of broadly neutralizing antibodies protects mice from lethal challenge with SARS-CoV-2 delta and omicron variants

Multiple new variants of severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)have constantly emerged,as the delta and omicron variants,which have developed resistance to currently gained neutralizing antibodies.This highlights a critical need to discover new therapeutic agents to overcome the variants mutations.Despite the availability of vaccines against coronavirus disease 2019(COVID-19),the use of broadly neutralizing antibodies has been considered as an alternative way for the prevention or treatment of SARS-Co V-2 variants infection.Here,we show that the nasal delivery of two previously characterized broadly neutralizing antibodies(F61 and H121)protected K18-h ACE2 mice against lethal challenge with SARS-Co V-2 variants.The broadly protective efficacy of the F61 or F61/F121 cocktail antibodies was evaluated by lethal challenge with the wild strain(WIV04)and multiple variants,including beta(B.1.351),delta(B.1.617.2),and omicron(B.1.1.529)at 200or 1000 TCID_(50),and the minimum antibody administration doses(5-1.25 mg/kg body weight)were also evaluated with delta and omicron challenge.Fully prophylactic protections were found in all challenged groups with both F61 and F61/H121 combination at the administration dose of 20 mg/kg body weight,and corresponding mice lung viral RNA showed negative,with almost all alveolar septa and cavities remaining normal.Furthermore,low-dose antibody treatment induced significant prophylactic protection against lethal challenge with delta and omicron variants,whereas the F61/H121 combination showed excellent results against omicron infection.Our findings indicated the potential use of broadly neutralizing monoclonal antibodies as prophylactic and therapeutic agent for protection of current emerged SARS-Co V-2 variants infection.