Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment...Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.展开更多
Intervertebral disc degeneration （IDD） is characterized by disc dehydration and herniation, which is often associated with low back pain and lumbar radiculopathy due to nerve root compression or inflammation. The pa...Intervertebral disc degeneration （IDD） is characterized by disc dehydration and herniation, which is often associated with low back pain and lumbar radiculopathy due to nerve root compression or inflammation. The pathophysiology of IDD is not completely elucidated so far. Some researchers have indicated that disc degeneration begins as early as the second decade of life （Mayer et al., 2013）. Common risk factors are considered to associate with age, gender, smoking history, occupation, disc injury, and biomechanical factors. However, some epidemiologic studies highlighted that disc degeneration may be caused to a large degree by hereditary factors with apparently a relatively minor effects of environmental and behavioral risk factors （Videman et al., 1998; Cheung et al., 2006; Eser et al., 2010; Mayer et al., 2013; Vieira et al., 2014）, which indicated that genetic factors might play an important role in the pathogenesis of IDD.展开更多
Objective The aim of the study was to investigate the prognostic value of the preoperative peripheral neutrophil-to-lymphocyte ratio （NLR） in patients with hepatocellular cancer （HCC） and cirrhosis after hepa- tec...Objective The aim of the study was to investigate the prognostic value of the preoperative peripheral neutrophil-to-lymphocyte ratio （NLR） in patients with hepatocellular cancer （HCC） and cirrhosis after hepa- tectomy. Methods This retrospective study included 321 patients with HCC who underwent resection. The NLR was calculated using the neutrophil and lymphocyte counts in routine preoperative blood tests. Receiver operating characteristic curve analysis was performed to select the most appropriate NLR cutoff value. The preoperative NLR, patient demographics, and clinical and pathological data, including disease-free survival （DFS） and overall survival （OS）, were analyzed. Results The NLR was correlated with alpha-fetoprotein levels （X2 = 5.876, P = 0.015）, tumor size （X2 = 32.046, P 〈 0.001）, portal vein tumor thrombus （PVTT; x2 = 4.930, P = 0.026）, tumor encapsulation （x2 = 7.243, P = 0.007）, and recurrence （x2 = 7.717, P = 0.005）. Multivariate analyses illustrated that the number of tumors, PVTT, tumor size, and the NLR were independent factors for predicting DFS and OS. in patients with HCC and cirrhosis, but not among those without cirrhosis, a larger NLR predicted poorer postoperative DFS and OS （both P 〈 0.001）. Conclusion As a simple, effective independent predictor for patients with HCC, the preoperative NLR plays an important role in accurately predicting the postoperative outcomes of patients with HCC and cir- rhosis, but not those of patients without cirrhosis.展开更多
基金supported by the Ministry of Science and Technology of China(2020YFA0908900)National Natural Science Foundation of China(21935011 and 82072490)+1 种基金Shenzhen Science and Technology Innovation Commission(KQTD20200820113012029 and KJZD20230923114612025)Guangdong Provincial Key Laboratory of Advanced Biomaterials(2022B1212010003).
文摘Aging is a pivotal risk factor for intervertebral disc degeneration(IVDD)and chronic low back pain(LBP).The restoration of aging nucleus pulposus cells(NPCs)to a youthful epigenetic state is crucial for IVDD treatment,but remains a formidable challenge.Here,we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes(Oct4,Klf4 and Sox2)in Cavin2-modified exosomes(OKS@M-Exo)for treatment of IVDD and alleviating LBP.The functional OKS@M-Exo efficaciously alleviated senescence markers(p16^(INK4a),p21^(CIP1)and p53),reduced DNA damage and H4K20me3 expression,as well as restored proliferation ability and metabolic balance in senescent NPCs,as validated through in vitro experiments.In a rat model of IVDD,OKS@M-Exo maintained intervertebral disc height,nucleus pulposus hydration and tissue structure,effectively ameliorated IVDD via decreasing the senescence markers.Additionally,OKS@MExo reduced nociceptive behavior and downregulated nociception markers,indicating its efficiency in alleviating LBP.The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation.Collectively,reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.
文摘Intervertebral disc degeneration （IDD） is characterized by disc dehydration and herniation, which is often associated with low back pain and lumbar radiculopathy due to nerve root compression or inflammation. The pathophysiology of IDD is not completely elucidated so far. Some researchers have indicated that disc degeneration begins as early as the second decade of life （Mayer et al., 2013）. Common risk factors are considered to associate with age, gender, smoking history, occupation, disc injury, and biomechanical factors. However, some epidemiologic studies highlighted that disc degeneration may be caused to a large degree by hereditary factors with apparently a relatively minor effects of environmental and behavioral risk factors （Videman et al., 1998; Cheung et al., 2006; Eser et al., 2010; Mayer et al., 2013; Vieira et al., 2014）, which indicated that genetic factors might play an important role in the pathogenesis of IDD.
基金Supported by grants from the National Natural Science Foundation of China(No.81201918)the Science and Technology Project of Guangdong Province(No.2012B031800099)+1 种基金the Doctorial Fellowship of Higher Education of China(No.200805581172)the Scientific Research Foundation for Returned Overseas Chinese Scholars and the State Education Ministry(No.311,in 2015)
文摘Objective The aim of the study was to investigate the prognostic value of the preoperative peripheral neutrophil-to-lymphocyte ratio （NLR） in patients with hepatocellular cancer （HCC） and cirrhosis after hepa- tectomy. Methods This retrospective study included 321 patients with HCC who underwent resection. The NLR was calculated using the neutrophil and lymphocyte counts in routine preoperative blood tests. Receiver operating characteristic curve analysis was performed to select the most appropriate NLR cutoff value. The preoperative NLR, patient demographics, and clinical and pathological data, including disease-free survival （DFS） and overall survival （OS）, were analyzed. Results The NLR was correlated with alpha-fetoprotein levels （X2 = 5.876, P = 0.015）, tumor size （X2 = 32.046, P 〈 0.001）, portal vein tumor thrombus （PVTT; x2 = 4.930, P = 0.026）, tumor encapsulation （x2 = 7.243, P = 0.007）, and recurrence （x2 = 7.717, P = 0.005）. Multivariate analyses illustrated that the number of tumors, PVTT, tumor size, and the NLR were independent factors for predicting DFS and OS. in patients with HCC and cirrhosis, but not among those without cirrhosis, a larger NLR predicted poorer postoperative DFS and OS （both P 〈 0.001）. Conclusion As a simple, effective independent predictor for patients with HCC, the preoperative NLR plays an important role in accurately predicting the postoperative outcomes of patients with HCC and cir- rhosis, but not those of patients without cirrhosis.
