Biolog代谢表型技术解析小菜蛾肠道细菌河生肠杆菌的生物学特性

河生肠杆菌Enterobacter amnigenus为小菜蛾Plutella xylostella幼虫肠道优势可培养格兰氏阴性细菌,本文系统地阐述了河生肠杆菌在养分需求和环境适应力上的生物学特性。采用Biolog代谢表型技术,系统地研究了E.amnigenus的碳、氮、磷、硫需求及其在各种环境下的适应力。河生肠杆菌具有广泛的营养需求,可代谢38.42%的供试碳源、98.42%的供试氮源,以及100%的硫源和100%的磷源;高效代谢的碳源和氮源分别为有机酸类和糖类、及氨基酸类和肽类化合物。它表现出95种生物合成途径。河生肠杆菌具有广泛的环境适应力,能分别在高达6.5%氯化钠、5%硫酸钠、6%氯化钾、20%乙二醇、6%甲酸钠、4%尿素、10%乳酸钠、50 mmol/L苯甲酸钠(pH5.2)、200 mmol/L磷酸钠(pH7.0)、100 mmol/L硫酸铵(pH8.0)、100 mmol/L亚硝酸钠和100 mmol/L硝酸钠的渗透溶液中生长,而不能在11%~12%的乳酸钠渗透溶液中生长;其适应pH值范围为4.5~10.0,最适约为9.0。在多种氨基酸的作用下,河生肠杆菌具有脱羧酶和脱氨酶活性。小菜蛾肠道细菌河生肠杆菌具有广泛营养需求特性、渗透压与pH环境适应力。

Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease

Many placebo controlled trials and meta-analyses evaluated the efficacy of different drugs for the treatment of inflammatory bowel disease (IBD), including immunosuppressants and biologics. Their use is indicated in moderate to severe disease in non responders to corticosteroids and in steroid-dependent patients, as induction and maintainance treatment. Infliximab, as well as cyclosporine, is considered a second line therapy in the case of severe ulcerative colitis, or non-responders to intravenous corticosteroids. An adequate dosage and duration of therapy with thiopurines should be reached before evaluating their efficacy. Methotrexate is a valid option in patients with Crohn’s disease but its use is confined to patients who are intolerant or non-responders to thiopurines. Evidence for the use of methotrexate in ulcerative colitis is insufficient. The use of thalidomide and mycophenolate mofetil is not recommended in patients with inflammatory bowel disease, these treatments could be considered in case of failure of all other therapeutic options. In patients with moderately active ulcerative colitis, refractory to thiopurines, the use of tacrolimus is considered an alternative to biologics. An increase of the dose or a decrease in the interval of administration of biological treatment could be useful in the presence of an incomplete clinical response. In the case of primary failure of an anti-tumor necrosis factor alpha a switch to another one should be considered. Data on the efficacy of combination therapy are up to now insufficient to consider this strategy in all IBD patients. The final outcome of the treatment should be considered the clinical remission, with mucosa healing, and not the clinical response. The evaluation of serum concentration of thiopurine methyl transferase activity, thiopurine metabolites, biologic serum levels and antibiologic antibodies could be useful for the management of the treatment but it has not been routinely applied in clinical practice. The evidence of high risk development of lymphoma and cutaneous malignancies should be considered in patients treated with immunosuppressants and biologics for a long period.

Is non-biological treatment of rheumatoid arthritis as good as biologics?

The management of rheumatoid arthritis(RA) in the past three decades has undergone a paradigm shift from symptomatic relief to a "treat-to-target" approach. This has been possible through use of various conventional and biologic disease modifying anti-rheumatic drugs(DMARDs) which target disease pathogenesis at a molecular level. Cost and infection risk preclude regular use of biologics in resource-constrained settings. In therecent years, evidence has emerged that combination therapy with conventional DMARDs is not inferior to biologics in the management of RA and is a feasible cost-effective option.

Are we giving biologics too late? The case for early versus late use

Corticosteroids and immunomodulators have been the mainstay therapies for Crohn’s disease. Corticosteroids are highly effective to control symptoms in the short- term, but they are not effective in maintaining remission, they heal the mucosa in a reduced proportion of cases, and long-time exposure is associated with an increased risk of infections and mortality. Immunomodulators, azathioprine and methotrexate, heal the mucosa in a higher proportion of patients that corticosteroids but their onset of action is slow and they benefit less than half of patients with Crohn’s disease. In the last decade, medical therapy for Crohn’s disease has experienced a remarkable change due to the introduction of biologic therapy, and particularly the use of anti-tumour necrosis factor-alpha agents. Infliximab, adalimumab, and certolizumab pegol have demonstrated efficacy for induction and maintenance of remission in active Crohn’s disease. These agents have raised the bar for what is a suitable symptomatic response in Crohn’s disease and modification of the natural history of the disease has become a major goal in the treatment of Crohn’s disease. There are several data in the literature that suggest that early use of biologic therapy and achievement of mucosal healing contribute to disease course modification. However, many questions on early biological therapy for Crohn’s disease remain still unanswered.

Risk of hepatitis B virus reactivation in patients with autoimmune diseases undergoing non-tumor necrosis factor-targeted biologics

Hepatitis B virus reactivation(HBVr)can occur in patients treated with immunosuppressive medications.Risk stratification for HBVr based on hepatitis B virus(HBV)serology and viral load is an important strategy to determine appropriate HBV monitoring and antiviral prophylaxis use.Recent advances in the understanding of pathophysiology of autoimmune diseases have led the development of cytokine-targeted therapies.Tumor necrosis factor(TNF)-αinhibitors have been widely used for patients with inflammatory bowel disease,psoriasis,and rheumatic diseases.Further,the clinical benefits of interleukin(IL)-12/23,IL-17,or Janus kinases inhibitors have been demonstrated in these patients.It is well known that TNF-αinhibitor use can lead to HBVr,however,the risk of HBVr in patients undergoing non-TNF-targeted biologics have not been fully understood.In this review,we discuss the risk of HBVr in patients treated with non-TNF-targeted biologics,and immunological mechanisms of these medications causing HBVr.

Precision medicine in inflammatory bowel disease:Individualizing the use of biologics and small molecule therapies

The advent of biologics and small molecules in inflammatory bowel disease(IBD)has marked a significant turning point in the prognosis of IBD,decreasing the rates of corticosteroid dependence,hospitalizations and improving overall quality of life.The introduction of biosimilars has also increased affordability and enhanced access to these otherwise costly targeted therapies.Biologics do not yet represent a complete panacea:A subset of patients do not respond to first-line anti-tumor necrosis factor(TNF)-alpha agents or may subsequently demonstrate a secondary loss of response.Patients who fail to respond to anti-TNF agents typically have a poorer response rate to second-line biologics.It is uncertain which patient would benefit from a different sequencing of biologics or even a combination of biologic agents.The introduction of newer classes of biologics and small molecules may provide alternative therapeutic targets for patients with refractory disease.This review examines the therapeutic ceiling in current treatment strategies of IBD and the potential paradigm shifts in the future.

Role of the combination of biologics and/or small molecules in the treatment of patients with inflammatory bowel disease

Inflammatory bowel disease(IBD)is a group of chronic diseases that includes ulcerative colitis,Crohn’s disease,and indeterminate colitis.Patients with IBD require prolonged treatment and high utilization of healthcare resources for proper management.The treatment of patients with IBD is focused on achieving therapeutic goals including clinical,biochemical,and endoscopic variables that result in improvement of the quality of life and prevention of disability.Advanced IBD treatment includes tumor necrosis factor inhibitors,integrin antagonist,antagonist of the p40 subunit of interleukin 12/23,and small molecule drugs.However,despite the multiple treatments available,about 40%of patients are refractory to therapy and present with persistent symptoms that have a great impact on their quality of life,with hospitalization and surgery being necessary in many cases.Dual therapy,a strategy sometimes applicable to refractory IBD patients,includes the combination of two biologics or a biologic in combination with a small molecule drug.There are two distinct scenarios in IBD patients in which this approach can be used:(1)Refractory active luminal disease without extraintestinal manifestations;and(2)patients with IBD in remission,but with active extraintestinal manifestations or immune-mediated inflammatory diseases.This review provides a summary of the results(clinical response and remission)of different combinations of advanced drugs in patients with IBD,both in adults and in the pediatric population.In addition,the safety profile of different combinations of dual therapy is analyzed.The use of newer combinations,including recently approved treatments,the application of new biomarkers and artificial intelligence,and clinical trials to establish effectiveness during long-term followup,are needed to establish new strategies for the use of advanced treatments in patients with refractory IBD.

Current status of novel biologics and small molecule drugs in the individualized treatment of inflammatory bowel disease

Treatment strategies for inflammatory bowel disease(IBD)are rapidly evolving with the development of biologics and small molecule drugs(SMDs).However,these drugs are not guaranteed to be effective in all patients,and a“ceiling effect”of biologic monotherapy may occur.This issue highlights an unmet need for optimizing the use of biologics and predicting therapeutic responses.Thus,the development of new drugs with novel mechanisms of action is urgently needed for patients with primary nonresponse and secondary loss of response to conventional biologics and SMDs.In addition,combining different biologics or SMDs has been proposed as a novel strategy to enhance treatment efficacy in IBD,which theoretically has multidimensional anti-inflammatory potential.Based on the current evidence available for IBD,dual targeted therapy may be a promising strategy for refractory IBD patients who have failed in multiple biologic treatments or who have extraintestinal manifestation.Additionally,identifying the subgroup of IBD patients who are responding to biological combination therapies is also equally important in stable disease remission.In this review,we summarize the newly developed biologics and SMDs and the current status of biologics/SMDs to highlight the development of individualized treatment in IBD.

Are we giving biologics too much time? When should we stop treatment?

The optimal duration of biological treatment, particularly anti-TNF, in inflammatory bowel disease （IBD） is a very important question both for patients and physicians. There is no published evidence to clearly and definitely answer this question. However data on natural history of IBD, long term safety of biologics, immunosuppressors （IS） cessation and some preliminary studies on biologics cessation may help us to discuss this topic. The decision to stop a biological treatment is currently based on a compromise between the benefits and risks associated with the prolongation of this treatment. IBD, more particularly CD, are characterized by the development of complications and the need for recurrent hospitalizations and surgeries in approximately 2/3 of cases. In these patients potentially in need of biological treatments, it is probable that, as it has been demonstrated for IS, the longer a stable remission has be achieved under treatment, the lower the risk of relapse is alter treatment cessation. Further prospective studies should now aim at disclosing patient characteristics associated with a low risk of relapse to imple- ment this strategy.

Effectiveness, safety, and drug sustainability of biologics in elderly patients with inflammatory bowel disease: A retrospective study

BACKGROUND Biologic therapy resulted in a significant positive impact on the management of inflammatory bowel disease(IBD) however data on the efficacy and side effects of these therapies in the elderly is scant.AIM To evaluate retrospectively the drug sustainability, effectiveness, and safety of the biologic therapies in the elderly IBD population.METHODS Consecutive elderly(≥ 60 years old) IBD patients, treated with biologics [infliximab(IFX), adalimumab(ADAL), vedolizumab(VDZ), ustekinumab(UST)] followed at the McGill University Inflammatory Bowel Diseases Center were included between January 2000 and 2020.Efficacy was measured by clinical scores at 3, 6-9 and 12-18 mo after initiation of the biologic therapy. Patients completing induction therapy were included. Adverse events(AEs) or serious AE were collected during and within three months of stopping of the biologic therapy.RESULTS We identified a total of 147 elderly patients with IBD treated with biologicals during the study period, including 109 with Crohn’s disease and 38 with ulcerative colitis. Patients received the following biologicals: IFX(28.5%), ADAL(38.7%), VDZ(15.6%), UST(17%). The mean duration of biologic treatment was 157.5(SD = 148) wk. Parallel steroid therapy was given in 34% at baseline,19% at 3 mo, 16.3% at 6-9 mo and 6.5% at 12-18 mo. The remission rates at 3, 6-9 and 12-18 mo were not significantly different among biological therapies. Kaplan-Meyer analysis did not show statistical difference for drug sustainability(P = 0.195), time to adverse event(P = 0.158) or infection rates(P = 0.973) between the four biologics studied. The most common AEs that led to drug discontinuation were loss of response, infusion/injection reaction and infection.CONCLUSION Current biologics were not different regarding drug sustainability, effectiveness, and safety in the elderly IBD population. Therefore, we are not able to suggest a preferred sequencing order among biologicals.

Predictive value of blood concentration of biologics on endoscopic inactivity in inflammatory bowel disease:A systematic review

BACKGROUND Although blood concentration of biologics is an important composition of disease management in inflammatory bowel disease(IBD)patients,complexity and uncertainty of biological management encourage many disputes in predicting the outcome of IBD patients through blood concentration of biologics.AIM To verify the predictive value of blood concentration of biologics on endoscopic inactivity in IBD patients under different situations.METHODS We searched PubMed/MEDLINE,Embase,and Web of Science up to May 2020 and identified IBD patients as the research cohort as well as the correlations between blood concentration of biologics and endoscopic inactivity in IBD patients as the research direction.RESULTS A total of 23 articles with 30 clinical studies and 1939 IBD patients were included.The predictive cut-off value of blood concentration of infliximab on mucosal healing should be 2.7-10.6μg/mL in IBD.Blood concentration of infliximab reaching 5.0-12.7μg/mL or more increased the probability of fistula healing/closure in perianal fistulizing Crohn's disease.Blood concentration of adalimumab reaching 7.2-16.2μg/mL or more could predict mucosal healing in IBD.The predictive cut-off value of blood concentration of adalimumab on fistula healing/closure should be 5.9-9.8μg/mL in perianal fistulizing Crohn's disease.Blood concentration of vedolizumab surpassing 25.0μg/mL indicated mucosal healing in ulcerative colitis patients under maintenance therapy and the predictive cut-off value of blood concentration on mucosal healing or endoscopic remission under induction therapy in IBD could be 8.0-28.9μg/mL.CONCLUSION Blood concentration of biologics should not be utilized to predict endoscopic inactivity of IBD independently due to discrepancies in clinical studies,whereas conducting therapeutic drug monitoring intensively contributes to precise therapy.

Biologics in non-infectious uveitis past,present and future

Our increase in knowledge of the pathophysiology of non-infectious uveitis(NIU)and other immune-mediated diseases has been mirrored over the last two decades by the expansion of therapeutic options in the realm of immunosuppressive medications.Principal among these advances is the emergence of biologics,which offer the promise of targeted therapy and the hope of reduced toxicity when compared to corticosteroids and“standard”immunosuppression.Among the biologics,monoclonal antibodies blocking tumor necrosis factor alpha(TNF-α)have been shown to be a very effective therapeutic target for uveitis and many associated systemic inflammatory diseases.Multiple TNF blockers have shown benefit for uveitis,and in 2016,adalimumab became the first biologic and non-corticosteroid immunosuppressive to obtain Food and Drug Administration(FDA)approval in the treatment of NIU.Although effective,TNF blockers are not universally so,and safety concerns such as infection and demyelinating disease must be carefully considered and ruled out prior to their use,especially in patients with intermediate uveitis with which multiple sclerosis is a known association.Ongoing study has identified novel targets for regulation in the treatment of immune-mediated and inflammatory diseases.Interferons,interleukin and Janus kinase inhibitors in addition to antibodies targeting T cell and B cell activation highlight the expanding field of treatment modalities in NIU.Ongoing study will be required to better determine the safety and efficacy of biologics in the armamentarium of immunosuppressive treatments for NIU.

Angioedema associated with Crohn's disease:Response to biologics

A 46-year-old female patient with terminal ileum Crohn’s disease and ankylosing spondylitis presented with recurrent angioedema and urticaria. Investigations ruled out hereditary angioedema, and environmental or food allergen triggers. She was diagnosed with chronic idiopathic urticaria with angioedema, and was treated with a trial of intravenous immunoglobulin immunotherapy, danazol, prednisone and hydroxyzine. Due to ongoing bowel and arthritic complaints, she was started on infliximab infusions and within 2 treatments, she had complete resolution of the angioedema and urticaria, as well as of the bowel and arthritic symptoms. Unfortunately she developed allergic reactions to the infliximab and was switched to another anti-tumor necrosis factor （TNF）-a agent, adalimumab. Since then, she has had no further angioedema or urticaria, and her Crohn’s disease has been quiescent. This is the first known case report of chronic idiopathic urticaria with angioedema coexistent with Crohn’s disease that was successfully treated with anti-TNF-α agents.

Na^(+)/K^(+)-ATPase:ion pump,signal transducer,or cytoprotective protein,and novel biological functions

Na^(+)/K^(+)-ATPase is a transmembrane protein that has important roles in the maintenance of electrochemical gradients across cell membranes by transporting three Na^(+)out of and two K^(+)into cells.Additionally,Na^(+)/K^(+)-ATPase participates in Ca^(2+)-signaling transduction and neurotransmitter release by coordinating the ion concentration gradient across the cell membrane.Na^(+)/K^(+)-ATPase works synergistically with multiple ion channels in the cell membrane to form a dynamic network of ion homeostatic regulation and affects cellular communication by regulating chemical signals and the ion balance among different types of cells.Therefo re,it is not surprising that Na^(+)/K^(+)-ATPase dysfunction has emerged as a risk factor for a variety of neurological diseases.However,published studies have so far only elucidated the important roles of Na^(+)/K^(+)-ATPase dysfunction in disease development,and we are lacking detailed mechanisms to clarify how Na^(+)/K^(+)-ATPase affects cell function.Our recent studies revealed that membrane loss of Na^(+)/K^(+)-ATPase is a key mechanism in many neurological disorders,particularly stroke and Parkinson's disease.Stabilization of plasma membrane Na^(+)/K^(+)-ATPase with an antibody is a novel strategy to treat these diseases.For this reason,Na^(+)/K^(+)-ATPase acts not only as a simple ion pump but also as a sensor/regulator or cytoprotective protein,participating in signal transduction such as neuronal autophagy and apoptosis,and glial cell migration.Thus,the present review attempts to summarize the novel biological functions of Na^(+)/K^(+)-ATPase and Na^(+)/K^(+)-ATPase-related pathogenesis.The potential for novel strategies to treat Na^(+)/K^(+)-ATPase-related brain diseases will also be discussed.

Chronic Hepatitis B Virus Infection: Biological Parameters in Patients Treated with Tenofovir Disoproxil Fumarate

Chronic hepatitis B causes a liver disease characterized by inflammation of the liver parenchyma. The aim of this study was to investigate the evolution of biological parameters in patients treated with Tenofovir for chronic B infection at the Commune V referral health center in Bamako. We obtained a prevalence of 14.15%. The most represented age group was 31 - 40 years, with 36.8%. The sex ratio was 1.44 in favour of men. Viral load was undetectable after 18 months of treatment in 25 patients (42.37%). Tenofovir, the 1st-line drug in Mali, is effective on the biological parameters monitored in patients.

Biological soil crusts and their potential applications in the sand land over Qinghai-Tibet Plateau

The Qinghai-Tibet Plateau is now experiencing ecological degradation risks as a result of climate change and human activities.The alpine grassland ecology in permafrost zones is fragile and susceptible to deterioration due to its high altitude,low temperature,and limited oxygen,which complicates the repair of damaged land.Biological soil crusts(BSCs)are crucial for land restoration in plateau regions because they can thrive in harsh conditions and have environmentally beneficial traits.Inoculated biological soil crust(IBSC)has shown success in low-altitude desert regions,but may not be easily duplicated to the plateau environment.Therefore,it is essential to do a comprehensive and multifaceted analysis of the basic theoretical comprehension and practical application of BSCs on the Tibetan Plateau.This review article aims to provide a brief summary of the ecological significance and the mechanisms related to the creation,growth,and progression of BSCs.It discusses the techniques used for cultivating BSCs in laboratories and using them in the field,focusing on the Qinghai-Tibet Plateau circumstance.We thoroughly discussed the potential and the required paths for further studies.This study may be used as a basis for selecting suitable microbial strains and accompanying supplemental actions for implementing IBSCs in the Qinghai-Tibet Plateau.

Secondary Metabolites of Entomopathogenic Fungi, Biological Alternative for the Control of Agricultural Pests and Disease: Present and Perspectives

The use of entomopathogenic fungi (EF) in recent years has been highly effective against the different orders of insects considered pests of agricultural importance and their conidia have been commonly applied, but it has been reported that these are sensitive to the environmental conditions. For this reason, biopesticides products have been formulated based on secondary metabolites, recently. These biomolecules participate as biological control agent, such as: cyclic depsipeptides, amino acids, polyketides, polyphenols and terpenoids, affecting their morphology, life cycle and insect behavior. The use of secondary metabolites of entomopathogenic fungi opens the possibility of application in a more efficient way for the control of agricultural pests in a compatible with the environment and human health;therefore, it is important to know, analyzing the type of molecules, their effects, and their different methods of application.

Evaluation of the Efficacy of an Aloe barbadensis Based Biological Insecticide against Pests of Abelmochus esculentus for Promoting Ecological Agriculture (Far-North, Cameroon)

Chemical insecticides have been considered as a means to combat crop pests. Although their effectiveness is evident, their impact on the environment is increasingly being discussed. The aim of this study is to determine the agro-ecological potential of a biological insecticide (C25H32O12) based on Aloe barbadensis in a Sahelian context. For this purpose, a completely randomized block experimental design with 3 replications and 4 treatments was set up to experiment with Aloe barbadensis as a bioinsecticide against pests of Abelmoschus esculentus. However, data were collected using an observation and parameter monitoring grid. This includes the cultivation of Abelmoschus esculentus, soil preparation, seeding and watering, plot labeling, preparation of the bioinsecticide (selection and preparation of raw materials, grinding of Aloe barbadensis miller and extraction of the crude bioinsecticide, quantification of treatment doses and dilution, and obtaining the formulated bioinsecticide), plant watering, plant treatment, and finally parameter monitoring. The results obtained reveal that the level of damage is significantly high in the control treatment T0 (63%) compared to the other treatments, with 29% for treatment T1, 7% for T2, and 1% for T3, implying a strong action capability of this insecticide against pests of Abelmoschus esculentus. Therefore, it can be concluded that for a normal growing season of Abelmoschus esculentus, this biological insecticide should be sprayed 12 times. Furthermore, this biological insecticide is unique in that it does not inflict any gastric toxicity on the pests, which gives it the characteristic of being a repellent. It is a biological insecticide whose efficacy period has been tested, with a minimum duration of 21 days. In conclusion, this formulated bioinsecticide based on Aloe barbadensis demonstrates significant efficacy against pests of Abelmoschus esculentus. In the future, we will consider experimenting with its effectiveness against pests of other plants.

The biological functions and metabolic pathways of valine in swine

Valine is an essential amino acid and a type of branched-chain amino acid. Due to the involvement of branchedchain amino acids in various metabolic pathways, there has been a surge of interests in valine nutrition and its role in animal physiology. In pigs, the interactions between valine and other branched-chain amino acids or aromatic amino acids are complex. In this review, we delve into the interaction mechanism, metabolic pathways, and biological functions of valine. Appropriate valine supplementation not only enhances growth and reproductive performances, but also modulates gut microbiota and immune functions. Based on past observations and interpretations, we provide recommended feed levels of valine for weaned piglets, growing pigs, gilts, lactating sows, barrows and entire males. The summarized valine nutrient requirements for pigs at different stages offer valuable insights for future research and practical applications in animal husbandry.

Comparative proteomics reveals the response and adaptation mechanisms of white Hypsizygus marmoreus against the biological stress caused by Penicillium

White Hypsizygus marmoreus is a popular edible mushroom.Its mycelium is easy to be contaminated by Penicillium,which leads to a decrease in its quality and yield.Penicillium could compete for limited space and nutrients through rapid growth and produce a variety of harmful gases,such as benzene,aldehydes,phenols,etc.,to inhibit the growth of H.marmoreus mycelium.A series of changes occurred in H.marmoreus proteome after contamination when detected by the label-free tandem mass spectrometry(MS/MS)technique.Some proteins with up-regulated expression worked together to participate in some processes,such as the non-toxic transformation of harmful gases,glutathione metabolism,histone modification,nucleotide excision repair,clearing misfolded proteins,and synthesizing glutamine,which were mainly used in response to biological stress.The proteins with down-regulated expression are mainly related to the processes of ribosome function,protein processing,spliceosome,carbon metabolism,glycolysis,and gluconeogenesis.The reduction in the function of these proteins affected the production of the cell components,which might be an adjustment to adapt to growth retardation.This study further enhanced the understanding of the biological stress response and the growth restriction adaptation mechanisms in edible fungi.It also provided a theoretical basis for protein function exploration and edible mushroom food safety research.