The retina is one of the most energy demanding tissues in the body. Like most neurons in the central nervous system, retinal neurons consume high amounts of adenosine-5′-triphosphate（ATP） to generate visual signal ...The retina is one of the most energy demanding tissues in the body. Like most neurons in the central nervous system, retinal neurons consume high amounts of adenosine-5′-triphosphate（ATP） to generate visual signal and transmit the information to the brain. Disruptions in retinal metabolism can cause neuronal dysfunction and degeneration resulting in severe visual impairment and even blindness. The homeostasis of retinal metabolism is tightly controlled by multiple signaling pathways, such as the unfolded protein response（UPR）, and the close interactions between retinal neurons and other retinal cell types including vascular cells and Müller glia. The UPR is a highly conserved adaptive cellular response and can be triggered by many physiological stressors and pathophysiological conditions. Activation of the UPR leads to changes in glycolytic rate, ATP production, de novo serine synthesis, and the hexosamine biosynthetic pathway, which are considered critical components of Müller glia metabolism and provide metabolic support to surrounding neurons. When these pathways are disrupted, neurodegeneration occurs rapidly. In this review, we summarize recent advance in studies of the UPR in Müller glia and highlight the potential role of the UPR in retinal degeneration through regulation of Müller glia metabolism.展开更多
Objective:To investigate the effect of alendronate on bone mass and organ pathology of ovariectomized mice.Methods:Thirty SPF grade C57 female mice were randomly divided into three groups(n=10):Sham operation group(Sh...Objective:To investigate the effect of alendronate on bone mass and organ pathology of ovariectomized mice.Methods:Thirty SPF grade C57 female mice were randomly divided into three groups(n=10):Sham operation group(Sham),ovariectomized group(OVX)and ovariectomized+alendronate group(ALN).The sodium alendronate was injected subcutaneously at 400μg/kg twice a week in the ALN group.The equal volume of normal saline was injected subcutaneously twice a week in the SHAM group and OVX group.After 12 weeks of drug administration,the samples were taken.The organ coefficients,main organ pathological sections,and bone histopathological sections were observed,and the micro CT,L4 biomechanics and serum biochemical indicators were analyzed.Results:The uterine coefficient of Sham group was(0.0054±0.0007)significantly higher than that of OVX group(0.0026±0.0009)and ALN group(0.0025±0.0007),and the difference was statistically significant(P<0.05).No obvious lesions or toxic or side effects were observed in the main organs.Compared with the OVX group,the ALN group with decalcified sections of bone tissue had compact trabecular structure and fewer adipocytes.Micro-CT results showed that the Tb.BMD,Tb.N,Tb.Th and Tb.BV/TV values of the ALN group were significantly increased compared with those of the OVX group,but the Tb.Sp value was significantly decreased,and the difference was statistically significant(P<0.05).In L4 vertebral body biomechanics,the elastic modulus(50.29±13.43)and maximum load number(29.83±4.92)of ALN group were significantly higher than those of OVX group(14.77±3.12)and maximum load number(11.57±3.18),and the difference was statistically significant(P<0.05).Compared with the OVX group,the serum OCN and PINP indicators of bone formation in the ALN group were increased,while the bone resorption indicators TRACP-5b and CTX-I were decreased,with statistical significance(P<0.05).Conclusion:Alendronate sodium improves bone quality by increasing bone density,improving bone microstructure,increasing bone strength,promoting bone formation and inhibiting bone resorption,without obvious toxic and side effects on organs.展开更多
Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume respon...Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.展开更多
Background:Retinal diseases can lead to severe visual impairment and even blindness,but current treatments are limited.For precise targeted therapy,the pathophysiological mechanisms of the diseases still need to be fu...Background:Retinal diseases can lead to severe visual impairment and even blindness,but current treatments are limited.For precise targeted therapy,the pathophysiological mechanisms of the diseases still need to be further explored.Iron serves an essential role in many biological activities and helps maintain the function and morphology of the retina.The vision problems caused by retinal diseases are affecting more and more people,the study of iron metabolism in retinal diseases possesses great potential for clinical application.Main text:Iron maintains a dynamic balance in the retina but in excess is toxic to the retina.Iron overload can lead to various pathological changes in the retina through oxidative stress,inflammation,cell death,angiogenesis and other pathways.It is therefore involved in the progression of retinal diseases such as age-related macular degeneration,glaucoma,diabetic retinopathy,retinitis pigmentosa,and hereditary iron overload.In recent years,iron chelators have been shown to be effective in the treatment of retinal diseases,but the exact mechanism is not yet fully understood.This question prompted further investigation into the specific mechanisms by which iron metabolism is involved in retinal disease.Conclusions:This review summarizes iron metabolism processes in the retina and mechanistic studies of iron metabolism in the progression of retinal disease.It also highlights the therapeutic potential of iron chelators in retinal diseases.展开更多
AIM To study the expression and significance of laminin in human colorectal carcinoma. METHODS Using the monoclonal antibody to laminin and streptavidin peroxidase immunohistochemical method, the expression of lam...AIM To study the expression and significance of laminin in human colorectal carcinoma. METHODS Using the monoclonal antibody to laminin and streptavidin peroxidase immunohistochemical method, the expression of laminin in 63 cases of human colorectal carcinoma tissues was determined. RESULTS In normal large intestinal mucosa adjacent to carcinoma, laminin was largely restricted to basement membrane in continuous linear pattern. In contrast, human colorectal carcinomas exhibited a progressive loss of an intact basement membrane that was correlated with decreasing differentiation degree. Well and moderately differentiated tumors exhibited a thin basement membrane with intermittent disruptions, and poorly differentiated tumors exhibited no areas of intact basement membrane. An association was found between lack of basement membrane laminin immunohistochemical staining in colorectal carcinoma and poorly differentiated tumor ( P <0 01) . CONCLUSION Immunohistochemical staining for laminin could provide a very useful index for the determination of the differentiation degree of colorectal carcinoma.展开更多
Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components.The emerging field of immunometabolism highlights the importance of...Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components.The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells.Macrophages are embryo-or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome,atherosclerosis,fibrosis or cancer.Macrophage metabolism has largely been studied in vitro.However,different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions.This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions.Here,we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.展开更多
BACKGROUND pT2+prostate cancer(PCa),a term first used in 2004,refers to organ-confined PCa characterized by a positive surgical margin(PSM)without extracapsular extension.Patients with a PSM are vulnerable to biochemi...BACKGROUND pT2+prostate cancer(PCa),a term first used in 2004,refers to organ-confined PCa characterized by a positive surgical margin(PSM)without extracapsular extension.Patients with a PSM are vulnerable to biochemical recurrence(BCR)following radical prostatectomy(RP);however,whether adjuvant radiotherapy(aRT)is imperative to PSM after RP remains controversial.This study had the longest follow-up on pT2+PCa after robotic-assisted RP since 2004.Moreover,we discussed our viewpoints on pT2+PCa based on real-world experiences.AIM To conclude a 10-year surveillance on pT2+PCa and compare our results with those of the published literature.METHODS Forty-eight patients who underwent robotic-assisted RP between 2008 and 2011 were enrolled.Two serial tests of prostate specific antigen(PSA)≥0.2 ng/mL were defined as BCR.Various designed factors were analyzed using statistical tools for BCR risk.SAS 9.4 was applied and significance was defined as P<0.05.Univariate,multivariate,linear regression,and receiver operating characteristic(ROC)curve analyses were performed for statistical analyses.RESULTS With a median follow-up period of 9 years,25(52%)patients had BCR(BCR group),and the remaining 23(48%)patients did not(non-BCR group).The median time for BCR test was 4 years from the first postoperative PSA nadir.Preoperative PSA was significantly different between the BCR and non-BCR groups(P<0.001),and ROC curve analysis of preoperative PSA suggested a cutoff value of 19.09 ng/mL(sensitivity,0.600;specificity:0.739).The linear regression analysis showed no correlation between time to BCR and preoperative PSA(Pearson’s correlation,0.13;adjusted R2=0.026).CONCLUSION Robotic-assisted RP in pT2+PCa of worse conditions can provide better BCR-free survival.A surgical technique limiting the PSM in favorable situations is warranted to lower the pT2+PCa BCR rate.Preoperative PSA cut-off value of 19.09 ng/mL is a predictive factor for BCR.Based on our experiences and review of the literature,we do not recommend routine aRT for pT2+PCa.展开更多
Metabolic liver diseases(MLD)are the second most common indication for liver transplantation(LT)in children.This is based on the fact that the majority of enzymes involved in various metabolic pathways are present wit...Metabolic liver diseases(MLD)are the second most common indication for liver transplantation(LT)in children.This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation.LT is also performed in metabolic disorders for end-stage liver disease,its sequelae including hepatocellular cancer.It is also performed for preventing metabolic crisis’,arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia.Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis,cholestasis,inflammation,variable amount of fibrosis,and cirrhosis.The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT.A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters.Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver.The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.展开更多
Background: Astrocytic tumors of the retina are rare. We report and discuss the clinical features of two cases of retinal astrocytoma along with presenting a current literature review. Case Presentation: Case 1 was a ...Background: Astrocytic tumors of the retina are rare. We report and discuss the clinical features of two cases of retinal astrocytoma along with presenting a current literature review. Case Presentation: Case 1 was a 46-year-old Japanese female who became aware of her decreased visual acuity. A fundus photograph indicated the presence of a 5 mm hemispherical yellow-white tumor, retinal edema and hard exudate around the tumor. In case 2, a 36-year-old Japanese female became aware of her myodesopsia, and presented with a retinal tumor and vitreous hemorrhage in her right eye. Since the tumors occurred in the peripheral retina in both cases, endoresections were performed. Histological examination showed that the tumors were composed of spindle-shaped cells with small nuclei, which was consistent with astrocytes. Conclusion: Pathologically, it can be difficult to differentiate astrocytic tumors. Therefore, when making a diagnosis, it is important that comprehensive examinations be done in conjunction with the clinical findings. Since retinal astrocytoma has a favorable prognosis, provided proper treatment is administered, utilization of endoresection for peripheral astrocytoma may be advantageous in this patient group.展开更多
Background:To treat vascular proliferative diseases,anti-VEGF therapies have shown systemic adverse effects attributable to the lack of selectivity between pathological and physiological angiogenesis.Thus,identifying ...Background:To treat vascular proliferative diseases,anti-VEGF therapies have shown systemic adverse effects attributable to the lack of selectivity between pathological and physiological angiogenesis.Thus,identifying the molecular mechanisms that are only specific to pathological cell types is crucial to develop better precision medicine.Methods:Here,we used different cell type enrichment approaches combined with single-cell RNA sequencing to define the transcriptomic changes within each retinal cell types in a mouse model of ischemic retinopathy.This retinal model develops pathological neovascularization(NV)in response to local hypoxia following oxygen-induced vessel obliteration(P7 to P12).The NV phenotype is characterized by the progressive appearance of vascular tufts resulting from misguided,abnormal proliferation of endothelial cells that we monitored at 3 consecutive time points-P12,P14 and P17(peak of NV).Results:By following the dynamic response to hypoxia,our experimental design reveals how pathological angiogenesis is specifically associated with significant metabolic adaptations in different subtypes of endothelial cells(i.e.,Tips vs Stalk cells).We also identify a pathological subtype of glial cells over-expressing VEGFA and pro-inflammatory IL-1 receptor subunits.This subtype of activated glial cells was targeted using selective IL1R antagonist treatment which reduced glial activation,inflammation,NV and promotes physiological angiogenesis,therefore improving tissue regeneration.Conclusions:Our results illustrate how analyzing cell type heterogeneity in tissues developing pathological angiogenesis allows establishing better targeting therapies to restore vascular integrity.展开更多
Alzheimer's disease(AD)is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss.Emerging evidence suggests that autophagy plays an important role in the pathogene...Alzheimer's disease(AD)is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss.Emerging evidence suggests that autophagy plays an important role in the pathogenesis of AD through the regulation of amyloid-beta(Aβ)and tau metabolism,and that autophagy dysfunction exacerbates amyloidosis and tau pathology.Therefore,targeting autophagy may be an effective approach for the treatment of AD.Animal models are considered useful tools for investigating the pathogenic mechanisms and therapeutic strategies of diseases.This review aims to summarize the pathological alterations in autophagy in representative AD animal models and to present recent studies on newly discovered autophagy-stimulating interventions in animal AD models.Finally,the opportunities,difficulties,and future directions of autophagy targeting in AD therapy are discussed.展开更多
Axonal regeneration in the central nervous system is an energy-intensive process.In contrast to mammals,adult zebrafish can functionally recover from neuronal injury.This raises the question of how zebrafish can cope ...Axonal regeneration in the central nervous system is an energy-intensive process.In contrast to mammals,adult zebrafish can functionally recover from neuronal injury.This raises the question of how zebrafish can cope with this high energy demand.We previously showed that in adult zebrafish,subjected to an optic nerve crush,an antagonistic axon-dendrite interplay exists wherein the retraction of retinal ganglion cell dendrites is a prerequisite for effective axonal repair.We postulate a‘dendrites for regeneration’paradigm that might be linked to intraneuronal mitochondrial reshuffling,as ganglion cells likely have insufficient resources to maintain dendrites and restore axons simultaneously.Here,we characterized both mitochondrial distribution and mitochondrial dynamics within the different ganglion cell compartments(dendrites,somas,and axons)during the regenerative process.Optic nerve crush resulted in a reduction of mitochondria in the dendrites during dendritic retraction,whereafter enlarged mitochondria appeared in the optic nerve/tract during axonal regrowth.Upon dendritic regrowth in the retina,mitochondrial density inside the retinal dendrites returned to baseline levels.Moreover,a transient increase in mitochondrial fission and biogenesis was observed in retinal ganglion cell somas after optic nerve damage.Taken together,these findings suggest that during optic nerve injury-induced regeneration,mitochondria shift from the dendrites to the axons and back again and that temporary changes in mitochondrial dynamics support axonal and dendritic regrowth after optic nerve crush.展开更多
Alzheimer’s disease(AD)is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors,accompanied by dysregulation of numerous intracellular signaling a...Alzheimer’s disease(AD)is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors,accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain.At the cellular and molecular levels,the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities,compromised bioenergetics,impaired lipid metabolism,and reduced overall metabolic capacity,which lead to abnormal neural network activity and impaired neuroplasticity,thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles.The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise.Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state,inhibit different pathophysiological molecular pathways associated with AD,influence the pathological process of AD,and exert a protective effect,there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise.Here,we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD,including glucose metabolism,lipid metabolism,Aβmetabolism and transport,iron metabolism and tau pathology.How metabolic states influence brain health is also presented.A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.展开更多
基金supported,in part,by NIH/NEI grants EY019949 and EY025061an Unrestricted Grant to the Department of Ophthalmology,SUNY-Buffalo,from Research to Prevent Blindness
文摘The retina is one of the most energy demanding tissues in the body. Like most neurons in the central nervous system, retinal neurons consume high amounts of adenosine-5′-triphosphate（ATP） to generate visual signal and transmit the information to the brain. Disruptions in retinal metabolism can cause neuronal dysfunction and degeneration resulting in severe visual impairment and even blindness. The homeostasis of retinal metabolism is tightly controlled by multiple signaling pathways, such as the unfolded protein response（UPR）, and the close interactions between retinal neurons and other retinal cell types including vascular cells and Müller glia. The UPR is a highly conserved adaptive cellular response and can be triggered by many physiological stressors and pathophysiological conditions. Activation of the UPR leads to changes in glycolytic rate, ATP production, de novo serine synthesis, and the hexosamine biosynthetic pathway, which are considered critical components of Müller glia metabolism and provide metabolic support to surrounding neurons. When these pathways are disrupted, neurodegeneration occurs rapidly. In this review, we summarize recent advance in studies of the UPR in Müller glia and highlight the potential role of the UPR in retinal degeneration through regulation of Müller glia metabolism.
基金General program of National Natural Science Foundation of China(81770879)Gansu Youth Science and Technology Fund Program(20JR5RA589)Joint Service Support Force 940 Hospital Laboratory Cultivation Project(2021yxky081)。
文摘Objective:To investigate the effect of alendronate on bone mass and organ pathology of ovariectomized mice.Methods:Thirty SPF grade C57 female mice were randomly divided into three groups(n=10):Sham operation group(Sham),ovariectomized group(OVX)and ovariectomized+alendronate group(ALN).The sodium alendronate was injected subcutaneously at 400μg/kg twice a week in the ALN group.The equal volume of normal saline was injected subcutaneously twice a week in the SHAM group and OVX group.After 12 weeks of drug administration,the samples were taken.The organ coefficients,main organ pathological sections,and bone histopathological sections were observed,and the micro CT,L4 biomechanics and serum biochemical indicators were analyzed.Results:The uterine coefficient of Sham group was(0.0054±0.0007)significantly higher than that of OVX group(0.0026±0.0009)and ALN group(0.0025±0.0007),and the difference was statistically significant(P<0.05).No obvious lesions or toxic or side effects were observed in the main organs.Compared with the OVX group,the ALN group with decalcified sections of bone tissue had compact trabecular structure and fewer adipocytes.Micro-CT results showed that the Tb.BMD,Tb.N,Tb.Th and Tb.BV/TV values of the ALN group were significantly increased compared with those of the OVX group,but the Tb.Sp value was significantly decreased,and the difference was statistically significant(P<0.05).In L4 vertebral body biomechanics,the elastic modulus(50.29±13.43)and maximum load number(29.83±4.92)of ALN group were significantly higher than those of OVX group(14.77±3.12)and maximum load number(11.57±3.18),and the difference was statistically significant(P<0.05).Compared with the OVX group,the serum OCN and PINP indicators of bone formation in the ALN group were increased,while the bone resorption indicators TRACP-5b and CTX-I were decreased,with statistical significance(P<0.05).Conclusion:Alendronate sodium improves bone quality by increasing bone density,improving bone microstructure,increasing bone strength,promoting bone formation and inhibiting bone resorption,without obvious toxic and side effects on organs.
基金supported by the National Natural Science Foundation of China,No.31930068National Key Research and Development Program of China,Nos.2018YFA0107302 and 2021YFA1101203(all to HX).
文摘Müller glia,as prominent glial cells within the retina,plays a significant role in maintaining retinal homeostasis in both healthy and diseased states.In lower vertebrates like zebrafish,these cells assume responsibility for spontaneous retinal regeneration,wherein endogenous Müller glia undergo proliferation,transform into Müller glia-derived progenitor cells,and subsequently regenerate the entire retina with restored functionality.Conversely,Müller glia in the mouse and human retina exhibit limited neural reprogramming.Müller glia reprogramming is thus a promising strategy for treating neurodegenerative ocular disorders.Müller glia reprogramming in mice has been accomplished with remarkable success,through various technologies.Advancements in molecular,genetic,epigenetic,morphological,and physiological evaluations have made it easier to document and investigate the Müller glia programming process in mice.Nevertheless,there remain issues that hinder improving reprogramming efficiency and maturity.Thus,understanding the reprogramming mechanism is crucial toward exploring factors that will improve Müller glia reprogramming efficiency,and for developing novel Müller glia reprogramming strategies.This review describes recent progress in relatively successful Müller glia reprogramming strategies.It also provides a basis for developing new Müller glia reprogramming strategies in mice,including epigenetic remodeling,metabolic modulation,immune regulation,chemical small-molecules regulation,extracellular matrix remodeling,and cell-cell fusion,to achieve Müller glia reprogramming in mice.
文摘Background:Retinal diseases can lead to severe visual impairment and even blindness,but current treatments are limited.For precise targeted therapy,the pathophysiological mechanisms of the diseases still need to be further explored.Iron serves an essential role in many biological activities and helps maintain the function and morphology of the retina.The vision problems caused by retinal diseases are affecting more and more people,the study of iron metabolism in retinal diseases possesses great potential for clinical application.Main text:Iron maintains a dynamic balance in the retina but in excess is toxic to the retina.Iron overload can lead to various pathological changes in the retina through oxidative stress,inflammation,cell death,angiogenesis and other pathways.It is therefore involved in the progression of retinal diseases such as age-related macular degeneration,glaucoma,diabetic retinopathy,retinitis pigmentosa,and hereditary iron overload.In recent years,iron chelators have been shown to be effective in the treatment of retinal diseases,but the exact mechanism is not yet fully understood.This question prompted further investigation into the specific mechanisms by which iron metabolism is involved in retinal disease.Conclusions:This review summarizes iron metabolism processes in the retina and mechanistic studies of iron metabolism in the progression of retinal disease.It also highlights the therapeutic potential of iron chelators in retinal diseases.
文摘AIM To study the expression and significance of laminin in human colorectal carcinoma. METHODS Using the monoclonal antibody to laminin and streptavidin peroxidase immunohistochemical method, the expression of laminin in 63 cases of human colorectal carcinoma tissues was determined. RESULTS In normal large intestinal mucosa adjacent to carcinoma, laminin was largely restricted to basement membrane in continuous linear pattern. In contrast, human colorectal carcinomas exhibited a progressive loss of an intact basement membrane that was correlated with decreasing differentiation degree. Well and moderately differentiated tumors exhibited a thin basement membrane with intermittent disruptions, and poorly differentiated tumors exhibited no areas of intact basement membrane. An association was found between lack of basement membrane laminin immunohistochemical staining in colorectal carcinoma and poorly differentiated tumor ( P <0 01) . CONCLUSION Immunohistochemical staining for laminin could provide a very useful index for the determination of the differentiation degree of colorectal carcinoma.
基金SKW and the project that gave rise to these results received support in the form of a fellowship from the La Caixa Foundation(ID 100010434)The fellowship code is LCF/BQ/PR20/11770008+5 种基金GD is supported by a European Molecular Biology Organization Long-term Fellowship(ALTF 379-2019)This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No.892965IHM is supported by a La Caixa INPhINIT fellowship(ID 100010434,fellowship code:LCF/BQ/IN17/11620074)Work in the DS laboratory is funded by the CNIC,by the European Research Council(ERC-2016-Consolidator Grant 725091)by the Agencia Estatal de Investigación(PID2019-108157RB)by the Comunidad de Madrid(B2017/BMD-3733 Immunothercan-CM),by Atresmedia(Constantes y Vitales prize),by the Fondo Solidario Juntos(Banco Santander),and by the FundacióLa Maratóde TV3(201723).The CNIC is supported by the Instituto de Salud Carlos III(ISCIII),the MICINN and the Pro CNIC Foundation.
文摘Cellular metabolism orchestrates the intricate use of tissue fuels for catabolism and anabolism to generate cellular energy and structural components.The emerging field of immunometabolism highlights the importance of cellular metabolism for the maintenance and activities of immune cells.Macrophages are embryo-or adult bone marrow-derived leukocytes that are key for healthy tissue homeostasis but can also contribute to pathologies such as metabolic syndrome,atherosclerosis,fibrosis or cancer.Macrophage metabolism has largely been studied in vitro.However,different organs contain diverse macrophage populations that specialize in distinct and often tissue-specific functions.This context specificity creates diverging metabolic challenges for tissue macrophage populations to fulfill their homeostatic roles in their particular microenvironment and conditions their response in pathological conditions.Here,we outline current knowledge on the metabolic requirements and adaptations of macrophages located in tissues during homeostasis and selected diseases.
文摘BACKGROUND pT2+prostate cancer(PCa),a term first used in 2004,refers to organ-confined PCa characterized by a positive surgical margin(PSM)without extracapsular extension.Patients with a PSM are vulnerable to biochemical recurrence(BCR)following radical prostatectomy(RP);however,whether adjuvant radiotherapy(aRT)is imperative to PSM after RP remains controversial.This study had the longest follow-up on pT2+PCa after robotic-assisted RP since 2004.Moreover,we discussed our viewpoints on pT2+PCa based on real-world experiences.AIM To conclude a 10-year surveillance on pT2+PCa and compare our results with those of the published literature.METHODS Forty-eight patients who underwent robotic-assisted RP between 2008 and 2011 were enrolled.Two serial tests of prostate specific antigen(PSA)≥0.2 ng/mL were defined as BCR.Various designed factors were analyzed using statistical tools for BCR risk.SAS 9.4 was applied and significance was defined as P<0.05.Univariate,multivariate,linear regression,and receiver operating characteristic(ROC)curve analyses were performed for statistical analyses.RESULTS With a median follow-up period of 9 years,25(52%)patients had BCR(BCR group),and the remaining 23(48%)patients did not(non-BCR group).The median time for BCR test was 4 years from the first postoperative PSA nadir.Preoperative PSA was significantly different between the BCR and non-BCR groups(P<0.001),and ROC curve analysis of preoperative PSA suggested a cutoff value of 19.09 ng/mL(sensitivity,0.600;specificity:0.739).The linear regression analysis showed no correlation between time to BCR and preoperative PSA(Pearson’s correlation,0.13;adjusted R2=0.026).CONCLUSION Robotic-assisted RP in pT2+PCa of worse conditions can provide better BCR-free survival.A surgical technique limiting the PSM in favorable situations is warranted to lower the pT2+PCa BCR rate.Preoperative PSA cut-off value of 19.09 ng/mL is a predictive factor for BCR.Based on our experiences and review of the literature,we do not recommend routine aRT for pT2+PCa.
文摘Metabolic liver diseases(MLD)are the second most common indication for liver transplantation(LT)in children.This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation.LT is also performed in metabolic disorders for end-stage liver disease,its sequelae including hepatocellular cancer.It is also performed for preventing metabolic crisis’,arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia.Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis,cholestasis,inflammation,variable amount of fibrosis,and cirrhosis.The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT.A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters.Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver.The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.
文摘Background: Astrocytic tumors of the retina are rare. We report and discuss the clinical features of two cases of retinal astrocytoma along with presenting a current literature review. Case Presentation: Case 1 was a 46-year-old Japanese female who became aware of her decreased visual acuity. A fundus photograph indicated the presence of a 5 mm hemispherical yellow-white tumor, retinal edema and hard exudate around the tumor. In case 2, a 36-year-old Japanese female became aware of her myodesopsia, and presented with a retinal tumor and vitreous hemorrhage in her right eye. Since the tumors occurred in the peripheral retina in both cases, endoresections were performed. Histological examination showed that the tumors were composed of spindle-shaped cells with small nuclei, which was consistent with astrocytes. Conclusion: Pathologically, it can be difficult to differentiate astrocytic tumors. Therefore, when making a diagnosis, it is important that comprehensive examinations be done in conjunction with the clinical findings. Since retinal astrocytoma has a favorable prognosis, provided proper treatment is administered, utilization of endoresection for peripheral astrocytoma may be advantageous in this patient group.
文摘Background:To treat vascular proliferative diseases,anti-VEGF therapies have shown systemic adverse effects attributable to the lack of selectivity between pathological and physiological angiogenesis.Thus,identifying the molecular mechanisms that are only specific to pathological cell types is crucial to develop better precision medicine.Methods:Here,we used different cell type enrichment approaches combined with single-cell RNA sequencing to define the transcriptomic changes within each retinal cell types in a mouse model of ischemic retinopathy.This retinal model develops pathological neovascularization(NV)in response to local hypoxia following oxygen-induced vessel obliteration(P7 to P12).The NV phenotype is characterized by the progressive appearance of vascular tufts resulting from misguided,abnormal proliferation of endothelial cells that we monitored at 3 consecutive time points-P12,P14 and P17(peak of NV).Results:By following the dynamic response to hypoxia,our experimental design reveals how pathological angiogenesis is specifically associated with significant metabolic adaptations in different subtypes of endothelial cells(i.e.,Tips vs Stalk cells).We also identify a pathological subtype of glial cells over-expressing VEGFA and pro-inflammatory IL-1 receptor subunits.This subtype of activated glial cells was targeted using selective IL1R antagonist treatment which reduced glial activation,inflammation,NV and promotes physiological angiogenesis,therefore improving tissue regeneration.Conclusions:Our results illustrate how analyzing cell type heterogeneity in tissues developing pathological angiogenesis allows establishing better targeting therapies to restore vascular integrity.
基金supported by the National Natural Science Foundation of China (82271455)Guangdong Basic and Applied Basic Research Foundation (2022A1515012416)+6 种基金Science and Technology Development FundMacao SAR (0128/2019/A3,0025/2022/A1)Shenzhen Fundamental Research Program (SGDX20210823103804030)University of Macao Grants (MYRG2022-00094-ICMS)awarded to J.H.L.partially supported by the National Key R&D Program of China (2021YFA0805901)National Natural Science Foundation of China (82070199)Guangdong Basic and Applied Basic Research Foundation (2021A1515220078)awarded to D.S.T。
文摘Alzheimer's disease(AD)is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss.Emerging evidence suggests that autophagy plays an important role in the pathogenesis of AD through the regulation of amyloid-beta(Aβ)and tau metabolism,and that autophagy dysfunction exacerbates amyloidosis and tau pathology.Therefore,targeting autophagy may be an effective approach for the treatment of AD.Animal models are considered useful tools for investigating the pathogenic mechanisms and therapeutic strategies of diseases.This review aims to summarize the pathological alterations in autophagy in representative AD animal models and to present recent studies on newly discovered autophagy-stimulating interventions in animal AD models.Finally,the opportunities,difficulties,and future directions of autophagy targeting in AD therapy are discussed.
基金financially supported by the Katholieke Universiteit Leuven Research Council (C14/18/053)the research foundation Flanders (FWO) (G082221N)+1 种基金a personal L’Oréal/UNESCO (For Women in Science) fellowshipa personal FWO fellowship
文摘Axonal regeneration in the central nervous system is an energy-intensive process.In contrast to mammals,adult zebrafish can functionally recover from neuronal injury.This raises the question of how zebrafish can cope with this high energy demand.We previously showed that in adult zebrafish,subjected to an optic nerve crush,an antagonistic axon-dendrite interplay exists wherein the retraction of retinal ganglion cell dendrites is a prerequisite for effective axonal repair.We postulate a‘dendrites for regeneration’paradigm that might be linked to intraneuronal mitochondrial reshuffling,as ganglion cells likely have insufficient resources to maintain dendrites and restore axons simultaneously.Here,we characterized both mitochondrial distribution and mitochondrial dynamics within the different ganglion cell compartments(dendrites,somas,and axons)during the regenerative process.Optic nerve crush resulted in a reduction of mitochondria in the dendrites during dendritic retraction,whereafter enlarged mitochondria appeared in the optic nerve/tract during axonal regrowth.Upon dendritic regrowth in the retina,mitochondrial density inside the retinal dendrites returned to baseline levels.Moreover,a transient increase in mitochondrial fission and biogenesis was observed in retinal ganglion cell somas after optic nerve damage.Taken together,these findings suggest that during optic nerve injury-induced regeneration,mitochondria shift from the dendrites to the axons and back again and that temporary changes in mitochondrial dynamics support axonal and dendritic regrowth after optic nerve crush.
文摘Alzheimer’s disease(AD)is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors,accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain.At the cellular and molecular levels,the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities,compromised bioenergetics,impaired lipid metabolism,and reduced overall metabolic capacity,which lead to abnormal neural network activity and impaired neuroplasticity,thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles.The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise.Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state,inhibit different pathophysiological molecular pathways associated with AD,influence the pathological process of AD,and exert a protective effect,there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise.Here,we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD,including glucose metabolism,lipid metabolism,Aβmetabolism and transport,iron metabolism and tau pathology.How metabolic states influence brain health is also presented.A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.
