BACKGROUND Tenofovir alafenamide fumarate(TAF)is one of the first-line treatments used to treat chronic hepatitis B patients;TAF has strong antiviral activity and a high barrier to resistance.Although virological brea...BACKGROUND Tenofovir alafenamide fumarate(TAF)is one of the first-line treatments used to treat chronic hepatitis B patients;TAF has strong antiviral activity and a high barrier to resistance.Although virological breakthroughs in patients during TAF treatment are rare,patients with incomplete responses to TAF are occasionally observed.AIM To investigate responsible mutations in the reverse transcriptase region of hepatitis B virus(HBV)for TAF-incomplete responses.METHODS Thirteen chronic hepatitis B patients who received TAF monotherapy were included.A TAF-incomplete responder was defined as one who was continuously positive for HBV DNA over 2 years after TAF treatment initiation.The emergences of mutations in TAF-incomplete responders were evaluated before,one year after,and two years after treatment by deep sequencing of HBV DNA and RNA.RESULTS Two patients were continuously positive for HBV DNA over two years.The rtL269I mutation,one of the CYEI mutations linked to tenofovir resistance,was detected in both patients by direct sequencing.The deep sequencing analysis revealed that a combination of rtT118A and rtL220I mutations and the rtL269I mutation were predominantly detected in HBV DNA even when these mutations were barely detected in HBV RNA.This suggests a superior replication capability of the HBV variants with these mutations under TAF treatment.CONCLUSION The deep sequencing analysis of HBV DNA and RNA and comparing the detection rates of mutations were useful for estimating responsible mutations for TAF-incomplete responses.Such analysis is needed to evaluate the association between mutations that emerge during TAF treatment and incomplete responses to TAF.展开更多
Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues.Dimethyl fumarate(DMF)has been used in the treatment of various immune-inflammat...Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues.Dimethyl fumarate(DMF)has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions.Here,we investigated for the first time the therapeutic effect of DMF on periodontitis.In vivo studies showed that DMF significantly inhibited periodontal destruction,enhanced mitophagy,and decreased the M1/M2 macrophage ratio.In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages,with improved mitochondrial function,inhibited oxidative stress,and increased mitophagy in RAW 264.7 cells.Furthermore,DMF increased intracellular mitochondrial Tu translation elongation factor(TUFM)levels to maintain mitochondrial homeostasis,promoted mitophagy,and modulated macrophage polarization,whereas TUFM knockdown decreased the protective effect of DMF.Finally,mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway.Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages,resulting in a shift in the balance of macrophage polarization,thereby attenuating periodontitis.Importantly,this study provides new insights into the prevention of periodontitis.展开更多
BACKGROUND Both tenofovir alafenamide(TAF)and tenofovir disoproxil fumarate(TDF)are the first-line treatments for chronic hepatitis B(CHB).We have showed switching from TDF to TAF for 96 weeks resulted in further alan...BACKGROUND Both tenofovir alafenamide(TAF)and tenofovir disoproxil fumarate(TDF)are the first-line treatments for chronic hepatitis B(CHB).We have showed switching from TDF to TAF for 96 weeks resulted in further alanine aminotransferase(ALT)improvement,but data remain lacking on the long-term benefits of TDF switching to TAF on hepatic fibrosis.AIM To assess the benefits of TDF switching to TAF for 3 years on ALT,aspartate aminotransferase(AST),and hepatic fibrosis improvement in patients with CHB.METHODS A single center retrospective study on 53 patients with CHB who were initially treated with TDF,then switched to TAF to determine dynamic patterns of ALT,AST,AST to platelet ratio index(APRI),fibrosis-4(FIB-4)scores,and shear wave elastography(SWE)reading improvement at switching week 144,and the associated factors.RESULTS The mean age was 55(28-80);45.3%,males;15.1%,clinical cirrhosis;mean baseline ALT,24.8;AST,25.7 U/L;APRI,0.37;and FIB-4,1.66.After 144 weeks TDF switching to TAF,mean ALT and AST were reduced to 19.7 and 21,respectively.From baseline to switching week 144,the rates of ALT and AST<35(male)/25(female)and<30(male)/19(female)were persistently increased;hepatic fibrosis was also improved by APRI<0.5,from 79.2%to 96.2%;FIB-4<1.45,from 52.8%to 58.5%,respectively;mean APRI was reduced to 0.27;FIB-4,to 1.38;and mean SWE reading,from 7.05 to 6.30 kPa after a mean of 109 weeks switching.The renal function was stable and the frequency of patients with glomerular filtration rate>60 mL/min was increased from 86.5%at baseline to 88.2%at switching week 144.CONCLUSION Our data confirmed that switching from TDF to TAF for 3 years results in not only persistent ALT/AST improvement,but also hepatic fibrosis improvement by APRI,FIB-4 scores,as well as SWE reading,the important clinical benefits of long-term hepatitis B virus antiviral treatment with TAF.展开更多
Psoriasis is a potentially debilitating inflammatory dermatosis affecting 0.2%-4.8% of the population worldwide causing a significant occupational, personal or psychosocial morbidity to these patients for life. The ba...Psoriasis is a potentially debilitating inflammatory dermatosis affecting 0.2%-4.8% of the population worldwide causing a significant occupational, personal or psychosocial morbidity to these patients for life. The basic aim of psoriasis therapy is to control the disease to maximum possible extent and improve the patient's quality of life. Management of triggers for flareups, lifestyle modifications, and dietary supplements are often recommended. Intermittent or rotational therapy with frequent alterations in treatment options is usually needed to reduce toxicity of anti-psoriatic drugs in the absence of safer alternatives. Currently, several biological agents categorized as either T-cell targeted(e.g., Alefacept, Efalizumab) or cytokine modulating(e.g., Adalimumab, Infliximab, Etanercept) are available for treating severe psoriasis. However, their high cost is often precluding for most patients. The usefulness of systemic(methotrexate, cyclosporine, acitretin or several other therapeutic agents) or topical(tar, anthralin, corticosteroids or calcipotriol ointments, phototherapy with or without psoralens) therapies has been well established for the management of psoriasis. The literature is also replete with benefits of less used non-standard and unconventional treatment modalities(hydroxycarbamide, azathioprine, leflunomide, mycophenolate mofetil, isotretinoin, fumarates, topical calcineurin inhibitors, peroxisome proliferator-activated receptors agonists, statins, sulfasalazine, pentoxifylline, colchicine, grenz ray therapy, excimer laser, climatotherapy and balneophototherapy, peritoneal dialysis, tonsillectomy, ichthyotherapy, etc.). These can be used alternatively to treat psoriasis patients who have mild/minimal lesions, are intolerant to conventional drugs, have developed side effects or achieved recommended cumulative dose, where comorbidities pose unusual therapeutic challenges, or may be as intermittent, rotational or combination treatment alternatives.展开更多
Background: In rumen fermentation, fumaric acid(FA) could competitively utilize hydrogen with methanogenesis to enhance propionate production and suppress methane emission, but both effects were diet-dependent. This s...Background: In rumen fermentation, fumaric acid(FA) could competitively utilize hydrogen with methanogenesis to enhance propionate production and suppress methane emission, but both effects were diet-dependent. This study aimed to explore the effects of FA supplementation on methanogenesis and rumen fermentation in goats fed diets varying in forage and concentrate particle size.Methods: Four rumen-cannulated goats were used in a 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments: low or high ratio of forage particle size: concentrate particle size(Fps:Cps), without or with FA supplementation(24 g/d). Fps:Cps was higher in the diet with chopped alfalfa hay plus ground corn than in that with ground alfalfa hay plus crushed corn.Results: Both increasing dietary Fps:Cps and FA supplementation shifted ruminal volatile fatty acid(VFA) patterns toward more propionate and less acetate in goats. An interaction between dietary Fps:Cps and FA supplementation was observed for the ratio of acetate to propionate(A:P), which was more predominant when FA was supplemented in the low-Fps:Cps diet. Methane production was reduced by FA, and the reduction was larger in the low-Fps:Cps diet(31.72%) than in the high-Fps:Cps diet(17.91%). Fumaric acid decreased ruminal total VFA concentration and increased ruminal p H. No difference was found in ruminal DM degradation of concentrate or alfalfa hay by dietary Fps:Cps or FA. Goats presented a lower ruminal methanogen abundance with FA supplementation and a higher B. fibrisolvens abundance with high dietary Fps:Cps.Conclusions: Adjusting dietary Fps:Cps is an alternative dietary model for studying diet-dependent effects without changing dietary chemical composition. Fumaric acid supplementation in the low-Fps:Cps diet showed greater responses in methane mitigation and propionate increase.展开更多
Hepatitis B virus(HBV)infection is one of the main causes of morbidity and mortality worldwide.Most children acquire the infection perinatally or during early childhood and develop a chronic hepatitis characterized by...Hepatitis B virus(HBV)infection is one of the main causes of morbidity and mortality worldwide.Most children acquire the infection perinatally or during early childhood and develop a chronic hepatitis characterized by a high viral replication and a low-inflammation phase of infection,with normal or only slightly raised aminotransferases.Although a conservative approach in children is usually recommended,different therapies exist and different therapeutic approaches are possible.The main goals of antiviral treatment for children with chronic HBV infection are to suppress viral replication and to warn the disease progression to cirrhosis and hepatocellular carcinoma,although these complications are rare in children.Both United States Food and Drug Administration(USFDA)and European Medicines Agency(EMA)have approved interferon alfa-2b for children aged 1 year and older,pegylated interferon alfa-2a and lamivudine for children aged 3 years and older,entecavir for use in children aged 2 years and older,and adefovir for use in those 12 years of age and older.Tenofovir disoproxil fumarate is approved by EMA for children aged 2 years and older and by USFDA for treatment in children aged 12 years and older.Finally,EMA has approved the use of tenofovir alafenamide for treatment of children aged 12 years and older or for children weighing more than 35 kg independent of age.This narrative review will provide the framework for summarizing indications to antiviral therapy in the management of chronic HBV infection in children and adolescents.展开更多
Hepatitis B virus(HBV)is the leading cause of chronic viral hepatitis.Annually,almost two million children younger than 5 years acquire the infection,mostly through vertical or horizontal transmission in early life.Ve...Hepatitis B virus(HBV)is the leading cause of chronic viral hepatitis.Annually,almost two million children younger than 5 years acquire the infection,mostly through vertical or horizontal transmission in early life.Vertical transmission of HBV is a high efficacy phenomenon ranging,in the absence of any preventive interventions,from 70%to 90%for hepatitis e antigen positive mothers and from 10%to 40%for hepatitis e antigen-negative mothers.Maternal viraemia is a preeminent risk factor for vertical transmission of HBV.Maternal screening is the first step to prevent vertical transmission of HBV.Hepatitis B passive and active immunoprophylaxis at birth together with antiviral treatment of highly viraemic mothers are the key strategies for global elimination of HBV infection.Strategies are needed to promote implementation of birth-dose vaccination and hepatitis B immunoglobulins in low-and middle-income countries where the prevalence of the infection is at the highest.展开更多
Extraction equilibrium features of succinic acid, malic acid,maleic acid and fumaric acid were investi- gated systematically withtrioctylamine (TOA) in chloroform, 4-methyl-2-pentanone (MIBK) and1-octanol. Fourier tra...Extraction equilibrium features of succinic acid, malic acid,maleic acid and fumaric acid were investi- gated systematically withtrioctylamine (TOA) in chloroform, 4-methyl-2-pentanone (MIBK) and1-octanol. Fourier transform-infrared (FTIR) spectroscopic analysisof organic samples loaded with the acid shows that amine forms 1:1complex of ion-pair association with succinic acid, malic acid andmaleic acid, and 1:1, 2:1 complex of ion-pair association withfumaric acid. It is proposed that the complex forms depend on thesecond dissociation constant of the dibasic acid, pK_a2.展开更多
The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitocho...The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liverdamage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.展开更多
The aim of this work was to study effects of ketotifen fumarate(KF)on prevention of tissue damage in testes of rats with experimental autoimmune orchitis(EAO)and on the contralateral testis in a model of prolonged tes...The aim of this work was to study effects of ketotifen fumarate(KF)on prevention of tissue damage in testes of rats with experimental autoimmune orchitis(EAO)and on the contralateral testis in a model of prolonged testicular cord torsion(TCT).Rats with EAO or TCT were injected intraperitoneally once daily with KF or saline solution(vehicle group).Incidence and severity of testicular damage were evaluated by histopathology using an EAO score or a Johnsen score.Mast cells(MC)were identified by histochemistry and quantified.In EAO model,KF significantly reduced severity of histopathological testicular damage compared to rats in the vehicle group.KF also reduced the number of testicular MC compared to vehicle group.Similarly,in TCT model,multifocal damage of the contralateral testis was observed 30 days after testicular torsion characterized by sloughing of the germinal epithelium,seminiferous tubule atrophy,and interstitial edema.Focal signs of inflammation and fibrosis of seminiferous tubular walls were also observed.In contrast,sections of contralateral testis of rats injected with KF and killed 30 days after surgery showed normal histological features.A significant decrease in the number of MC was observed in rats treated with KF compared to untreated animals.In conclusion,we demonstrated that treatment with KF reduced testicular inflammatory process and MC infiltrates in both EAO and TCT models.The results suggest a promising treatment for infertile male patients with testicular pathologies associated with inflammation and germ cell loss.展开更多
To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI). METHODSRats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, t...To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI). METHODSRats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined. RESULTSHistological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group. CONCLUSIONDMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI.展开更多
Tenofovir disoproxil fumarate(TDF)is a potent nucleotide analogue with high barrier to resistance,which is recommended for multi-drug resistant hepatitis B virus(HBV)infection.However,nephrotoxicity has been reported ...Tenofovir disoproxil fumarate(TDF)is a potent nucleotide analogue with high barrier to resistance,which is recommended for multi-drug resistant hepatitis B virus(HBV)infection.However,nephrotoxicity has been reported during TDF treatment,and tenofovir alafenamide(TAF),which has comparable efficacy to TDF and improves bone and renal safety,can be used as a replacement strategy.Herein,we describe a clinical case concerning a 60-year-old individual suffering liver cirrhosis and renal dysfunction,and being infected with multidrug-resistant HBV.When failing treatment with TDF,he received TAF as a rescue therapy.TAF effectively inhibited HBV replication without worsening renal function or serum phosphorus abnormality.Furthermore,hepatocellular carcinoma(HCC)occurred during TAF treatment despite controlling the viral load.The risk of HCC could not be eliminated and should be monitored during TAF treatment.展开更多
Mast cells are immune cells of the myeloid lineage that are found throughout the body,including the central nervous system.They perform many functions associated with innate and specific immunity,angiogenesis,and vasc...Mast cells are immune cells of the myeloid lineage that are found throughout the body,including the central nervous system.They perform many functions associated with innate and specific immunity,angiogenesis,and vascular homeostasis.Moreover,they have been implicated in a series of pathologies(e.g.,hypersensitivity reactions,tumors,and inflammatory disorders).In this review,we propose that this cell could be a relevant therapeutic target in multiple sclerosis,which is a central nervous system degenerative disease.To support this proposition,we describe the general biological properties of mast cells,their contribution to innate and specific immunity,and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development.The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis,including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.展开更多
基金Supported by the Japan Agency for Medical Research and Development(AMED),No.JP22fk0310503.
文摘BACKGROUND Tenofovir alafenamide fumarate(TAF)is one of the first-line treatments used to treat chronic hepatitis B patients;TAF has strong antiviral activity and a high barrier to resistance.Although virological breakthroughs in patients during TAF treatment are rare,patients with incomplete responses to TAF are occasionally observed.AIM To investigate responsible mutations in the reverse transcriptase region of hepatitis B virus(HBV)for TAF-incomplete responses.METHODS Thirteen chronic hepatitis B patients who received TAF monotherapy were included.A TAF-incomplete responder was defined as one who was continuously positive for HBV DNA over 2 years after TAF treatment initiation.The emergences of mutations in TAF-incomplete responders were evaluated before,one year after,and two years after treatment by deep sequencing of HBV DNA and RNA.RESULTS Two patients were continuously positive for HBV DNA over two years.The rtL269I mutation,one of the CYEI mutations linked to tenofovir resistance,was detected in both patients by direct sequencing.The deep sequencing analysis revealed that a combination of rtT118A and rtL220I mutations and the rtL269I mutation were predominantly detected in HBV DNA even when these mutations were barely detected in HBV RNA.This suggests a superior replication capability of the HBV variants with these mutations under TAF treatment.CONCLUSION The deep sequencing analysis of HBV DNA and RNA and comparing the detection rates of mutations were useful for estimating responsible mutations for TAF-incomplete responses.Such analysis is needed to evaluate the association between mutations that emerge during TAF treatment and incomplete responses to TAF.
基金Natural Science Foundation of China(grant nos.82270991)Zhejiang Provincial Natural Science Foundation of China/Outstanding Youth Science Foundation(grant no.LR21H140002)+4 种基金Medical Health Science and Technology Major Project of Zhejiang Provincial Health Commission(grant no.WKJ-ZJ-2311)Wenzhou Science and Technology Bureau Public Welfare Social Development(Medical and Health)Science and Technology Project(grant no.ZY2021015)Opening Research Fund from Shanghai Key Laboratory of Stomatology,Shanghai Ninth People’s Hospital,College of Stomatology,Shanghai Jiao Tong University School of Medicine(grant no.2022SKLS-KFKT011)Guangxi Key Laboratory of the Rehabilitation and Reconstruction for Oral and Maxillofacial Research(grant no.GXKLRROM2106)State Key Laboratory of Oral Diseases Open Fund(grant no.SKLOD2024OF08).
文摘Periodontitis is a common oral disease characterized by progressive alveolar bone resorption and inflammation of the periodontal tissues.Dimethyl fumarate(DMF)has been used in the treatment of various immune-inflammatory diseases due to its excellent anti-inflammatory and antioxidant functions.Here,we investigated for the first time the therapeutic effect of DMF on periodontitis.In vivo studies showed that DMF significantly inhibited periodontal destruction,enhanced mitophagy,and decreased the M1/M2 macrophage ratio.In vitro studies showed that DMF inhibited macrophage polarization toward M1 macrophages and promoted polarization toward M2 macrophages,with improved mitochondrial function,inhibited oxidative stress,and increased mitophagy in RAW 264.7 cells.Furthermore,DMF increased intracellular mitochondrial Tu translation elongation factor(TUFM)levels to maintain mitochondrial homeostasis,promoted mitophagy,and modulated macrophage polarization,whereas TUFM knockdown decreased the protective effect of DMF.Finally,mechanistic studies showed that DMF increased intracellular TUFM levels by protecting TUFM from degradation via the ubiquitin-proteasomal degradation pathway.Our results demonstrate for the first time that DMF protects mitochondrial function and inhibits oxidative stress through TUFM-mediated mitophagy in macrophages,resulting in a shift in the balance of macrophage polarization,thereby attenuating periodontitis.Importantly,this study provides new insights into the prevention of periodontitis.
文摘BACKGROUND Both tenofovir alafenamide(TAF)and tenofovir disoproxil fumarate(TDF)are the first-line treatments for chronic hepatitis B(CHB).We have showed switching from TDF to TAF for 96 weeks resulted in further alanine aminotransferase(ALT)improvement,but data remain lacking on the long-term benefits of TDF switching to TAF on hepatic fibrosis.AIM To assess the benefits of TDF switching to TAF for 3 years on ALT,aspartate aminotransferase(AST),and hepatic fibrosis improvement in patients with CHB.METHODS A single center retrospective study on 53 patients with CHB who were initially treated with TDF,then switched to TAF to determine dynamic patterns of ALT,AST,AST to platelet ratio index(APRI),fibrosis-4(FIB-4)scores,and shear wave elastography(SWE)reading improvement at switching week 144,and the associated factors.RESULTS The mean age was 55(28-80);45.3%,males;15.1%,clinical cirrhosis;mean baseline ALT,24.8;AST,25.7 U/L;APRI,0.37;and FIB-4,1.66.After 144 weeks TDF switching to TAF,mean ALT and AST were reduced to 19.7 and 21,respectively.From baseline to switching week 144,the rates of ALT and AST<35(male)/25(female)and<30(male)/19(female)were persistently increased;hepatic fibrosis was also improved by APRI<0.5,from 79.2%to 96.2%;FIB-4<1.45,from 52.8%to 58.5%,respectively;mean APRI was reduced to 0.27;FIB-4,to 1.38;and mean SWE reading,from 7.05 to 6.30 kPa after a mean of 109 weeks switching.The renal function was stable and the frequency of patients with glomerular filtration rate>60 mL/min was increased from 86.5%at baseline to 88.2%at switching week 144.CONCLUSION Our data confirmed that switching from TDF to TAF for 3 years results in not only persistent ALT/AST improvement,but also hepatic fibrosis improvement by APRI,FIB-4 scores,as well as SWE reading,the important clinical benefits of long-term hepatitis B virus antiviral treatment with TAF.
文摘Psoriasis is a potentially debilitating inflammatory dermatosis affecting 0.2%-4.8% of the population worldwide causing a significant occupational, personal or psychosocial morbidity to these patients for life. The basic aim of psoriasis therapy is to control the disease to maximum possible extent and improve the patient's quality of life. Management of triggers for flareups, lifestyle modifications, and dietary supplements are often recommended. Intermittent or rotational therapy with frequent alterations in treatment options is usually needed to reduce toxicity of anti-psoriatic drugs in the absence of safer alternatives. Currently, several biological agents categorized as either T-cell targeted(e.g., Alefacept, Efalizumab) or cytokine modulating(e.g., Adalimumab, Infliximab, Etanercept) are available for treating severe psoriasis. However, their high cost is often precluding for most patients. The usefulness of systemic(methotrexate, cyclosporine, acitretin or several other therapeutic agents) or topical(tar, anthralin, corticosteroids or calcipotriol ointments, phototherapy with or without psoralens) therapies has been well established for the management of psoriasis. The literature is also replete with benefits of less used non-standard and unconventional treatment modalities(hydroxycarbamide, azathioprine, leflunomide, mycophenolate mofetil, isotretinoin, fumarates, topical calcineurin inhibitors, peroxisome proliferator-activated receptors agonists, statins, sulfasalazine, pentoxifylline, colchicine, grenz ray therapy, excimer laser, climatotherapy and balneophototherapy, peritoneal dialysis, tonsillectomy, ichthyotherapy, etc.). These can be used alternatively to treat psoriasis patients who have mild/minimal lesions, are intolerant to conventional drugs, have developed side effects or achieved recommended cumulative dose, where comorbidities pose unusual therapeutic challenges, or may be as intermittent, rotational or combination treatment alternatives.
基金supported by the National Key Research and Development Program of China(2017YFD0500500)Key Research and Development Program of Shaanxi Province(2017ZDXM-NY-086)
文摘Background: In rumen fermentation, fumaric acid(FA) could competitively utilize hydrogen with methanogenesis to enhance propionate production and suppress methane emission, but both effects were diet-dependent. This study aimed to explore the effects of FA supplementation on methanogenesis and rumen fermentation in goats fed diets varying in forage and concentrate particle size.Methods: Four rumen-cannulated goats were used in a 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments: low or high ratio of forage particle size: concentrate particle size(Fps:Cps), without or with FA supplementation(24 g/d). Fps:Cps was higher in the diet with chopped alfalfa hay plus ground corn than in that with ground alfalfa hay plus crushed corn.Results: Both increasing dietary Fps:Cps and FA supplementation shifted ruminal volatile fatty acid(VFA) patterns toward more propionate and less acetate in goats. An interaction between dietary Fps:Cps and FA supplementation was observed for the ratio of acetate to propionate(A:P), which was more predominant when FA was supplemented in the low-Fps:Cps diet. Methane production was reduced by FA, and the reduction was larger in the low-Fps:Cps diet(31.72%) than in the high-Fps:Cps diet(17.91%). Fumaric acid decreased ruminal total VFA concentration and increased ruminal p H. No difference was found in ruminal DM degradation of concentrate or alfalfa hay by dietary Fps:Cps or FA. Goats presented a lower ruminal methanogen abundance with FA supplementation and a higher B. fibrisolvens abundance with high dietary Fps:Cps.Conclusions: Adjusting dietary Fps:Cps is an alternative dietary model for studying diet-dependent effects without changing dietary chemical composition. Fumaric acid supplementation in the low-Fps:Cps diet showed greater responses in methane mitigation and propionate increase.
文摘Hepatitis B virus(HBV)infection is one of the main causes of morbidity and mortality worldwide.Most children acquire the infection perinatally or during early childhood and develop a chronic hepatitis characterized by a high viral replication and a low-inflammation phase of infection,with normal or only slightly raised aminotransferases.Although a conservative approach in children is usually recommended,different therapies exist and different therapeutic approaches are possible.The main goals of antiviral treatment for children with chronic HBV infection are to suppress viral replication and to warn the disease progression to cirrhosis and hepatocellular carcinoma,although these complications are rare in children.Both United States Food and Drug Administration(USFDA)and European Medicines Agency(EMA)have approved interferon alfa-2b for children aged 1 year and older,pegylated interferon alfa-2a and lamivudine for children aged 3 years and older,entecavir for use in children aged 2 years and older,and adefovir for use in those 12 years of age and older.Tenofovir disoproxil fumarate is approved by EMA for children aged 2 years and older and by USFDA for treatment in children aged 12 years and older.Finally,EMA has approved the use of tenofovir alafenamide for treatment of children aged 12 years and older or for children weighing more than 35 kg independent of age.This narrative review will provide the framework for summarizing indications to antiviral therapy in the management of chronic HBV infection in children and adolescents.
文摘Hepatitis B virus(HBV)is the leading cause of chronic viral hepatitis.Annually,almost two million children younger than 5 years acquire the infection,mostly through vertical or horizontal transmission in early life.Vertical transmission of HBV is a high efficacy phenomenon ranging,in the absence of any preventive interventions,from 70%to 90%for hepatitis e antigen positive mothers and from 10%to 40%for hepatitis e antigen-negative mothers.Maternal viraemia is a preeminent risk factor for vertical transmission of HBV.Maternal screening is the first step to prevent vertical transmission of HBV.Hepatitis B passive and active immunoprophylaxis at birth together with antiviral treatment of highly viraemic mothers are the key strategies for global elimination of HBV infection.Strategies are needed to promote implementation of birth-dose vaccination and hepatitis B immunoglobulins in low-and middle-income countries where the prevalence of the infection is at the highest.
基金Supported by the National Natural Science Foundation of China (No. 29836130).
文摘Extraction equilibrium features of succinic acid, malic acid,maleic acid and fumaric acid were investi- gated systematically withtrioctylamine (TOA) in chloroform, 4-methyl-2-pentanone (MIBK) and1-octanol. Fourier transform-infrared (FTIR) spectroscopic analysisof organic samples loaded with the acid shows that amine forms 1:1complex of ion-pair association with succinic acid, malic acid andmaleic acid, and 1:1, 2:1 complex of ion-pair association withfumaric acid. It is proposed that the complex forms depend on thesecond dissociation constant of the dibasic acid, pK_a2.
文摘The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liverdamage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.
基金This work was supported by grants from Found ation“Florencio Fiorini”the University of Buenos Aires(UBACYT 2014-201722320160100058BA).
文摘The aim of this work was to study effects of ketotifen fumarate(KF)on prevention of tissue damage in testes of rats with experimental autoimmune orchitis(EAO)and on the contralateral testis in a model of prolonged testicular cord torsion(TCT).Rats with EAO or TCT were injected intraperitoneally once daily with KF or saline solution(vehicle group).Incidence and severity of testicular damage were evaluated by histopathology using an EAO score or a Johnsen score.Mast cells(MC)were identified by histochemistry and quantified.In EAO model,KF significantly reduced severity of histopathological testicular damage compared to rats in the vehicle group.KF also reduced the number of testicular MC compared to vehicle group.Similarly,in TCT model,multifocal damage of the contralateral testis was observed 30 days after testicular torsion characterized by sloughing of the germinal epithelium,seminiferous tubule atrophy,and interstitial edema.Focal signs of inflammation and fibrosis of seminiferous tubular walls were also observed.In contrast,sections of contralateral testis of rats injected with KF and killed 30 days after surgery showed normal histological features.A significant decrease in the number of MC was observed in rats treated with KF compared to untreated animals.In conclusion,we demonstrated that treatment with KF reduced testicular inflammatory process and MC infiltrates in both EAO and TCT models.The results suggest a promising treatment for infertile male patients with testicular pathologies associated with inflammation and germ cell loss.
文摘To investigate the hypothesis that treatment with dimethyl fumarate (DMF) may ameliorate liver ischemia/reperfusion injury (I/RI). METHODSRats were divided into 3 groups: sham, control (CTL), and DMF. DMF (25 mg/kg, twice/d) was orally administered for 2 d before the procedure. The CTL and DMF rats were subjected to ischemia for 1 h and reperfusion for 2 h. The serum alanine aminotransferase (ALT) and malondialdehyde (MDA) levels, adenosine triphosphate (ATP), NO × metabolites, anti-oxidant enzyme expression level, anti-inflammatory effect, and anti-apoptotic effect were determined. RESULTSHistological tissue damage was significantly reduced in the DMF group (Suzuki scores: sham: 0 ± 0; CTL: 9.3 ± 0.5; DMF: 2.5 ± 1.2; sham vs CTL, P < 0.0001; CTL vs DMF, P < 0.0001). This effect was associated with significantly lower serum ALT (DMF 5026 ± 2305 U/L vs CTL 10592 ± 1152 U/L, P = 0.04) and MDA (DMF 18.2 ± 1.4 μmol/L vs CTL 26.0 ± 1.0 μmol/L, P = 0.0009). DMF effectively improved the ATP content (DMF 20.3 ± 0.4 nmol/mg vs CTL 18.3 ± 0.6 nmol/mg, P = 0.02), myeloperoxidase activity (DMF 7.8 ± 0.4 mU/mL vs CTL 6.0 ± 0.5 mU/mL, P = 0.01) and level of endothelial nitric oxide synthase expression (DMF 0.38 ± 0.05-fold vs 0.17 ± 0.06-fold, P = 0.02). The higher expression levels of anti-oxidant enzymes (catalase and glutamate-cysteine ligase modifier subunit and lower levels of key inflammatory mediators (nuclear factor-kappa B and cyclooxygenase-2 were confirmed in the DMF group. CONCLUSIONDMF improved the liver function and the anti-oxidant and inflammation status following I/RI. Treatment with DMF could be a promising strategy in patients with liver I/RI.
基金Supported by the Chinese Foundation for Hepatitis Prevention and Control-WBE Liver Fibrosis Foundation,No.WBE20161013the Science and Technology project of Changzhou,No.CJ20160024 and No.CJ20179030
文摘Tenofovir disoproxil fumarate(TDF)is a potent nucleotide analogue with high barrier to resistance,which is recommended for multi-drug resistant hepatitis B virus(HBV)infection.However,nephrotoxicity has been reported during TDF treatment,and tenofovir alafenamide(TAF),which has comparable efficacy to TDF and improves bone and renal safety,can be used as a replacement strategy.Herein,we describe a clinical case concerning a 60-year-old individual suffering liver cirrhosis and renal dysfunction,and being infected with multidrug-resistant HBV.When failing treatment with TDF,he received TAF as a rescue therapy.TAF effectively inhibited HBV replication without worsening renal function or serum phosphorus abnormality.Furthermore,hepatocellular carcinoma(HCC)occurred during TAF treatment despite controlling the viral load.The risk of HCC could not be eliminated and should be monitored during TAF treatment.
基金supported by Sao Paulo Research Foundation(FAPESP,grant Nos.2015/03965-2 and 2014/00239-6)the National Council for Scientific and Technological Development(CNPq,grant Nos.307603/2018-0 and 307269/2017-5)Coordination for the Improvement of Higher Education Personnel(CAPES,Finance Code 001)。
文摘Mast cells are immune cells of the myeloid lineage that are found throughout the body,including the central nervous system.They perform many functions associated with innate and specific immunity,angiogenesis,and vascular homeostasis.Moreover,they have been implicated in a series of pathologies(e.g.,hypersensitivity reactions,tumors,and inflammatory disorders).In this review,we propose that this cell could be a relevant therapeutic target in multiple sclerosis,which is a central nervous system degenerative disease.To support this proposition,we describe the general biological properties of mast cells,their contribution to innate and specific immunity,and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development.The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis,including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.
