Aldo-keto reductase family member C3(AKR1C3)promotes hepatocellular carcinoma cell growth by producing prostaglandin F2α

Hepatocellular carcinoma(HCC)is a leading cause of death worldwide.Current therapies are effective for HCC patients with early disease,but many patients suffer recurrence after surgery and have a poor response to chemotherapy.Therefore,new therapeutic targets are needed.We analyzed gene expression profiles between HCC tissues and normal adjacent tissues from public databases and found that the expression of genes involved in lipid metabolism was significantly different.The analysis showed that AKR1C3 was upregulated in tumors,and high AKR1C3 expression was associated with a poorer prognosis in HCC patients.In vitro,assays demonstrated that the knockdown of AKR1C3 or the addition of the AKR1C3 inhibitor indomethacin suppressed the growth and colony formation of HCC cell lines.Knockdown of AKR1C3 in Huh7 cells reduced tumor growth in vivo.To explore the mechanism,we performed pathway enrichment analysis,and the results linked the expression of AKR1C3 with prostaglandin F2 alpha(PGF2a)downstream target genes.Suppression of AKR1C3 activity reduced the production of PGF2a,and supplementation with PGF2a restored the growth of indomethacin-treated Huh7 cells.Knockdown of the PGF receptor(PTGFR)and treatment with a PTGFR inhibitor significantly reduced HCC growth.We showed that indomethacin potentiated the sensitivity of Huh7 cells to sorafenib.In summary,our results indicate that AKR1C3 upregulation may promote HCC growth by promoting the production of PGF2α,and suppression of PTGFR limited HCC growth.Therefore,targeting the AKR1C3-PGF2a-PTGFR axis may be a new strategy for the treatment of HCC.

Tanshinone ⅡA improves Alzheimer’s disease via RNA nuclearenriched abundant transcript 1/microRNA-291a-3p/member RAS oncogene family Rab22a axis

BACKGROUND Alzheimer’s disease(AD)is a neurodegenerative condition characterized by oxidative stress and neuroinflammation.Tanshinone ⅡA(Tan-ⅡA),a bioactive compound isolated from Salvia miltiorrhiza plants,has shown potential neuroprotective effects;however,the mechanisms underlying such a function remain unclear.AIM To investigate potential Tan-ⅡA neuroprotective effects in AD and to elucidate their underlying mechanisms.METHODS Hematoxylin and eosin staining was utilized to analyze structural brain tissue morphology.To assess changes in oxidative stress and neuroinflammation,we performed enzyme-linked immunosorbent assay and western blotting.Additionally,the effect of Tan-ⅡA on AD cell models was evaluated in vitro using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Genetic changes related to the long non-coding RNA(lncRNA)nuclear-enriched abundant transcript 1(NEAT1)/microRNA(miRNA,miR)-291a-3p/member RAS oncogene family Rab22a axis were assessed through reverse transcription quantitative polymerase chain reaction.RESULTS In vivo,Tan-ⅡA treatment improved neuronal morphology and attenuated oxidative stress and neuroinflammation in the brain tissue of AD mice.In vitro experiments showed that Tan-ⅡA dose-dependently ameliorated the amyloid-beta 1-42-induced reduction of neural stem cell viability,apoptosis,oxidative stress,and neuroinflammation.In this process,the lncRNA NEAT1-a potential therapeutic target-is highly expressed in AD mice and downregulated via Tan-ⅡA treatment.Mechanistically,NEAT1 promotes the transcription and translation of Rab22a via miR-291a-3p,which activates nuclear factor kappa-B(NF-κB)signaling,leading to activation of the pro-apoptotic B-cell lymphoma 2-associated X protein and inhibition of the anti-apoptotic B-cell lymphoma 2 protein,which exacerbates AD.Tan-ⅡA intervention effectively blocked this process by inhibiting the NEAT1/miR-291a-3p/Rab22a axis and NF-κB signaling.CONCLUSION This study demonstrates that Tan-ⅡA exerts neuroprotective effects in AD by modulating the NEAT1/miR-291a-3p/Rab22a/NF-κB signaling pathway,serving as a foundation for the development of innovative approaches for AD therapy.

Mutations in Ras homolog family member A in patients with peripheral T-cell lymphoma and implications for personalized medicine

Genome sequencing has revealed frequent mutations in Ras homolog family member A(RHOA)among various cancers with unique aberrant profiles and pathogenic effects,especially in peripheral T-cell lymphoma(PTCL).The discrete positional distribution and types of RHOA amino acid substitutions vary according to the tumor type,thereby leading to different functional and biological properties,which provide new insight into the molecular pathogenesis and potential targeted therapies for various tumors.However,the similarities and discrepancies in characteristics of RHOA mutations among various histologic subtypes of PTCL have not been fully elucidated.Herein we highlight the inconsistencies and complexities of the type and location of RHOA mutations and demonstrate the contribution of RHOA variants to the pathogenesis of PTCL by combining epigenetic abnormalities and activating multiple downstream pathways.The promising potential of targeting RHOA as a therapeutic modality is also outlined.This review provides new insight in the field of personalized medicine to improve the clinical outcomes for patients.

Survey on hospice care attitude of family members of advanced cancer patients at different ages

BACKGROUND Hospice care plays an important role in improving the quality of life of advanced cancer patients,but controversy remains over whether age affects the attitudes of family members toward hospice care.AIM To investigate the attitudes of family members of advanced cancer patients of different ages toward hospice care.METHODS The study participants were 175 family members of patients with advanced cancer from January 2020 and October 2022.The participants were divided into youth(<40 years,n=65),middle-aged(40–60 years,n=59),and elderly(>60 years,n=51)groups.Researchers investigated and compared the degree of awareness regarding hospice care,attitudes,and whether the family members of patients would choose hospice care.RESULTS Among the family members of 175 patients,approximately 28%(49/175)were aware of hospice care.Awareness of hospice care,the proportion of hospice care acceptance and adaptation attitudes,and the proportion of those who chose hospice care in the youth group were higher in the middle-aged and elderly groups(P<0.05).No statistically significant difference was found in these three indicators between the middle-aged and elderly groups(P>0.05).Hospice care was chosen mainly to relieve pain and reduce unnecessary treatment,whereas the reasons for not choosing hospice care were mainly distrust and ethical concerns.CONCLUSION The family members of patients with advanced cancer had relatively low awareness of hospice care,while youth had a higher awareness of hospice care,acceptance,and adaptation attitudes,and were more willing to choose hospice care.

MiRNA-145-5p inhibits gastric cancer progression via the serpin family E member 1-extracellular signal-regulated kinase-1/2 axis

BACKGROUND MicroRNAs(miRNAs)regulate gene expression and play a critical role in cancer physiology.However,there is still a limited understanding of the function and regulatory mechanism of miRNAs in gastric cancer(GC).AIM To investigate the role and molecular mechanism of miRNA-145-5p(miR145-5p)in the progression of GC.METHODS Real-time polymerase chain reaction(RT-PCR)was used to detect miRNA expression in human GC tissues and cells.The ability of cancer cells to migrate and invade was assessed using wound-healing and transwell assays,respectively.Cell proliferation was measured using cell counting kit-8 and colony formation assays,and apoptosis was evaluated using flow cytometry.Expression of the epithelial-mesenchymal transition(EMT)-associated protein was determined by Western blot.Targets of miR-145-5p were predicated using bioinformatics analysis and verified using a dual-luciferase reporter system.Serpin family E member 1(SERPINE1)expression in GC tissues and cells was evaluated using RT-PCR and immunohistochemical staining.The correlation between SERPINE1 expression and overall patient survival was determined using Kaplan-Meier plot analysis.The association between SERPINE1 and GC progression was also tested.A rescue experiment of SERPINE1 overexpression was conducted to verify the relationship between this protein and miR-145-5p.The mechanism by which miR-145-5p influences GC progression was further explored by assessing tumor formation in nude mice.RESULTS GC tissues and cells had reduced miR-145-5p expression and SERPINE1 was identified as a direct target of this miRNA.Overexpression of miR-145-5p was associated with decreased GC cell proliferation,invasion,migration,and EMT,and these effects were reversed by forcing SERPINE1 expression.Kaplan-Meier plot analysis revealed that patients with higher SERPINE1 expression had a shorter survival rate than those with lower SERPINE1 expression.Nude mouse tumorigenesis experiments confirmed that miR-145-5p targets SERPINE1 to regulate extracellular signal-regulated kinase-1/2(ERK1/2).CONCLUSION This study found that miR-145-5p inhibits tumor progression and is expressed in lower amounts in patients with GC.MiR-145-5p was found to affect GC cell proliferation,migration,and invasion by negatively regulating SERPINE1 levels and controlling the ERK1/2 pathway.

Analysis of the Current Status and Influencing Factors of Family Members’Collateral Stigma in Schizophrenia Patients

Objective: To investigate the associated collateral stigma of the family members of schizophrenia patients and analyze its current status and influencing factors. Methods: The Link Depreciation-Discrimination Perception Scale was used to investigate the status quo of the associated stigma of the family members of 169 schizophrenia patients diagnosed in 4 hospitals in a certain province. The results of the investigation were analyzed and summarized. Results: The detection rate of stigma associated with the family members of schizophrenia patients was 72.78%, with a score of 28.41 ± 3.92 points. The main influencing factors were the family member’s education level, the patient’s illness duration, the family member’s occupation, and the family-patient relationship. Conclusion: The detection rate of stigma associated with schizophrenia was relatively high. This requires increased attention and appropriate nursing intervention.

Crosstalk among canonical Wnt and Hippo pathway members in skeletal muscle and at the neuromuscular junction

Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.

CHIP regulates bone mass by targeting multiple TRAF family members in bone marrow stromal cells

Carboxyl terminus of Hsp70-interacting protein（CHIP or STUB1） is an E3 ligase and regulates the stability of several proteins which are involved in different cellular functions. Our previous studies demonstrated that Chip deficient mice display bone loss phenotype due to increased osteoclast formation through enhancing TRAF6 activity in osteoclasts. In this study we provide novel evidence about the function of CHIP. We found that osteoblast differentiation and bone formation were also decreased in Chip KO mice. In bone marrow stromal（BMS） cells derived from Chip^-/- mice, expression of a panel of osteoblast marker genes was significantly decreased. ALP activity and mineralized bone matrix formation were also reduced in Chip-deficient BMS cells. We also found that in addition to the regulation of TRAF6, CHIP also inhibits TNFα-induced NF-κB signaling through promoting TRAF2 and TRAF5 degradation. Specific deletion of Chip in BMS cells downregulated expression of osteoblast marker genes which could be reversed by the addition of NF-κB inhibitor. These results demonstrate that the osteopenic phenotype observed in Chip^-/- mice was due to the combination of increased osteoclast formation and decreased osteoblast differentiation. Taken together, our findings indicate a significant role of CHIP in bone remodeling.

Vestigial like family member 3 is a novel prognostic biomarker for gastric cancer

BACKGROUND Vestigial like family member 3(VGLL3)is associated with the prognosis of epithelial ovarian cancer and soft tissue sarcoma,but its role in gastric cancer(GC)is unclear.AIM To explore the expression pattern and clinical significance of VGLL3 in GC.METHODS Integrative analysis was performed on the GC transcriptome profiles and survival information deposited in the ONCOMINE,GEPIA,and ONCOLNC databases.The expression levels of VGLL3 mRNA and protein were analyzed in the freshly resected tumor and normal gastric tissues from GC patients by quantitative RT-PCR and Western blot,respectively.In addition,the in situ expression of VGLL3 in the GC tissues was determined by immunohistochemistry(IHC),and the patients were accordingly classified into the high and low expression groups.The correlation of VGLL3 expression status with patient prognosis was then determined by univariate and multivariate Cox regression analyses.RESULTS Analysis of the ONCOMINE and GEPIA databases showed that VGLL3 was significantly up-regulated in GC tissues(P=0.003),and associated with the tumor TNM stage(P=0.0163).The high VGLL3 expression group had a significantly worse prognosis compared to the low expression group,as per both GEPIA(P=0.0057)and ONCOLNC(P=0.01).The bioinformatics results were validated by the significantly higher VGLL3 mRNA and protein levels in the GC tissues compared to the adjacent normal tissues(P<0.001)in a cohort of 30 GC patients.Furthermore,high in situ expression of VGLL3 protein was associated with more advanced N and TNM stages and HER2 mutation(P<0.05)in a cohort of 172 patients.Kaplan-Meier analysis showed that the high VGLL3 expression group had a worse prognosis compared to the low expression group(P=0.019).Multivariate analysis showed that VGLL3 expression status was an independent risk factor for prognosis.In addition,the prognostic risk model nomogram showed that VGLL3 was the most important indicator,with an area under the receiver operating characteristic(ROC)curve(AUC)of 0.613 for 3-year survival and 0.706 for 5-year survival.Finally,the protein interaction network analysis revealed that VGLL3 is likely involved in the Hippo signaling pathway.CONCLUSION VGLL3 is overexpressed in GC tissues and associated with a poor prognosis,indicating its potential as a novel prognosis biomarker and therapeutic target for GC.

Solute carrier family 2 members 1 and 2 as prognostic biomarkers in hepatocellular carcinoma associated with immune infiltration

BACKGROUND Metabolic reprogramming has been identified as a core hallmark of cancer.Solute carrier family 2 is a major glucose carrier family.It consists of 14 members,and we mainly study solute carrier family 2 member 1(SLC2A1)and solute carrier family 2 member 2(SLC2A2)here.SLC2A1,mainly existing in human erythrocytes,brain endothelial cells,and normal placenta,was found to be increased in hepatocellular carcinoma(HCC),while SLC2A2,the major transporter of the normal liver,was decreased in HCC.AIM To identify if SLC2A1 and SLC2A2 were associated with immune infiltration in addition to participating in the metabolic reprogramming in HCC.METHODS The expression levels of SLC2A1 and SLC2A2 were tested in HepG2 cells,HepG215 cells,and multiple databases.The clinical characteristics and survival data of SLC2A1 and SLC2A2 were examined by multiple databases.The correlation between SLC2A1 and SLC2A2 was analyzed by multiple databases.The functions and pathways in which SLC2A1,SLC2A2,and frequently altered neighbor genes were involved were discussed in String.Immune infiltration levels and immune marker genes associated with SLC2A1 and SLC2A2 were discussed from multiple databases.RESULTS The expression level of SLC2A1 was up-regulated,but the expression level of SLC2A2 was down-regulated in HepG2 cells,HepG215 cells,and liver cancer patients.The expression levels of SLC2A1 and SLC2A2 were related to tumor volume,grade,and stage in HCC.Interestingly,the expression levels of SLC2A1 and SLC2A2 were negatively correlated.Further,high SLC2A1 expression and low SLC2A2 expression were linked to poor overall survival and relapse-free survival.SLC2A1,SLC2A2,and frequently altered neighbor genes played a major role in the occurrence and development of tumors.Notably,SLC2A1 was positively correlated with tumor immune infiltration,while SLC2A2 was negatively correlated with tumor immune infiltration.Particularly,SLC2A2 methylation was positively correlated with lymphocytes.CONCLUSION SLC2A1 and SLC2A2 are independent therapeutic targets for HCC,and they are quintessential marker molecules for predicting and regulating the number and status of immune cells in HCC.

Associative stigma in family members of psychotic patients in Flanders:An exploratory study

AIM: To assess presence and severity of associative stigma in family members of psychotic patients and factors for higher associative stigma.METHODS: Standardized semi-structured interview of 150 family members of psychotic patients receiving full time treatment. This study on associative stigma in family members of psychotic patients was part of a larger research program on the burden of the family, using "Interview for the Burden of the Family" and the chapters stigma, treatment and attribution from the "Family interview Schedule". The respondents were relatives, one per patient, either partner or parent. The patients had been diagnosed with schizophrenia or schizo-affective disorder. All contacts with patients and relatives were in Dutch. Relatives were deemed suitable to participate in this research if they saw the patient at least once a week. Recruitment took place in a standardized way: after obtaining the patient's consent, the relatives were approached to participate. The results were analyzed using SPSS Version 18.0. RESULTS: The prevalence of associative stigma in this sample is 86%. Feelings of depression in the majority of family members are prominent. Twenty-one point three percent experienced guilt more or less frequent, while shame was less pronounced. Also, 18.6% of allrespondents indicated that they tried to hide the illness of their family member for others regularly or more. Three six point seven percent really kept secret about it in certain circumstances and 29.3% made efforts to explain what the situation or psychiatric condition of their family member really is like. Factors with marked significance towards higher associative stigma are a worsened relationship between the patient and the family member, conduct problems to family members, the patients' residence in a residential care setting, and hereditary attributional factors like genetic hereditability and character. The level of associative stigma has significantly been predicted by the burden of aggressive disruptions to family housemates of the psychotic patient.CONCLUSION: Family members of psychotic patients in Flanders experience higher associative stigma compared to previous international research. Disruptive behavior by the patient towards in-housing family members is the most accurate predictor of higher associative stigma.

Psychological state and needs of family member caregivers for victims of traumatic brain injury:A cross-sectional descriptive study

Objective:Here we evaluated the impact of varying severity of traumatic brain injury on the psychological state and demands of family caregivers.Further,we determined the most significant and least significant daily needs among family caregivers.Methods:We performed a cross-sectional descriptive study in three public hospitals in Tai'an,China.Three hundred caregivers related to traumatic brain injury victims were randomly selected.Patients had varying degrees of injuries(mild to severe).The Symptom Checklist-90(SCL-90)was used to assess family caregivers'psychological statuses.The Critical Care Family Needs Inventory(CCFNI)was used to determine family caregivers'needs.Finally,the Glasgow Coma Scale(GCS)was employed to define patients'level of traumatic brain injury.Results:SCL-90 scores for each psychological dimension were significantly higher with increasing TBI severity(p<0.05).Similarly,CCFNI scores were significantly higher with increasing TBI severity(p<0.05)for information,reassurance,and accessibility.These same dimensions were found to be the most important needs for family members of TBI injury victims,while support and comfort were the least important dimensions.Conclusions:The more severe pathogenic condition of the patient,the heavier the psychological pressure is on their family member caregivers.Medical staff should therefore pay close attention to the psychological health of family caregivers of TBI patients,especially family caregivers of critical cases.Interventions should be accordingly designed and conducted to meet the needs of family caregivers.

Estimation of Reference Values for PFOS and PFOA in Human Biomonitoring and Relevance of Exposure among Family Members in China

The reference values of serum perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) concentrations were evaluated based on the human blood samples collected from Kashi, Xinjiang. And human serum samples of family members from Liaoning were evaluated for levels of PFOS and PFOA with the purpose to compare exposure pathways for family members. Among the 110 blood specimens from Kashi, the detection frequency of PFOS and PFOA was 93% and 6%, respectively. Reference values of serum PFOS, evaluated as the 90th percentiles of the concentrations, were determined to be 6.44 μg/L. Significant positive correlations were observed for serum levels of PFOS and PFOA among family members in Liaoning. Specially, stronger correlation between mother and offspring was observed than that between father and offspring. And stronger correlation of serum PFOS and PFOA levels was observed among fam- ily members in rural areas than those in big and small-medium cities. Difference in the association of serum PFOS and PFOA level among family members suggested that exposure in the outdoor and working environment of different oc- cupations should be evaluated. Present study provides reference values for exposure assessment in China and potential pathways of human exposure to PFOS and PFOA.

Clinical and prognostic significance of expression of phosphoglycerate mutase family member 5 and Parkin in advanced colorectal cancer

BACKGROUND Drugs targeting mitochondria can induce mitophagy and restrain proliferation in colorectal cancer(CRC)cells.Phosphoglycerate mutase family member 5(PGAM5)activates serine/threonine PTEN-induced putative kinase 1/Parkin pathway-mediated mitophagy.However,there are few studies on the clinical and prognostic significance of expression of PGAM5 protein and mitophagy-related protein Parkin in patients.AIM To assess the clinical significance of PGAM5 and Parkin proteins,as biomarkers for diagnosis and prognosis of CRC,by studying their expression in advanced CRC tissues and their association with clinicopathological parameters.METHODS The expression of PGAM5 and Parkin in CRC tissues from 100 patients was determined by immunohistochemistry.Each case was evaluated by using a combined scoring method based on signal intensity staining(scored 0-3)and the proportion of positively stained cancer cells(scored 0-4).The final staining score was calculated as the intensity score multiplied by the proportion score.Specimens were categorized as either high or low expression according to the Youden index,and the association between the expression of PGAM5 or Parkin and clinicopathological factors was ascertained.Additionally,we employed western blot to measure PGAM5 and Parkin protein expression in six matched pairs of CRC and adjacent non-tumor tissues.RESULTS Immunohistochemical and western blot findings showed that both PGAM5 and Parkin protein expression in tumor tissues was significantly higher than that in the adjacent tissues:PGAM5 and Parkin were mainly expressed in the cytoplasm of colonic epithelial cells.PGAM5 and Parkin protein levels were significantly positively correlated in advanced CRC tissues.Moreover,reduced Parkin protein expression was an independent prognostic factor for overall survival and progression-free survival in CRC patients as evinced by multivariate analysis.CONCLUSION The expression of PGAM5 protein and mitophagy-related protein Parkin has diagnostic significance for CRC and may become new biomarkers.Parkin may be a potential marker for the survival of CRC patients.

Cytochrome P450 family 17 subfamily A member 1 mutation causes severe pseudohermaphroditism: A case report

BACKGROUND 17α-Hydroxylase deficiency(17-OHD)is a rare form of congenital adrenal hyperplasia,characterized by hypertension,hypokalemia,and gonadal dysplasia.However,due to the lack of a comprehensive understanding of this disease,it is prone to misdiagnosis and missed diagnosis,and there is no complete cure.CASE SUMMARY We report a female patient with 17-OHD.The patient was admitted to the Department of Neurology of our hospital due to limb weakness.During treatment,it was found that the patient’s condition was difficult to correct except for hypokalemia,and her blood pressure was difficult to control with various antihypertensive drugs.She was then transferred to our department for further treatment.On physical examination,the patient's gonadal development was found to be abnormal,and chromosome analysis demonstrated karyotype 46,XY.Considering the possibility of 17-OHD,the cytochrome P450 family 17 subfamily A member 1(CYP17A1)test was performed to confirm the diagnosis.CONCLUSION The clinical manifestations of 17-OHD are complex.Hormone determination,imaging examination,chromosome determination and CYP17A1 gene test are helpful for early diagnosis.

A Preliminary Study on the HCV Infection Status of Patients with Hemophilia and Their Family Members

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Family with sequence similarity 134 member B-mediated reticulophagy ameliorates hepatocyte apoptosis induced by dithiothreitol

BACKGROUND Endoplasmic reticulum(ER)stress-related hepatocyte apoptosis is responsible for multiple hepatic diseases.Previous studies have revealed that endoplasmic reticulophagy(ER-phagy)promotes the selective clearance of damaged ER fragments during ER stress,playing a crucial role in maintaining ER homeostasis and inhibiting apoptosis.Family with sequence similarity 134 member B(FAM134B)is a receptor involved in ER-phagy that can form a complex with calnexin(CNX)and microtubule-associated protein 1 light chain 3(LC3).The complex can mediate the selective isolation of ER fragments to attenuate hepatocyte apoptosis.However,the precise regulatory mechanisms remain unclear.AIM To elucidate the effect of FAM134B-mediated ER-phagy on ER stress-induced apoptosis in buffalo rat liver 3A(BRL-3A)rat hepatocytes and the potential regulatory mechanisms.METHODS ER stress-related hepatocyte apoptosis was induced using dithiothreitol(DTT).Proteins related to ER stress and autophagy were measured with western blotting.Protein complex interactions with FAM134B were isolated by co-immunoprecipitation.ER-phagy was evaluated in immunofluorescence experiments.Cell cycle distribution and apoptosis were measured by flow cytometry.Mitochondrial Ca^(2+) levels were evaluated by the co-localization of intracellular Ca^(2+)-tracker and Mitotracker.The small interfering RNA against FAM134B was used to knockdown FAM134B in BRL-3A cells.RESULTS ER stress-related and autophagy-related proteins in BRL-3A cells were elevated by both short and long-term DTT treatment.Furthermore,co-immunoprecipitation confirmed an interaction between FAM134B,CNX,FAM134B,and LC3 in BRL-3A cells.Immunofluorescence assays revealed that autolysosomes significantly decreased following short-term DTT treatment,but increased after long-term treatment.Mitochondrial Ca2+levels and apoptotic rates were dramatically elevated,and more cells were arrested in the G1 stage after short-term DTT treatment;however,these decreased 48 h later.Moreover,FAM134B downregulation accelerated mitochondrial apoptotic pathway activation and aggravated hepatocyte apoptosis under ER stress.CONCLUSION FAM134B-mediated ER-phagy attenuates hepatocyte apoptosis by suppressing the mitochondrial apoptotic pathway.Our findings provide new evidence highlighting the importance of FAM134Bmediated ER-phagy in attenuating hepatocyte apoptosis.

Tumor necrosis family receptor superfamily member 9/tumor necrosis factor receptor-associated f

Hepatitis C virus(HCV)infection is an excellent immunological model for understanding the mechanisms developed by non-cytopathic viruses and tumors to evade the adaptative immune response.The antigen-specific cytotoxic T cell response is essential for keeping HCV under control,but during persistent infection,these cells become exhausted or even deleted.The exhaustion process is progressive and depends on the infection duration and level of antigenemia.During high antigenic load and long duration of infection,T cells become extremely exhausted and ultimately disappear due to apoptosis.The development of exhaustion involves the impairment of positive co-stimulation induced by regulatory cytokines,such as transforming growth factor beta 1.This cytokine downregulates tumor necrosis factor receptor(TNFR)-associated factor 1(TRAF1),the signal transducer of the T cell co-stimulatory molecule TNFR superfamily member 9(known as 4-1BB).This impairment correlates with the low reactivity of T cells and an exhaustion phenotype.Treatment with interleukin-7 in vitro restores TRAF1 expression and rescues T cell effector function.The process of TRAF1 loss and its in vitro recovery is hierarchical,and more affected by severe disease progression.In conclusion,TRAF1 dynamics on T cells define a new pathogenic model that describes some aspects of the natural history of HCV,and sheds light on novel immunotherapy strategies for chronic viral infections and cancer.

MiR-16-5p plays an inhibitory role in human non-small cell lung cancer through Fermitin family member 2

Increasing evidence indicates that aberrant expressions of some microRNAs are associated with cancer progression.However,the roles and biological mechanisms of miRNA-16-5p in human non-small cell lung cancer(NSCLC)are not to be well studied.Here,we validated that the expression of miR-16-5p was decreased significantly in NSCLC samples and cell lines.The correlation between the clinicopathological features of NSCLC and the miR-16-5p expression showed that the expression of miR-16-5p in non-small cell lung cancer was linked with the advanced TNM stage,positive lymph node metastasis,with short overall survival(OS).Also,a negative correlation between miR-16-5p and Fermitin family member 2(FERMT2)was observed,implying there may be a potential link about their regulation.The hypothesis was further confirmed by in-silico analysis and dual-luciferase reporter assay.Moreover,we demonstrated that the transfections of miR-16-5p mimics could alter some biological characteristics of NSCLC cells remarkably accomplished by the expression variance of FERMT2 in vitro and in vivo assays.Summarily,this study demonstrated that miR-16-5p,as a tumor suppression factor in NSCLC by targeting FERMT2,could serve as one promising biomarker in the prediction for NSCLC patients.