Allogeneic hematopoietic stem cell transplantation is a deterministic curative procedure for various hematologic disorders and congenital immunodeficiency.Despite its increased use,the mortality rate for patients unde...Allogeneic hematopoietic stem cell transplantation is a deterministic curative procedure for various hematologic disorders and congenital immunodeficiency.Despite its increased use,the mortality rate for patients undergoing this procedure remains high,mainly due to the perceived risk of exacerbating graft-versushost disease(GVHD).However,even with immunosuppressive agents,some patients still develop GVHD.Advanced mesenchymal stem/stromal cell(MSC)strategies have been proposed to achieve better therapeutic outcomes,given their immunosuppressive potential.However,the efficacy and trial designs have varied among the studies,and some research findings appear contradictory due to the challenges in characterizing the in vivo effects of MSCs.This review aims to provide real insights into this clinical entity,emphasizing diagnostic,and therapeutic considerations and generating pathophysiology hypotheses to identify research avenues.The indications and timing for the clinical application of MSCs are still subject to debate.展开更多
BACKGROUND Numerous reports have demonstrated that the pathophysiology of graft-versushost disease(GVHD)during hematopoietic stem cell transplantation(HSCT)is closely related to vascular endothelial disorders and coag...BACKGROUND Numerous reports have demonstrated that the pathophysiology of graft-versushost disease(GVHD)during hematopoietic stem cell transplantation(HSCT)is closely related to vascular endothelial disorders and coagulation abnormalities.We previously presented the discovery of a principle and the development of a novel instrument for measuring whole blood coagulation.This was achieved by assessing the variations in the dielectric properties of whole blood.AIM To investigate how GVHD affects the changes of dielectric properties of whole blood in patients with HSCT.METHODS We examined the changes of dielectric properties of whole blood and erythrocyte proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis sequentially in patients with HSCT and compared it with clinical symptoms and inflammatory parameters of GVHD.RESULTS During severe GVHD,the dielectric relaxation strength markedly increased and expression of band3 decreased.The dielectric relaxation strength normalized with the improvement of GVHD.In vitro analysis confirmed that the increase of relaxation strength was associated with severe erythrocyte aggregates,but not with decreased expression of band3.CONCLUSION Severe erythrocyte aggregates observed in GVHD may cause coagulation abnormalities and circulatory failure,which,together with the irreversible erythrocyte dysfunction we recently reported,could lead to organ failure.展开更多
BACKGROUND: Graft-versus-host disease (GVHD) is associated with high mortality. Early diagnosis is essential to start treatment and to improve outcomes. Because of the inflammatory nature, we hypothesis that cytoki...BACKGROUND: Graft-versus-host disease (GVHD) is associated with high mortality. Early diagnosis is essential to start treatment and to improve outcomes. Because of the inflammatory nature, we hypothesis that cytokine profile of patients with GVHD may serve as diagnostic markers. The present study was to evaluate the role of cytokine profile in the diagnosis of GVHD. METHODS: An immunoassay was used to detect 29 cytokines simultaneously in the serum; the measuring sensitivity of all cytokines was pg/mL. Healthy subjects undergoing annual routine physical examinations served as negative controls; 23 patients with hepatocellular carcinoma (HCC) who had undergone liver transplantation (the LT group) comprised the test subjects. A total of 22 kidney recipients with biopsyconfirmed GVHD (the RT group) were included for comparison. HCC patients with radical surgery (the HCC group, n=22) served as positive control. The liver contents of the three cytokines, IL-2, IL-18, and IFN-γ, were detected with immunohistochemistry. Serum granzyme B and perforin were measured by flow cytometry.RESULTS: Of the 29 cytokines, the levels of IL-2 and IL-18 were increased significantly in liver recipients with GVHD compared with healthy controls (P〈0.05). The serum levels of these three cytokines in the healthy, HCC, LT, and RT groups were IL-2: 0.90±0.02, 4.14±0.61, 5.10±0.89, and 1.48±0.09 pg/mL; IL-18: 80.61±9.35, 109.51±10.93, 230.11±12.92, and 61.98±7.88 pg/mL; IFN-γ: 24.06±3.88, 24.84±3.21, 40.37±5.88, and 15.33±4.72 pg/mL, respectively. Immunohistochemistry showed that these 3 cytokines expressions in the liver were parallel to the serum cytokine. After standard anti-GVHD treatment, the expressions of IL-2, IL-18, and IFN-y were de- creased in the liver (P〈0.05). Serum granzyme B and perforin were significantly increased in GVHD patients (P〈0.05). CONCLUSIONS: IL-2, IL-18 and IFN-γ were from liver and might serve as biomarkers for monitoring GVHD develop- ment and the effects of anti-GVHD treatment. Granzyme B and perforin may play a role in increasing IL-2, IL-18, and IFN-y levels in GVHD patients.展开更多
Summary: Although mesenchymal stem cells (MSCs) are increasingly used to treat graft-versus-host disease (GVHD), their immune regulatory mechanism in the process is elusive. The present study aimed to investigate...Summary: Although mesenchymal stem cells (MSCs) are increasingly used to treat graft-versus-host disease (GVHD), their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs (UCB-hMSCs) on GVHD patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK ceils, Treg cells and dendritic cells (DCs) and cytokines including interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3^+, CD3+CD4^+ and CD3+CD8^+ cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4^+ and CD8^+ Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.展开更多
AIM: To investigate the abnormalities in the meibomian gland in patients with dry eye disease(DED) associated with chronic ocular graft-versus-host disease(coGVHD) in comparison with Sj?gren's syndrome(SS), a majo...AIM: To investigate the abnormalities in the meibomian gland in patients with dry eye disease(DED) associated with chronic ocular graft-versus-host disease(coGVHD) in comparison with Sj?gren's syndrome(SS), a major form of aqueous deficient DED and meibomian gland dysfunction(MGD), a common cause of evaporative DED.METHODS: A total 135 eyes of 135 subjects included in this study: patients with DED associated with coGVHD(n=30), patients with SS(n=35), patients with MGD(n=35), and normal controls(n=35). All participants completed the Ocular Surface Disease Index(OSDI) questionnaire, ocular surface examination [Schirmer test, tear film breakup time(TFBUT), and ocular surface staining], and meibomian gland assessment [meiboscore(gland dropout detected on meibography using infrared camera of the Keratograph 5 M), meibum expressibility score(MES), meibum quality score(MQS), lid margin abnormality]. In addition, correlations of meibomian gland characteristics with ocular surface parameters as well as disease severity score were investigated in coGVHD group.RESULTS: The coGVHD group showed significantly higher meiboscore, MES, and MQS than the other 3 groups(all P<0.05). In the coGVHD group, parameters of meibomian gland showed a significant correlation each other and those of ocular surface. The correlation between meibomian gland parameters and severity score of co GVHD was also established(meiboscore, r=0.62; MES, r=0.47; MQS, r=0.47; lid margin abnormality score, r=0.55; all P<0.05).CONCLUSION: Patients with DED associated with co GVHD show poorer gland morphology and worse glandfunction than other types of DED. In addition, meibomian gland damage is not only associated with ocular surface damage but also disease severity of coGVHD.展开更多
BACKGROUND Graft-versus-host disease(GVHD)following liver transplantation(LT)is an unpredictable complication with poor outcome.However,consensus regarding the diagnosis and therapeutic regimen for the disease is yet ...BACKGROUND Graft-versus-host disease(GVHD)following liver transplantation(LT)is an unpredictable complication with poor outcome.However,consensus regarding the diagnosis and therapeutic regimen for the disease is yet lacking.The present study summarized the clinical experience on the diagnosis and treatment of acute GVHD(aGVHD)following LT and reviewed the pertinent literature.CASE SUMMARY Between January 1^(st),2000 and December 31^(st),2020,a total of 1053 LT were performed in the First Affiliated Hospital of Xi’an Jiaotong University.Six recipients developed aGVHD with clinical symptoms of fever,rash,diarrhea,and pancytopenia.The incidence of aGVHD was 0.57%.The median time from LT to the clinical presentation of aGVHD was 22.17 d.The median time from the beginning of the clinical symptom to histopathological diagnosis was 7.5 d.All six cases underwent treatment of immunosuppressant adjustment,corticosteroids,human normal immunoglobulin,and antithymocyte globulin/IL-2 antagonists.Despite intensive treatment strategies,4 patients were deceased due to sepsis,multiple organ failure,and cerebral hemorrhage.The remaining two cases were discharged as treatment successfully.However,one died because of tuberculosis infection on the 6 th month of follow-up,the other one was alive healthy during 30 mo of follow-up.CONCLUSION The rapid diagnosis of aGVHD is mainly based on the time from the first symptom,histopathological features,and the donor T-lymphocyte chimerism.Our cases report highlights massive corticosteroid therapy and age difference between donors and recipients could accelerate to aGVHD.Moreover,gut microbial interventions and donor-targeted serotherapy may provide novel therapeutics.展开更多
BACKGROUND Oral mucositis is often observed with graft-versus-host disease(GVHD);however,the occurrence of oral granuloma is rare.The rapid increase in granulomatous lesions should be distinguished from malignant tumo...BACKGROUND Oral mucositis is often observed with graft-versus-host disease(GVHD);however,the occurrence of oral granuloma is rare.The rapid increase in granulomatous lesions should be distinguished from malignant tumors in patients with GVHD because malignant diseases can develop in those patients.This case is the youngest pediatric patient with granuloma associated with GVHD.CASE SUMMARY The patient was a 1-year and 5-mo-old girl who presented to our department for the management of oral nodules.At the age of 5 mo,she was diagnosed with primary immunodeficiency disease,cord blood transplant was performed at 11 mo and bone marrow transplant at 1 year of age.After transplantation,GVHD and oral mucositis developed,and tacrolimus was administered.Interestingly,nodules appeared on the lower lip and buccal mucosa,which spontaneously disappeared.Then,a new nodule appeared on the left lateral border of the tongue.Resection was performed and the histopathological diagnosis was granuloma.The origin of these nodules were considered to be the fibroblasts activated under inflammation caused by GVHD because the calcineurin inhibitor tacrolimus acted on their proliferation.CONCLUSION It is very important to distinguish oral granulomatous lesions from malignancies if GVHD is present at the base and if immunosuppressive agents and steroids are being administered.展开更多
This study examined the expressions of human serum tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell ...This study examined the expressions of human serum tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their clinical significance. The serum TF and TFPI levels were detected by ELISA in 28 allo-HSCT recipients before and after the transplanta-tion and the changes of TF and TFPI levels were dynamically monitored at different phases of the disease. No significant differences in the serum TF and TFPI levels were found in allo-HSCT recipi-ents in the absence of aGVHD or with gradeⅠaGVHD before and after the transplantation. The lev-els of serum TF and TFPI were substantially increased in the patients with gradeⅡ aGVHD at the peak of aGVHD (P〈0.05) and they were even higher in the patients with grade Ⅲ–Ⅳ aGVHD (P〈0.01). When the conditions became stable after treatment with immunosuppressive agents, the serum TFPI level was decreased to the baseline level (P〉0.05) and the TF level was lowered but still higher than the baseline level (P〈0.05). It was concluded that the levels of serum TF and TFPI were increased significantly in the patients with grade Ⅱ–Ⅳ aGVHD after allo-HSCT and decreased markedly after the treatment. Monitoring the levels of serum TF and TFPI in the patients with allo-HSCT is important to predict the occurrence, outcome and prognosis of aGVHD.展开更多
We present a case report of a chronic graft-versus-host disease manifestation in 33-year-old patient with an unusual complication of vaginal stenosis with complete obstruction after allogeneic bone marrow transplantat...We present a case report of a chronic graft-versus-host disease manifestation in 33-year-old patient with an unusual complication of vaginal stenosis with complete obstruction after allogeneic bone marrow transplantation for myelocytic leukemia. The patient complained on a progressive dyspareunia and sexual intercourse inability. She has received hormone replacement therapy due to the ovarian failure after the chemotherapy treatment. The hormonal treatment was used in continuous combined manner and hematocolpos wasn’t seen during an abdominal ultrasound examination. The reconstructive surgery was performed by the modified Vecchietti’s neovagina technique with a Remeex®system after histological confirmation of main diagnosis. The immediate postoperative course was uneventful with gradual normalization of sexual function.展开更多
Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-C...Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-CMV disease,the mucosal findings and the clinical course showed marked improvements during long-term clinical observation.The endoscopic findings were remarkable,with diffuse sloughing mucosa in the stomach and highly active inflammation and deep discrete ulcers throughout the colon.Changes in the CMV quantitative polymerase chain reaction results were correlated with the endoscopic mucosal findings and were useful for assessing the efficacy of the treatment.Although a definite diagnosis of GI-GVHD is generally made by endoscopy with biopsy,the gross appearance of this disease can vary depending on the endoscopy.In this paper,we also conduct a literature review of patients with GI-GVHD.展开更多
The most common approaches to prevent and treat graft-versus-host disease (GVHD) are intended to deplete or suppress the T cells capable of mediating or supporting alloresponses;however, this renders the recipients fu...The most common approaches to prevent and treat graft-versus-host disease (GVHD) are intended to deplete or suppress the T cells capable of mediating or supporting alloresponses;however, this renders the recipients functionally T cell deficient and hence highly susceptible to infections and tumor recurrence. Depletion is often accomplished through the use of broadly reactive antibodies, while functional impairment is typically achieved by pharmacological agents that require long-term administration (usually six months or more), have significant side effects, and may not result in tolerance (i.e., nonresponsiveness) of donor T cells to conditioning regimen-resistant host alloantigen-bearing cells. As our knowledge of immune system homeostasis has increased, cell populations with immune regulatory function have been identified and characterized. Although such cell populations are typically present in low frequencies, methods to isolate and expand these cells have permitted their supplementation to the donor graft or infusion late post-transplant in order to stifle GVHD. This review discusses the biology and preclinical proof of concept of GVHD models, along with GVHD outcomes that focus exclusively on immune regulatory cell therapies that have progressed to clinical testing.展开更多
Aim Allogeneic hematopoietic stem cell transplantation (HSCT) has curable potential for hematopoietic malignancies through graft-versus-leukemia (GVL) effects but is often associated with life-threatening graft-ve...Aim Allogeneic hematopoietic stem cell transplantation (HSCT) has curable potential for hematopoietic malignancies through graft-versus-leukemia (GVL) effects but is often associated with life-threatening graft-versus-host disease (GVHD). Donor T cells play an important role in the pathological process of GVHD. In this study, to determinate immunoisolation through encapsulating T cells with biomaterials could be a promising approach to atten- uate GVHD. Methods T cells were isolated from spleens of donor C57B1/6 mice by magnetic cell separation and coated by layer-by-layer in chitosan and alginate. BALB/c recipient mice were established by GVHD mode and leukemia mode. Xenogen IVIS imaging system was used for live animal imaging. Donor BMCs and T cell subsets were analyzed by flow cytometry. Results In this study, we successfully encapsulated T cells of mice in multilay- ers of chitosan and alginate. In vitro studies showed that the encapsulation did not change the phenotype of T cells as defined through the following parameters: size, viability, proliferation, antibody binding, cytokine secretion, and cytotoxicity. Mice transplanted with encapsulated allogeneic T cells exhibited less severe acute GVHD and pro- longed survival. The mice showed a lower GVHD score, less liver damage, a smaller CD8/CD4 T cell ratio, and a higher number of donor BM-derived cells following transplantation with encapsulated donor T cells. When this GVHD model was combined with implantation of A20 lymphoma cells, GVL of encapsulated T cells was not com- promised, while GVHD was still suppressed and the mouse survival also prolonged. Conclusion These studies demonstrate that encapsulation of T cells with bio-degradable materials could attenuate the severity of GVHD but re- taine GVL, which presents a novel and potentially safer and effective approach of allogeneic HSCT for future clini- cal application.展开更多
Background:With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation(UCBT),the correlation between immune reconstitution(IR)after UCBT and graft-vers...Background:With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation(UCBT),the correlation between immune reconstitution(IR)after UCBT and graft-versus-host disease(GVHD)has been reported successively,but reports on double-negative T(DNT)cell reconstitution and its association with acute GVHD(aGVHD)after UCBT are lacking.Methods:A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology,the First Affiliated Hospital of USTC,between August 2018 and June 2021.IR differences were compared between the patients with and without aGVHD.Results:The absolute number of DNT cells in the healthy Chinese population was 109(70-157)/μL,accounting for 5.82(3.98-8.19)%of lymphocytes.DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation.Importantly,the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year(F=4.684,P=0.039 and F=5.583,P=0.026,respectively).In addition,the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased,and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD(HR=0.46,95%confidence interval[CI]:0.23-0.93;P=0.031).Conclusions:Compared to the number of DNT cells in Chinese healthy people,the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow.In addition,the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.展开更多
AIM:To evaluate the diagnostic value of endoscopy in patients with gastrointestinal graft-versus-host disease (GI GVHD). METHODS:We identified 8 patients with GI GVHD following allogeneic hematopoietic stem cell trans...AIM:To evaluate the diagnostic value of endoscopy in patients with gastrointestinal graft-versus-host disease (GI GVHD). METHODS:We identified 8 patients with GI GVHD following allogeneic hematopoietic stem cell trans-plantation (HSCT). GVHD was defined histologically as the presence of gland apoptosis, not explained by other inflammatory or infectious etiologies. RESULTS:The symptoms of GI GVHD included anorexia, nausea, vomiting, watery diarrhea, abdominal pain, GI bleeding, etc. Upper endoscopic appearance varied from subtle mucosal edema, hyperemia, erythema to obvious erosion. Colonoscopic examination showed diffuse edema, hyperemia, patchy erosion, scattered ulcer, sloughing and active bleeding. Histological changes in GI GVHD included apoptosis of crypt epithelial cells, dropout of crypts, and lymphocytic infiltration in epithelium and lamina propria. The involvement of stomach and rectocolon varied from diffuse to focal. CONCLUSION:Endoscopy may play a significant role in early diagnosis of GI GVHD patients following allogeneic HSCT, and histologic examination of gastrointestinal biopsies is needed to confirm the final diagnosis.展开更多
Objective: To investigate the role of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ in pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic peripheral blood stem cell transplantation (allo-PBSCT)....Objective: To investigate the role of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ in pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Methods: Forty-two patients undergoing allo-PBSCT were included in this study. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to analyze gene expression of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ. Results: All patients achieved engraftment, 18 patients developed grade ⅠGVHD, 6 patients developed grade Ⅱ-Ⅳ GVHD. The gene expression of IL-2, IL-12, and IFN-γ increased, the gene expression of IL-4 and IL-10 decreased. Conclusion: Cytokines IL-2, IL-12, and IFN-γ lead to a positive regulation of the development in human aGVHD, and IL-4 and IL-10 play negative regulatory roles.展开更多
Germ cell tumors complicated by hematological malignancy(HM)are a rare clinical phenomenon.Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is a potentially effective therapy,but graft-versus-host disease(...Germ cell tumors complicated by hematological malignancy(HM)are a rare clinical phenomenon.Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is a potentially effective therapy,but graft-versus-host disease(GVHD)is a life-threatening complication.We report a case of a 13-year-old female patient diagnosed with germ cell tumors followed by acute lymphoblastic leukemia.After chemotherapy,she received allo-HSCT and her chimerism rate decreased rapidly to near zero by 6 months without evidence of HM recurrence.However,she developed severe,multiorgan GVHD-like manifestations.DNA analysis revealed the pathogenesis of GVHD to be loss of HLA heterozygosity in recipient hematopoietic cells.展开更多
Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exoso...Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.展开更多
Alzheimer's disease is the most common cause of dementia globally with an increasing incidence over the years,bringing a heavy burden to individuals and society due to the lack of an effective treatment.In this co...Alzheimer's disease is the most common cause of dementia globally with an increasing incidence over the years,bringing a heavy burden to individuals and society due to the lack of an effective treatment.In this context,sirtuin 2,the sirtuin with the highest expression in the brain,has emerged as a potential therapeutic target for neurodegenerative diseases.This review summarizes and discusses the complex roles of sirtuin 2 in different molecular mechanisms involved in Alzheimer's disease such as amyloid and tau pathology,microtubule stability,neuroinflammation,myelin formation,autophagy,and oxidative stress.The role of sirtuin 2 in all these processes highlights its potential implication in the etiology and development of Alzheimer's disease.However,its presence in different cell types and its enormous variety of substrates leads to apparently contra dictory conclusions when it comes to understanding its specific functions.Further studies in sirtuin 2 research with selective sirtuin2 modulators targeting specific sirtuin 2 substrates are necessary to clarify its specific functions under different conditions and to validate it as a novel pharmacological target.This will contribute to the development of new treatment strategies,not only for Alzheimer's disease but also for other neurodegenerative diseases.展开更多
Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and th...Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.展开更多
ATP-binding cassette(ABC)transporters are ubiquitous membrane-bound proteins that are responsible for the translocation of a broad spectrum of substrates across cellular membranes,including lipids,amino acids,nucleosi...ATP-binding cassette(ABC)transporters are ubiquitous membrane-bound proteins that are responsible for the translocation of a broad spectrum of substrates across cellular membranes,including lipids,amino acids,nucleosides,sugars,and xenobiotics.Interestingly,ABC transporters are highly expressed in the brain.While their functions in the brain still need to be elucidated,several members are implicated in the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease(AD),Parkinson’s disease(PD),and frontotemporal dementia.In this perspective,we will review current knowledge of ABC transporters in the central nervous system in terms of physiological functions and pathology in neurodegeneration.Furthermore,we will explore the possibilities of ABC transporters as potential targets in the development of therapeutics for neurodegenerative diseases.展开更多
文摘Allogeneic hematopoietic stem cell transplantation is a deterministic curative procedure for various hematologic disorders and congenital immunodeficiency.Despite its increased use,the mortality rate for patients undergoing this procedure remains high,mainly due to the perceived risk of exacerbating graft-versushost disease(GVHD).However,even with immunosuppressive agents,some patients still develop GVHD.Advanced mesenchymal stem/stromal cell(MSC)strategies have been proposed to achieve better therapeutic outcomes,given their immunosuppressive potential.However,the efficacy and trial designs have varied among the studies,and some research findings appear contradictory due to the challenges in characterizing the in vivo effects of MSCs.This review aims to provide real insights into this clinical entity,emphasizing diagnostic,and therapeutic considerations and generating pathophysiology hypotheses to identify research avenues.The indications and timing for the clinical application of MSCs are still subject to debate.
基金Supported by Grant-in-Aid for Scientific Research of Japan(KAKENHI),No.2459154and No.15K09639。
文摘BACKGROUND Numerous reports have demonstrated that the pathophysiology of graft-versushost disease(GVHD)during hematopoietic stem cell transplantation(HSCT)is closely related to vascular endothelial disorders and coagulation abnormalities.We previously presented the discovery of a principle and the development of a novel instrument for measuring whole blood coagulation.This was achieved by assessing the variations in the dielectric properties of whole blood.AIM To investigate how GVHD affects the changes of dielectric properties of whole blood in patients with HSCT.METHODS We examined the changes of dielectric properties of whole blood and erythrocyte proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis sequentially in patients with HSCT and compared it with clinical symptoms and inflammatory parameters of GVHD.RESULTS During severe GVHD,the dielectric relaxation strength markedly increased and expression of band3 decreased.The dielectric relaxation strength normalized with the improvement of GVHD.In vitro analysis confirmed that the increase of relaxation strength was associated with severe erythrocyte aggregates,but not with decreased expression of band3.CONCLUSION Severe erythrocyte aggregates observed in GVHD may cause coagulation abnormalities and circulatory failure,which,together with the irreversible erythrocyte dysfunction we recently reported,could lead to organ failure.
基金supported by grants from the National Natural Science Foundation of China(81372425,8157295481421062,91542205 and 81401319)
文摘BACKGROUND: Graft-versus-host disease (GVHD) is associated with high mortality. Early diagnosis is essential to start treatment and to improve outcomes. Because of the inflammatory nature, we hypothesis that cytokine profile of patients with GVHD may serve as diagnostic markers. The present study was to evaluate the role of cytokine profile in the diagnosis of GVHD. METHODS: An immunoassay was used to detect 29 cytokines simultaneously in the serum; the measuring sensitivity of all cytokines was pg/mL. Healthy subjects undergoing annual routine physical examinations served as negative controls; 23 patients with hepatocellular carcinoma (HCC) who had undergone liver transplantation (the LT group) comprised the test subjects. A total of 22 kidney recipients with biopsyconfirmed GVHD (the RT group) were included for comparison. HCC patients with radical surgery (the HCC group, n=22) served as positive control. The liver contents of the three cytokines, IL-2, IL-18, and IFN-γ, were detected with immunohistochemistry. Serum granzyme B and perforin were measured by flow cytometry.RESULTS: Of the 29 cytokines, the levels of IL-2 and IL-18 were increased significantly in liver recipients with GVHD compared with healthy controls (P〈0.05). The serum levels of these three cytokines in the healthy, HCC, LT, and RT groups were IL-2: 0.90±0.02, 4.14±0.61, 5.10±0.89, and 1.48±0.09 pg/mL; IL-18: 80.61±9.35, 109.51±10.93, 230.11±12.92, and 61.98±7.88 pg/mL; IFN-γ: 24.06±3.88, 24.84±3.21, 40.37±5.88, and 15.33±4.72 pg/mL, respectively. Immunohistochemistry showed that these 3 cytokines expressions in the liver were parallel to the serum cytokine. After standard anti-GVHD treatment, the expressions of IL-2, IL-18, and IFN-y were de- creased in the liver (P〈0.05). Serum granzyme B and perforin were significantly increased in GVHD patients (P〈0.05). CONCLUSIONS: IL-2, IL-18 and IFN-γ were from liver and might serve as biomarkers for monitoring GVHD develop- ment and the effects of anti-GVHD treatment. Granzyme B and perforin may play a role in increasing IL-2, IL-18, and IFN-y levels in GVHD patients.
基金supported by grants from the National Natural Science Foundation of China(No.81172826)Collaborative Innovation Center of Hematology,China
文摘Summary: Although mesenchymal stem cells (MSCs) are increasingly used to treat graft-versus-host disease (GVHD), their immune regulatory mechanism in the process is elusive. The present study aimed to investigate the curative effect of third-party umbilical cord blood-derived human MSCs (UCB-hMSCs) on GVHD patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their immune regulatory mechanism. Twenty-four refractory GVHD patients after allo-HSCT were treated with UCB-hMSCs. Immune cells including T lymphocyte subsets, NK ceils, Treg cells and dendritic cells (DCs) and cytokines including interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNF-α) were monitored before and after MSCs transfusion. The results showed that the symptoms of GVHD were alleviated significantly without increased relapse of primary disease and transplant-related complications after MSCs transfusion. The number of CD3^+, CD3+CD4^+ and CD3+CD8^+ cells decreased significantly, and that of NK cells remained unchanged, whereas the number of CD4^+ and CD8^+ Tregs increased and reached a peak at 4 weeks; the number of mature DCs, and the levels of TNF-α and IL-17 decreased and reached a trough at 2 weeks. It was concluded that MSCs ameliorate GVHD and spare GVL effect via immunoregulations.
基金Supported by the Chonnam National University Hospital Biomedical Research Institute(CRI 18093-1)Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Science,ICT&Future Planning(No.2017R1A2B4003367)
文摘AIM: To investigate the abnormalities in the meibomian gland in patients with dry eye disease(DED) associated with chronic ocular graft-versus-host disease(coGVHD) in comparison with Sj?gren's syndrome(SS), a major form of aqueous deficient DED and meibomian gland dysfunction(MGD), a common cause of evaporative DED.METHODS: A total 135 eyes of 135 subjects included in this study: patients with DED associated with coGVHD(n=30), patients with SS(n=35), patients with MGD(n=35), and normal controls(n=35). All participants completed the Ocular Surface Disease Index(OSDI) questionnaire, ocular surface examination [Schirmer test, tear film breakup time(TFBUT), and ocular surface staining], and meibomian gland assessment [meiboscore(gland dropout detected on meibography using infrared camera of the Keratograph 5 M), meibum expressibility score(MES), meibum quality score(MQS), lid margin abnormality]. In addition, correlations of meibomian gland characteristics with ocular surface parameters as well as disease severity score were investigated in coGVHD group.RESULTS: The coGVHD group showed significantly higher meiboscore, MES, and MQS than the other 3 groups(all P<0.05). In the coGVHD group, parameters of meibomian gland showed a significant correlation each other and those of ocular surface. The correlation between meibomian gland parameters and severity score of co GVHD was also established(meiboscore, r=0.62; MES, r=0.47; MQS, r=0.47; lid margin abnormality score, r=0.55; all P<0.05).CONCLUSION: Patients with DED associated with co GVHD show poorer gland morphology and worse glandfunction than other types of DED. In addition, meibomian gland damage is not only associated with ocular surface damage but also disease severity of coGVHD.
基金Supported by The National Natural Science Foundation of China,No.81870445Scientific Research Project of Military Healthcare,No.BZZ19J004.
文摘BACKGROUND Graft-versus-host disease(GVHD)following liver transplantation(LT)is an unpredictable complication with poor outcome.However,consensus regarding the diagnosis and therapeutic regimen for the disease is yet lacking.The present study summarized the clinical experience on the diagnosis and treatment of acute GVHD(aGVHD)following LT and reviewed the pertinent literature.CASE SUMMARY Between January 1^(st),2000 and December 31^(st),2020,a total of 1053 LT were performed in the First Affiliated Hospital of Xi’an Jiaotong University.Six recipients developed aGVHD with clinical symptoms of fever,rash,diarrhea,and pancytopenia.The incidence of aGVHD was 0.57%.The median time from LT to the clinical presentation of aGVHD was 22.17 d.The median time from the beginning of the clinical symptom to histopathological diagnosis was 7.5 d.All six cases underwent treatment of immunosuppressant adjustment,corticosteroids,human normal immunoglobulin,and antithymocyte globulin/IL-2 antagonists.Despite intensive treatment strategies,4 patients were deceased due to sepsis,multiple organ failure,and cerebral hemorrhage.The remaining two cases were discharged as treatment successfully.However,one died because of tuberculosis infection on the 6 th month of follow-up,the other one was alive healthy during 30 mo of follow-up.CONCLUSION The rapid diagnosis of aGVHD is mainly based on the time from the first symptom,histopathological features,and the donor T-lymphocyte chimerism.Our cases report highlights massive corticosteroid therapy and age difference between donors and recipients could accelerate to aGVHD.Moreover,gut microbial interventions and donor-targeted serotherapy may provide novel therapeutics.
文摘BACKGROUND Oral mucositis is often observed with graft-versus-host disease(GVHD);however,the occurrence of oral granuloma is rare.The rapid increase in granulomatous lesions should be distinguished from malignant tumors in patients with GVHD because malignant diseases can develop in those patients.This case is the youngest pediatric patient with granuloma associated with GVHD.CASE SUMMARY The patient was a 1-year and 5-mo-old girl who presented to our department for the management of oral nodules.At the age of 5 mo,she was diagnosed with primary immunodeficiency disease,cord blood transplant was performed at 11 mo and bone marrow transplant at 1 year of age.After transplantation,GVHD and oral mucositis developed,and tacrolimus was administered.Interestingly,nodules appeared on the lower lip and buccal mucosa,which spontaneously disappeared.Then,a new nodule appeared on the left lateral border of the tongue.Resection was performed and the histopathological diagnosis was granuloma.The origin of these nodules were considered to be the fibroblasts activated under inflammation caused by GVHD because the calcineurin inhibitor tacrolimus acted on their proliferation.CONCLUSION It is very important to distinguish oral granulomatous lesions from malignancies if GVHD is present at the base and if immunosuppressive agents and steroids are being administered.
文摘This study examined the expressions of human serum tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their clinical significance. The serum TF and TFPI levels were detected by ELISA in 28 allo-HSCT recipients before and after the transplanta-tion and the changes of TF and TFPI levels were dynamically monitored at different phases of the disease. No significant differences in the serum TF and TFPI levels were found in allo-HSCT recipi-ents in the absence of aGVHD or with gradeⅠaGVHD before and after the transplantation. The lev-els of serum TF and TFPI were substantially increased in the patients with gradeⅡ aGVHD at the peak of aGVHD (P〈0.05) and they were even higher in the patients with grade Ⅲ–Ⅳ aGVHD (P〈0.01). When the conditions became stable after treatment with immunosuppressive agents, the serum TFPI level was decreased to the baseline level (P〉0.05) and the TF level was lowered but still higher than the baseline level (P〈0.05). It was concluded that the levels of serum TF and TFPI were increased significantly in the patients with grade Ⅱ–Ⅳ aGVHD after allo-HSCT and decreased markedly after the treatment. Monitoring the levels of serum TF and TFPI in the patients with allo-HSCT is important to predict the occurrence, outcome and prognosis of aGVHD.
文摘We present a case report of a chronic graft-versus-host disease manifestation in 33-year-old patient with an unusual complication of vaginal stenosis with complete obstruction after allogeneic bone marrow transplantation for myelocytic leukemia. The patient complained on a progressive dyspareunia and sexual intercourse inability. She has received hormone replacement therapy due to the ovarian failure after the chemotherapy treatment. The hormonal treatment was used in continuous combined manner and hematocolpos wasn’t seen during an abdominal ultrasound examination. The reconstructive surgery was performed by the modified Vecchietti’s neovagina technique with a Remeex®system after histological confirmation of main diagnosis. The immediate postoperative course was uneventful with gradual normalization of sexual function.
基金Supported by Grant from the National Center for Global Health and Medicine
文摘Here,we report a case of fulminant gastrointestinal graft-versus-host disease(GI-GVHD) with cytomegalovirus(CMV) infection in 44-year-old woman.Despite the difficulties associated with the treatment of GIGVHD and GI-CMV disease,the mucosal findings and the clinical course showed marked improvements during long-term clinical observation.The endoscopic findings were remarkable,with diffuse sloughing mucosa in the stomach and highly active inflammation and deep discrete ulcers throughout the colon.Changes in the CMV quantitative polymerase chain reaction results were correlated with the endoscopic mucosal findings and were useful for assessing the efficacy of the treatment.Although a definite diagnosis of GI-GVHD is generally made by endoscopy with biopsy,the gross appearance of this disease can vary depending on the endoscopy.In this paper,we also conduct a literature review of patients with GI-GVHD.
基金supported by grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (R37 AI34495)National Heart, Lung, and Blood Institute, National Institutes of Health (R01 HL56067 and R01 HL11879)National Cancer Institute, National Institutes of Health (P01 CA142106 and P01 CA065493)
文摘The most common approaches to prevent and treat graft-versus-host disease (GVHD) are intended to deplete or suppress the T cells capable of mediating or supporting alloresponses;however, this renders the recipients functionally T cell deficient and hence highly susceptible to infections and tumor recurrence. Depletion is often accomplished through the use of broadly reactive antibodies, while functional impairment is typically achieved by pharmacological agents that require long-term administration (usually six months or more), have significant side effects, and may not result in tolerance (i.e., nonresponsiveness) of donor T cells to conditioning regimen-resistant host alloantigen-bearing cells. As our knowledge of immune system homeostasis has increased, cell populations with immune regulatory function have been identified and characterized. Although such cell populations are typically present in low frequencies, methods to isolate and expand these cells have permitted their supplementation to the donor graft or infusion late post-transplant in order to stifle GVHD. This review discusses the biology and preclinical proof of concept of GVHD models, along with GVHD outcomes that focus exclusively on immune regulatory cell therapies that have progressed to clinical testing.
文摘Aim Allogeneic hematopoietic stem cell transplantation (HSCT) has curable potential for hematopoietic malignancies through graft-versus-leukemia (GVL) effects but is often associated with life-threatening graft-versus-host disease (GVHD). Donor T cells play an important role in the pathological process of GVHD. In this study, to determinate immunoisolation through encapsulating T cells with biomaterials could be a promising approach to atten- uate GVHD. Methods T cells were isolated from spleens of donor C57B1/6 mice by magnetic cell separation and coated by layer-by-layer in chitosan and alginate. BALB/c recipient mice were established by GVHD mode and leukemia mode. Xenogen IVIS imaging system was used for live animal imaging. Donor BMCs and T cell subsets were analyzed by flow cytometry. Results In this study, we successfully encapsulated T cells of mice in multilay- ers of chitosan and alginate. In vitro studies showed that the encapsulation did not change the phenotype of T cells as defined through the following parameters: size, viability, proliferation, antibody binding, cytokine secretion, and cytotoxicity. Mice transplanted with encapsulated allogeneic T cells exhibited less severe acute GVHD and pro- longed survival. The mice showed a lower GVHD score, less liver damage, a smaller CD8/CD4 T cell ratio, and a higher number of donor BM-derived cells following transplantation with encapsulated donor T cells. When this GVHD model was combined with implantation of A20 lymphoma cells, GVL of encapsulated T cells was not com- promised, while GVHD was still suppressed and the mouse survival also prolonged. Conclusion These studies demonstrate that encapsulation of T cells with bio-degradable materials could attenuate the severity of GVHD but re- taine GVL, which presents a novel and potentially safer and effective approach of allogeneic HSCT for future clini- cal application.
基金National Natural Science Foundation of China(Nos.82270223,82170209,and 82100230)Anhui Provincial Key Research and Development Project(No.2022e07020015)+1 种基金Anhui Health Research Project(No.AHWJ2022a 011)Fundamental Research Funds for the Central Universities(Nos.WK9110000204,and WK9110000168)
文摘Background:With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation(UCBT),the correlation between immune reconstitution(IR)after UCBT and graft-versus-host disease(GVHD)has been reported successively,but reports on double-negative T(DNT)cell reconstitution and its association with acute GVHD(aGVHD)after UCBT are lacking.Methods:A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology,the First Affiliated Hospital of USTC,between August 2018 and June 2021.IR differences were compared between the patients with and without aGVHD.Results:The absolute number of DNT cells in the healthy Chinese population was 109(70-157)/μL,accounting for 5.82(3.98-8.19)%of lymphocytes.DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation.Importantly,the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year(F=4.684,P=0.039 and F=5.583,P=0.026,respectively).In addition,the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased,and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD(HR=0.46,95%confidence interval[CI]:0.23-0.93;P=0.031).Conclusions:Compared to the number of DNT cells in Chinese healthy people,the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow.In addition,the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.
文摘AIM:To evaluate the diagnostic value of endoscopy in patients with gastrointestinal graft-versus-host disease (GI GVHD). METHODS:We identified 8 patients with GI GVHD following allogeneic hematopoietic stem cell trans-plantation (HSCT). GVHD was defined histologically as the presence of gland apoptosis, not explained by other inflammatory or infectious etiologies. RESULTS:The symptoms of GI GVHD included anorexia, nausea, vomiting, watery diarrhea, abdominal pain, GI bleeding, etc. Upper endoscopic appearance varied from subtle mucosal edema, hyperemia, erythema to obvious erosion. Colonoscopic examination showed diffuse edema, hyperemia, patchy erosion, scattered ulcer, sloughing and active bleeding. Histological changes in GI GVHD included apoptosis of crypt epithelial cells, dropout of crypts, and lymphocytic infiltration in epithelium and lamina propria. The involvement of stomach and rectocolon varied from diffuse to focal. CONCLUSION:Endoscopy may play a significant role in early diagnosis of GI GVHD patients following allogeneic HSCT, and histologic examination of gastrointestinal biopsies is needed to confirm the final diagnosis.
文摘Objective: To investigate the role of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ in pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Methods: Forty-two patients undergoing allo-PBSCT were included in this study. Reverse-transcriptase polymerase chain reaction (RT-PCR) was used to analyze gene expression of cytokines IL-2, IL-4, IL-10, IL-12, and IFN-γ. Results: All patients achieved engraftment, 18 patients developed grade ⅠGVHD, 6 patients developed grade Ⅱ-Ⅳ GVHD. The gene expression of IL-2, IL-12, and IFN-γ increased, the gene expression of IL-4 and IL-10 decreased. Conclusion: Cytokines IL-2, IL-12, and IFN-γ lead to a positive regulation of the development in human aGVHD, and IL-4 and IL-10 play negative regulatory roles.
文摘Germ cell tumors complicated by hematological malignancy(HM)are a rare clinical phenomenon.Allogeneic hematopoietic stem cell transplantation(allo-HSCT)is a potentially effective therapy,but graft-versus-host disease(GVHD)is a life-threatening complication.We report a case of a 13-year-old female patient diagnosed with germ cell tumors followed by acute lymphoblastic leukemia.After chemotherapy,she received allo-HSCT and her chimerism rate decreased rapidly to near zero by 6 months without evidence of HM recurrence.However,she developed severe,multiorgan GVHD-like manifestations.DNA analysis revealed the pathogenesis of GVHD to be loss of HLA heterozygosity in recipient hematopoietic cells.
基金supported by grants from the Department of Science and Technology of Sichuan Province,Nos.2021ZYD0093(to LY),2022YFS0597(to LY),2021YJ0480(to YT),and 2022ZYD0076(to JY)。
文摘Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.
基金funded by FEDER/Ministerio de CienciaInnovacion y Universidades Agencia Estatal de Investigacion(MCIN/AEI 10.13039/501100011033)Grant(SAF2017-87595-R and PID2020-119729G8-100)(to EP)"Amigos de Ia Universidad de Navarra"and the Spanish Ministry of Universities for a fellowship(FPU)to NSS。
文摘Alzheimer's disease is the most common cause of dementia globally with an increasing incidence over the years,bringing a heavy burden to individuals and society due to the lack of an effective treatment.In this context,sirtuin 2,the sirtuin with the highest expression in the brain,has emerged as a potential therapeutic target for neurodegenerative diseases.This review summarizes and discusses the complex roles of sirtuin 2 in different molecular mechanisms involved in Alzheimer's disease such as amyloid and tau pathology,microtubule stability,neuroinflammation,myelin formation,autophagy,and oxidative stress.The role of sirtuin 2 in all these processes highlights its potential implication in the etiology and development of Alzheimer's disease.However,its presence in different cell types and its enormous variety of substrates leads to apparently contra dictory conclusions when it comes to understanding its specific functions.Further studies in sirtuin 2 research with selective sirtuin2 modulators targeting specific sirtuin 2 substrates are necessary to clarify its specific functions under different conditions and to validate it as a novel pharmacological target.This will contribute to the development of new treatment strategies,not only for Alzheimer's disease but also for other neurodegenerative diseases.
基金supported by Association 2HE(Center for Human Health and Environment)by Regione Puglia-Grant Malattie Rare DUP n.246 of 2019(to CB).
文摘Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.
文摘ATP-binding cassette(ABC)transporters are ubiquitous membrane-bound proteins that are responsible for the translocation of a broad spectrum of substrates across cellular membranes,including lipids,amino acids,nucleosides,sugars,and xenobiotics.Interestingly,ABC transporters are highly expressed in the brain.While their functions in the brain still need to be elucidated,several members are implicated in the pathogenesis of neurodegenerative diseases,including Alzheimer’s disease(AD),Parkinson’s disease(PD),and frontotemporal dementia.In this perspective,we will review current knowledge of ABC transporters in the central nervous system in terms of physiological functions and pathology in neurodegeneration.Furthermore,we will explore the possibilities of ABC transporters as potential targets in the development of therapeutics for neurodegenerative diseases.