FUBP3 mediates the amyloid-β-induced neuronal NLRP3 expression

Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangles,in the brain.The NLRP3 inflammasome may play a role in the transition from amyloid-βdeposition to tau phosphorylation and aggregation.Because NLRP3 is primarily found in brain microglia,and tau is predominantly located in neurons,it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines.Here,we found that neurons also express NLRP3 in vitro and in vivo,and that neuronal NLRP3 regulates tau phosphorylation.Using biochemical methods,we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons.In primary neurons and the neuroblastoma cell line Neuro2A,FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-βis present.In the brains of aged wild-type mice and a mouse model of Alzheimer's disease,FUBP3 expression was markedly increased in cortical neurons.Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses.We also found that FUBP3 trimmed the 5′end of DNA fragments that it bound,implying that FUBP3 functions in stress-induced responses.These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3,and that amyloid-βfundamentally alters the regulatory mechanism of NLRP3 expression in neurons.Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice,FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.

Nomogram to predict severe retinopathy of prematurity in Southeast China

AIM:To define the predictive factors of severe retinopathy of prematurity(ROP)and develop a nomogram for predicting severe ROP in southeast China.METHODS:Totally 554 infants diagnosed with ROP hospitalized in the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University and hospitalized in Taizhou Women and Children’s Hospital were included.Clinical data and 43 candidate predictive factors of ROP infants were collected retrospectively.Logistic regression model was used to identify predictive factors of severe ROP and to propose a nomogram for individual risk prediction,which was compared with WINROP model and Digirop-Birth model.RESULTS:Infants from the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University(n=478)were randomly allocated into training(n=402)and internal validation group(n=76).Infants from Taizhou Women and Children’s Hospital were set as external validation group(n=76).Severe ROP were found in 52 of 402 infants,12 of 76 infants,and 7 of 76 infants in training group,internal validation group,and external validation group,respectively.Birth weight[odds ratio(OR),0.997;95%confidence interval(CI),0.996-0.999;P<0.001],multiple births(OR,1.885;95%CI,1.013-3.506;P=0.045),and non-invasive ventilation(OR,0.288;95%CI,0.146-0.570;P<0.001)were identified as predictive factors for the prediction of severe ROP,by univariate analysis and multivariate analysis.For predicting severe ROP based on the internal validation group,the areas under receiver operating characteristic curve(AUC)was 78.1(95%CI,64.2-92.0)for the nomogram,32.9(95%CI,15.3-50.5)for WINROP model,70.2(95%CI,55.8-84.6)for Digirop-Birth model.In external validation group,AUC of the nomogram was also higher than that of WINROP model and Digirop-Birth model(80.2 versus 51.1 and 63.4).The decision curve analysis of the nomogram demonstrated better clinical efficacy than that of WINROP model and Digirop-Birth model.The calibration curves demonstrated a good consistency between the actual severe ROP incidence and the predicted probability.CONCLUSION:Birth weight,multiple births,and noninvasive ventilation are independent predictors of severe ROP.The nomogram has a good ability to predict severe ROP and performed well on internal validation and external validation in southeast China.

SIL1 improves cognitive impairment in APP23/PS45 mice by regulating amyloid precursor protein processing and Aβ generation

SIL1,an endoplasmic reticulum(ER)-resident protein,is reported to play a protective role in Alzheimer’s disease(AD).However,the effect of SIL1 on amyloid precursor protein(APP)processing remains unclear.In this study,the role of SIL1 in APP processing was explored both in vitro and in vivo.In the in vitro experiment,SIL1 was either overexpressed or knocked down in cells stably expressing the human Swedish mutant APP695.In the in vivo experiment,AAV-SIL1-EGFP or AAV-EGFP was microinjected into APP23/PS45 mice and their wild-type littermates.Western blotting(WB),immunohistochemistry,RNA sequencing(RNA-seq),and behavioral experiments were performed to evaluate the relevant parameters.Results indicated that SIL1 expression decreased in APP23/PS45 mice.Overexpression of SIL1 significantly decreased the protein levels of APP,presenilin-1(PS1),and C-terminal fragments(CTFs)of APP in vivo and in vitro.Conversely,knockdown of SIL1 increased the protein levels of APP,β-site APP cleavage enzyme 1(BACE1),PS1,and CTFs,as well as APP mRNA expression in 2EB2 cells.Furthermore,SIL1 overexpression reduced the number of senile plaques in APP23/PS45 mice.Importantly,Y-maze and Morris Water maze tests demonstrated that SIL1 overexpression improved cognitive impairment in APP23/PS45 mice.These findings indicate that SIL1 improves cognitive impairment in APP23/PS45 mice by inhibiting APP amyloidogenic processing and suggest that SIL1 is a potential therapeutic target for AD by modulating APP processing.

Basilic vein variation encountered during surgery for arm vein port:A case report

BACKGROUND Venous variations are uncommon and usually hard to identify,and basilic vein variation is particularly rare.Basilic vein variation usually presents without any clinical symptoms and is often regarded as a benign alteration.This case was a patient with congenital basilic vein variation encountered during surgery for an infusion port.CASE SUMMARY We documented and analyzed an uncommon anatomical variation in the basilic vein encountered during arm port insertion.This peculiarity has hitherto remained undescribed in the literature.We offer remedial strategies for addressing this anomaly in the future and precautionary measures to circumvent its occurrence.We conducted a comprehensive review of analogous cases in the literature,offering pertinent therapeutic recommendations and solutions,with the aim of enhancing the efficacy and safety of future arm port implantations.CONCLUSION Venous variation is rare and requires detailed intraoperative and postoperative examination to ensure accuracy,so as not to affect subsequent treatment.

Dialectical study of disulfidptosis and clinical outcome in patients with colorectal cancer

Background:Colorectal cancer(CRC)is a leading cause of cancer mortality globally.This study aims to develop a prognostic model based on disulfidptosis-related genes to assess survival outcomes in CRC,highlighting the tumor microenvironment’s role.Methods:The thought of traditional Chinese medicine syndrome differentiation and treatment runs through the whole study.We analyzed CRC tissue data from The Cancer Genome Atlas and the Gene Expression Omnibus using single-sample gene set enrichment and weighted gene correlation network analyses to identify prognostic markers and evaluate immune infiltration.We also investigated predictive drug sensitivities.Results:We identified seven disulfidptosis-related markers–complement C1q A chain(C1QA),solute carrier family 11 member 1(SLC11A1),cluster of differentiation 36(CD36),cluster of differentiation 6(CD6),interleukin 1 receptor associated kinase 3(IRAK3),S100 calcium binding protein A8(S100A8),and CD8 subunit alpha(CD8A)–that significantly influence prognosis.Patients classified in the low-risk group demonstrated improved overall survival compared to those in the high-risk group across training(P=0.0026)and validation cohorts(P=0.032).Differential gene expression was significant in the high-risk group(P<0.001),and prevalent mutations included APC regulator of WNT signaling pathway(APC),tumor protein P53(TP53),Titin(TTN),and Kirsten rat sarcoma viral oncogene(KRAS).The risk score correlated linearly with tumor microenvironment attributes.The results of drug analysis showed that some traditional drugs may have anticancer effects through the vertical action of disulfidptosis.Conclusion:Our prognostic model,integrating seven disulfidptosis-related genes,categorizes CRC patients by survival probability and underscores these genes as potential biomarkers linked to the tumor microenvironment.These findings support their use in refining therapeutic strategies for CRC.

Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice

Recent studies have shown that chlorogenic acid(CGA),which is present in coffee,has protective effects on the nervous system.However,its role in neonatal hypoxic-ischemic brain injury remains unclear.In this study,we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA.We found that CGA intervention effectively reduced the volume of cerebral infarct,alleviated cerebral edema,restored brain tissue structure after injury,and promoted axon growth in injured brain tissue.Moreover,CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival.In addition,changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA.Furthermore,CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2.In summary,our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis,providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.

Reperfusion after hypoxia-ischemia exacerbates brain injury with compensatory activation of the antiferroptosis system:based on a novel rat model

Hypoxic-ischemic encephalopathy,which predisposes to neonatal death and neurological sequelae,has a high morbidity,but there is still a lack of effective prevention and treatment in clinical practice.To better understand the pathophysiological mechanism underlying hypoxic-ischemic encephalopathy,in this study we compared hypoxic-ischemic reperfusion brain injury and simple hypoxic-ischemic brain injury in neonatal rats.First,based on the conventional RiceVannucci model of hypoxic-ischemic encephalopathy,we established a rat model of hypoxic-ischemic reperfusion brain injury by creating a common carotid artery muscle bridge.Then we performed tandem mass tag-based proteomic analysis to identify differentially expressed proteins between the hypoxic-ischemic reperfusion brain injury model and the conventional Rice-Vannucci model and found that the majority were mitochondrial proteins.We also performed transmission electron microscopy and found typical characteristics of ferroptosis,including mitochondrial shrinkage,ruptured mitochondrial membranes,and reduced or absent mitochondrial cristae.Further,both rat models showed high levels of glial fibrillary acidic protein and low levels of myelin basic protein,which are biological indicators of hypoxic-ischemic brain injury and indicate similar degrees of damage.Finally,we found that ferroptosis-related Ferritin(Fth1)and glutathione peroxidase 4 were expressed at higher levels in the brain tissue of rats with hypoxic-ischemic reperfusion brain injury than in rats with simple hypoxic-ischemic brain injury.Based on these results,it appears that the rat model of hypoxic-ischemic reperfusion brain injury is more closely related to the pathophysiology of clinical reperfusion.Reperfusion not only aggravates hypoxic-ischemic brain injury but also activates the anti-ferroptosis system.

Bexarotene improves motor function after spinal cord injury in mice

Spinal cord injury is a challenge in orthopedics because it causes irreversible damage to the central nervous system.Therefore,early treatment to prevent lesion expansion is crucial for the management of patients with spinal cord injury.Bexarotene,a type of retinoid,exerts therapeutic effects on patients with cutaneous T-cell lymphoma and Parkinson's disease.Bexarotene has been proven to promote autophagy,but it has not been used in the treatment of spinal cord injury.To investigate the effects of bexarotene on spinal cord injury,we established a mouse model of T11–T12 spinal cord contusion and performed daily intraperitoneal injection of bexarotene for 5 consecutive days.We found that bexarotene effectively reduced the deposition of collagen and the number of pathological neurons in the injured spinal cord,increased the number of synapses of nerve cells,reduced oxidative stress,inhibited pyroptosis,promoted the recovery of motor function,and reduced death.Inhibition of autophagy with 3-methyladenine reversed the effects of bexarotene on spinal cord injury.Bexarotene enhanced the nuclear translocation of transcription factor E3,which further activated AMP-activated protein kinase-S-phase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signaling pathways.Intravenous injection of transcription factor E3 sh RNA or intraperitoneal injection of compound C,an AMP-activated protein kinase blocker,inhibited the effects of bexarotene.These findings suggest that bexarotene regulates nuclear translocation of transcription factor E3 through the AMP-activated protein kinase-Sphase kinase-associated protein 2-coactivator-associated arginine methyltransferase 1 and AMP-activated protein kinase-mammalian target of rapamycin signal pathways,promotes autophagy,decreases reactive oxygen species level,inhibits pyroptosis,and improves motor function after spinal cord injury.

Functions and mechanisms of cytosolic phospholipase A_(2)in central nervous system trauma

Central nervous system(CNS)trauma,including traumatic brain injury and spinal cord injury,has a high rate of disability and mortality,and effective treatment is currently lacking.Previous studies have revealed that neural inflammation plays a vital role in CNS trauma.As the initial enzyme in neuroinflammation,cytosolic phospholipase A_(2)(cPLA2)can hydrolyze membranous phosphatides at the sn-2 position in a preferential way to release lysophospholipids andω3-polyunsaturated fatty acid dominated by arachidonic acid,thereby inducing secondary injuries.Although there is substantial fresh knowledge pertaining to cPLA2,in-depth comprehension of how cPLA2 participates in CNS trauma and the potential methods to amelio rate the clinical res ults after CNS trauma are still insufficient.The present review summarizes the latest understanding of how cPLA2 participates in CNS trauma,highlighting novel findings pertaining to how cPLA2 activation initiates the potential mechanisms specifically,neuroinflammation,lysosome membrane functions,and autophagy activity,that damage the CNS after trauma.Moreover,we focused on testing a variety of drugs capable of inhibiting cPLA2 or the upstream pathway,and we explored how those agents might be utilized as treatments to improve the results following CNS trauma.This review aimed to effectively understand the mechanism of cPLA2 activation and its role in the pathophysiological processes of CNS trauma and provide clarification and a new referential framework for future research.

Sepsis-induced immunosuppression:mechanisms,diagnosis and current treatment options

Sepsis is a common complication of combat injuries and trauma,and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection.It is also one of the significant causes of death and increased health care costs in modern intensive care units.The use of antibiotics,fluid resuscitation,and organ support therapy have limited prognostic impact in patients with sepsis.Although its pathophysiology remains elusive,immunosuppression is now recognized as one of the major causes of septic death.Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis.It is characterized by the release of antiinflammatory cytokines,abnormal death of immune effector cells,hyperproliferation of immune suppressor cells,and expression of immune checkpoints.By targeting immunosuppression,especially with immune checkpoint inhibitors,preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance.Here,we comprehensively discuss recent findings on the mechanisms,regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.

Knowledge,attitude,and practice of patients living with inflammatory bowel disease:A cross-sectional study

BACKGROUND Patients with inflammatory bowel diseases(IBDs)generally have poor knowledge,attitude,and practice of their disease,while the data from China are lacking.AIM To address this knowledge disparity among Chinese patients with IBD.METHODS This web-based,cross-sectional study was conducted on a cohort of IBD patients who visited the Second Affiliated Hospital of Wenzhou Medical University between December 2022 and February 2023.Their socio-demographic information and the knowledge,attitude,and practice scores were collected and estimated using a self-designed questionnaire.Pearson’s correlation analysis was used to determine the pairwise correlations among knowledge,attitude,and practice scores.A multivariate logistic regression analysis was further performed to determine the independent factors associated with their knowledge,attitude,and practice scores.RESULTS A total of 353 patients(224 males)with IBD completed the questionnaires.The mean knowledge,attitude,and practice scores were 10.05±3.46(possible range:0-14),41.58±5.23(possible range:0-56),44.20±7.39(possible range:0-56),respectively,indicating good knowledge,positive attitude,and proactive practice toward IBD.Pearson’s correlation analysis showed that the knowledge score had significant positive correlations with the attitude score(r=0.371,P<0.001)and practice score(r=0.100,P<0.001).The attitude score had a significant positive correlation with the practice score(r=0.452,P<0.001).Moreover,multivariate logistic regression analysis showed that aged 30-40 years[odds ratio(OR)=4.06,95%confidence interval(CI):1.04-15.82,P=0.043],middle school education(OR=3.98,95%CI:1.29-12.33,P=0.017),high school/technical secondary school education(OR=14.06,95%CI:3.92-50.38,P<0.001),and junior college/bachelor’s degree and above education(OR=15.20,95%CI:4.15-55.650,P<0.001)were independently associated with good knowledge.The higher knowledge score was independently associated with a positive attitude(OR=1.23,95%CI:1.11-1.36,P<0.001).The higher attitude score was independently associated with proactive practice(OR=1.20,95%CI:1.11-1.30,P<0.001).CONCLUSION Chinese patients with IBD might have good knowledge,a positive attitude,and proactive practice toward their disease.However,a small number of specific items require education.

Water-responsive gel extends drug retention and facilitates skin penetration for curcumin topical delivery against psoriasis

Psoriasis is a chronic inflammatory skin disease characterized by erythema,scaling,and skin thickening.Topical drug application is recommended as the first-line treatment.Many formulation strategies have been developed and explored for enhanced topical psoriasis treatment.However,these preparations usually have low viscosity and limited retention on the skin surface,resulting in low drug delivery efficiency and poor patient satisfaction.In this study,we developed the first water-responsive gel(WRG),which has a distinct water-triggered liquid-to-gel phase transition property.Specifically,WRG was kept in a solution state in the absence of water,and the addition of water induced an immediate phase transition and resulted in a high viscosity gel.Curcumin was used as a model drug to investigate the potential of WRG in topical drug delivery against psoriasis.In vitro and in vivo data showed that WRG formulation could not only extend skin retention but also facilitate the drug permeating across the skin.In a mouse model of psoriasis,curcumin loaded WRG(CUR-WRG)effectively ameliorated the symptoms of psoriasis and exerted a potent anti-psoriasis effect by extending drug retention and facilitating drug penetration.Further mechanism study demonstrated that the anti-hyperplasia,anti-inflammation,anti-angiogenesis,anti-oxidation,and immunomodulation properties of curcumin were amplified by enhanced topical drug delivery efficiency.Notably,neglectable local or systemic toxicity was observed for CUR-WRG application.This study suggests that WRG is a promising formulation for topically psoriasis treatment.

Iatrogenic flexor tendon rupture caused by misdiagnosing sarcoidosis-related flexor tendon contracture as tenosynovitis: A case report

BACKGROUND Sarcoidosis is a multisystem disease characterized by granuloma formation in various organs.Sarcoidosis-related flexor tendon contractures are uncommon in clinical settings.This contracture is similar to stenosing tenosynovitis and po-tentially leads to misdiagnosis and mistreatment.Herein,we report a rare case of sarcoidosis-related finger flexor tendon contracture that was misdiagnosed as tenosynovitis.A 44-year-old woman presented to our department with flexion contracture of the right ring and middle fingers.The patient was misdiagnosed with tenosynovitis and underwent acupotomy release of the A1 pulley of the middle finger in an-other hospital that resulted in iatrogenic rupture of both the superficial and profundus flexors.Radiological presentation showed multiple sarcoid involve-ments in the pulmonary locations and ipsilateral forearm.A diagnosis of sar-coidosis was made based on the presence of non-caseating granulomas with tubercles consisting of Langhans giant cells with lymphocyte infiltration on biopsy,and the patient underwent surgical repair for the contracture.After 2 mo,the patient experienced another spontaneous rupture of the repaired middle finger tendon and underwent surgical re-repair.Satisfactory results were achieved at the 10 mo follow-up after reoperation.CONCLUSION Sarcoidosis-related finger contractures are rare;thus,caution should be exercised when dealing with such patients to avoid incorrect treatment.

Biliary hemorrhage caused by a malignant small round cell tumor in the common bile duct:A case report

BACKGROUND Malignant small round cell tumor(MSRCT)metastasis to the common bile duct associated with recurrent biliary hemorrhage is extremely rare.Thus far,there have been no reports of metastatic small round cell tumors of the common bile duct.CASE SUMMARY Herein,we report the case of a 77-year-old female patient with an MSRCT in the common bile duct.The patient was admitted to hospital due to gastrointestinal hemorrhage and abdominal pain.We found a neoplasm in the common bile duct with active bleeding through a spyglass.We performed biopsy through the spyglass and placed a metal stent to stop bleeding.The pathological result suggested that it was an MSRCT metastasized from the back to the common bile duct.Later,we found using fluorescence in situ hybridization that the SS18 gene break test was negative,ruling out the diagnosis of synovial sarcoma.CONCLUSION MSRCT is a group of tumors with similar cell morphology and diffuse histological structure.Complete tumor resection results in improved survival in patients with MSRCT.Roux-en-Y cholangiojejunostomy was performed.After excision of the common bile duct tumor,the patient felt that the abdominal pain improved and hemorrhage disappeared.The patient underwent routine fecal examination one month after surgery,indicating a negative fecal occult blood test.On May 22,2023,the patient was reexamined by abdominal computed tomography,and no abdominal space occupying lesions or abdominal lymphadenopathy was found.

Pathological mechanisms and therapeutic outlooks for arthrofibrosis

Arthrofibrosis is a fibrotic joint disorder that begins with an inflammatory reaction to insults such as injury,surgery and infection.Excessive extracellular matrix and adhesions contract pouches,bursae and tendons,cause pain and prevent a normal range of joint motion,with devastating consequences for patient quality of life.Arthrofibrosis affects people of all ages,with published rates varying.The risk factors and best management strategies are largely unknown due to a poor understanding of the pathology and lack of diagnostic biomarkers.However,current research into the pathogenesis of fibrosis in organs now informs the understanding of arthrofibrosis.The process begins when stress signals stimulate immune cells.The resulting cascade of cytokines and mediators drives fibroblasts to differentiate into myofibroblasts,which secrete fibrillar collagens and transforming growth factor-β(TGF-β).Positive feedback networks then dysregulate processes that normally terminate healing processes.We propose two subtypes of arthrofibrosis occur:active arthrofibrosis and residual arthrofibrosis.In the latter the fibrogenic processes have resolved but the joint remains stiff.The best therapeutic approach for each subtype may differ significantly.Treatment typically involves surgery,however,a pharmacological approach to correct dysregulated cell signalling could be more effective.Recent research shows that myofibroblasts are capable of reversing differentiation,and understanding the mechanisms of pathogenesis and resolution will be essential for the development of cell-based treatments.Therapies with significant promise are currently available,with more in development,including those that inhibit TGF-βsignalling and epigenetic modifications.This review focuses on pathogenesis of sterile arthrofibrosis and therapeutic treatments.

Propofol postconditioning ameliorates hypoxia/reoxygenation induced H9c2 cell apoptosis and autophagy via upregulating forkhead transcription factors under hyperglycemia

Background:Administration of propofol,an intravenous anesthetic with antioxidant property,immediately at the onset of post-ischemic reperfusion(propofol postconditioning,P-PostC) has been shown to confer cardioprotection against ischemia–reperfusion(I/R) injury,while the underlying mechanism remains incompletely understood.The forkhead box O(FoxO) transcription factors are reported to play critical roles in activating cardiomyocyte survival signaling throughout the process of cellular injuries induced by oxidative stress and are also involved in hypoxic postconditioning mediated neuroprotection,however,the role of FoxO in postconditioning mediated protection in the heart and in particular in high glucose condition is unknown.Methods:Rat heart-derived H9c2 cells were exposed to high glucose(HG) for 48 h,then subjected to hypoxia/reoxygenation(H/R,composed of 8 h of hypoxia followed by 12 h of reoxygenation) in the absence or presence of postconditioning with various concentrations of propofol(P-PostC) at the onset of reoxygenation.After having identified the optical concentration of propofol,H9c2 cells were subjected to H/R and P-PostC in the absence or presence of FoxO1 or FoxO3a gene silencing to explore their roles in P-PostC mediated protection against apoptotic and autophagic cell deaths under hyperglycemia.Results:The results showed that HG with or without H/R decreased cell viability,increased lactate dehydrogenase(LDH) leakage and the production of reactive oxygen species(ROS) in H9c2 cells,all of which were significantly reversed by propofol(P-PostC),especially at the concentration of 25 μmol/L(P25)(P<0.05,NC vs.HG;HG vs.HG+HR;HG+HR+P12.5 or HG+HR+P25 or HG+HR+P50 vs.HG+HR).Moreover,we found that propofol(P25) decreased H9c2 cells apoptosis and autophagy that were concomitant with increased FoxO1 and FoxO3a expression(P<0.05,HG+HR+P25 vs.HG+HR).The protective effects of propofol(P25) against H/R injury were reversed by silencing FoxO1 or FoxO3a(P<0.05,HG+HR+P25 vs.HG+HR+P25+siRNA-1 or HG+HR+P25+siRNA-5).Conclusions:It is concluded that propofol postconditioning attenuated H9c2 cardiac cells apoptosis and autophagy induced by H/R injury through upregulating FoxO1 and FoxO3a under hyperglycemia.

Exosomes-the enigmatic regulators of bone homeostasis

Exosomes are a heterogeneous group of cell-derived membranous structures, which mediate crosstalk interaction between cells.Recent studies have revealed a close relationship between exosomes and bone homeostasis. It is suggested that bone cells can spontaneously secret exosomes containing proteins, lipids and nucleic acids, which then to regulate osteoclastogenesis and osteogenesis. However, the network of regulatory activities of exosomes in bone homeostasis as well as their therapeutic potential in bone injury remain largely unknown. This review will detail and discuss the characteristics of exosomes, the regulatory activities of exosomes in bone homeostasis as well as the clinical potential of exosomes in bone injury.

Human cytomegalovirus-encoded US28 may act as a tumor promoter in colorectal cancer

AIM: To assess human cytomegalovirus-encoded US28 gene function in colorectal cancer(CRC) pathogenesis.METHODS: Immunohistochemical analysis was performed to determine US28 expression in 103 CRC patient samples and 98 corresponding adjacent noncancerous samples. Patient data were compared by age, sex, tumor location, histological grade, Dukes' stage, and overall mean survival time. In addition, the US28 gene was transiently transfected into the CRC LOVO cell line, and cell proliferation was assessed using a cell counting kit-8 assay. Cell cycle analysis by flow cytometry and a cell invasion transwell assay were also carried out.RESULTS: US28 levels were clearly higher in CRC tissues(38.8%) than in adjacent noncancerous samples(7.1%)(P = 0.000). Interestingly, elevated US28 amounts in CRC tissues were significantly associated with histological grade, metastasis, Dukes' stage, and overall survival(all P < 0.05); meanwhile, US28 expression was not significantly correlated with age, sex or tumor location. In addition, multivariate Coxregression data revealed US28 level as an independent CRC prognostic marker(P = 0.000). LOVO cells successfully transfected with the US28 gene exhibited higher viability, greater chemotherapy resistance, accelerated cell cycle progression, and increased invasion ability.CONCLUSION: US28 expression is predictive of poor prognosis and may promote CRC.

Versatile subtypes of pericytes and their roles in spinal cord injury repair,bone development and repair

Vascular regeneration is a challenging topic in tissue repair. As one of the important components of the neurovascular unit(NVU),pericytes play an essential role in the maintenance of the vascular network of the spinal cord. To date, subtypes of pericytes have been identified by various markers, namely the PDGFR-β, Desmin, CD146, and NG2, each of which is involved with spinal cord injury(SCI) repair. In addition, pericytes may act as a stem cell source that is important for bone development and regeneration, whilst specific subtypes of pericyte could facilitate bone fracture and defect repair. One of the major challenges of pericyte biology is to determine the specific markers that would clearly distinguish the different subtypes of pericytes, and to develop efficient approaches to isolate and propagate pericytes. In this review, we discuss the biology and roles of pericytes, their markers for identification, and cell differentiation capacity with a focus on the potential application in the treatment of SCI and bone diseases in orthopedics.

The role of transporters in cancer redox homeostasis and cross-talk with nanomedicines

Tumor cell usually exhibits high levels of reactive oxygen species and adaptive antioxidant system due to the metabolic,genetic,and microenvironment-associated alterations.The altered redox homeostasis can promote tumor progression,development,and treatment resistance.Several membrane transporters are involved in the resetting redox homeostasis and play important roles in tumor progression.Therefore,targeting the involved transporters to disrupt the altered redox balance emerges as a viable strategy for cancer therapy.In addition,nanomedicines have drawn much attention in the past decades.Using nanomedicines to target or reset the redox homeostasis alone or combined with other therapies has brought convincing data in cancer treatment.In this review,we will introduce the altered redox balance in cancer metabolism and involved transporters,and highlight the recent advancements of redox-modulating nanomedicines for cancer treatment.