Viruses and autism: A Bi-mutual cause and effect

Autism spectrum disorder(ASD)is a group of heterogeneous,multi-factorial,neurodevelopmental disorders resulting from genetic and environmental factors interplay.Infection is a significant trigger of autism,especially during the critical developmental period.There is a strong interplay between the viral infection as a trigger and a result of ASD.We aim to highlight the mutual relationship between autism and viruses.We performed a thorough literature review and included 158 research in this review.Most of the literature agreed on the possible effects of the viral infection during the critical period of development on the risk of developing autism,especially for specific viral infections such as Rubella,Cytomegalovirus,Herpes Simplex virus,Varicella Zoster Virus,Influenza virus,Zika virus,and severe acute respiratory syndrome coronavirus 2.Viral infection directly infects the brain,triggers immune activation,induces epigenetic changes,and raises the risks of having a child with autism.At the same time,there is some evidence of increased risk of infection,including viral infections in children with autism,due to lots of factors.There is an increased risk of developing autism with a specific viral infection during the early developmental period and an increased risk of viral infections in children with autism.In addition,children with autism are at increased risk of infection,including viruses.Every effort should be made to prevent maternal and early-life infections and reduce the risk of autism.Immune modulation of children with autism should be considered to reduce the risk of infection.

Effect of Astragalus polysaccharides on Erythrocyte Immune Adherence of Chickens Inoculated with Infectious Bursal Disease Virus

Two hundred and forty specific pathogen free leghorn chickens were randomly divided into four groups and reared in isolated pens. The tested chickens were negative to infectious bursal disease virus （IBDV） at 25 d old. Group 1 was treated with saline, whereas Groups 2, 3, and 4 were inoculated with 0.3 mL IBDV suspension intranasally the next day. Groups 3 and 4 were also administered with Astragalus polysaccharides （APS） intramuscularly twice daily at 5 or 10 mg kg-1 BW, respectively, until 31 d old. The erythrocyte-C3b receptor rosette rate （E-C3bRR） and the erythrocyte-C3b immune complex rosette rate （E-ICRR） were measured at 25, 29, 32, 35, and 38 d old. The results showed that IBDV significantly reduced E-C3bRR and E-ICRR when compared with the control group （P 〈 0.05）, while simultaneous administration of APS with 1BDV maintained E-C3bRR at similar levels to the control group （P 〉 0.05） and increased E-ICRR when compared with the control group and the group non-treated with APS （P 〈 0.05）. APS treatment reduced the morbidity and mortality of chickens inoculated with IBDV （P 〈 0.05）. The results suggest that APS may enhance the immune adherence of chickens erythrocytes by affecting the activity and/or the number of complement receptors on the erythrocyte membrane. These findings can be beneficial in providing an understanding of the basic mechanisms required for the rational application of APS in modern medicine.

Role of inflammasome regulation on immune modulators

Inflammatory responses are essential in eliminating harmful substrates from damaged tissue and inducing recovery.Several cytokines participate in and facilitate this response. Certain cytokines such as interleukin(IL)-1β and IL-18 are initially produced in precursor form in response to toll-like receptor(TLR) ligands and undergo maturation by inflammasomes, which are cytosolic multi-protein complexes containing nucleotide-binding oligomerization domain(NOD)-containing protein 2-like receptors(NLRs). Immune modulators targeting inflammasomes have been investigated to control inflammatory diseases such as metabolic syndrome. However, most immune modulators possessing anti-inflammasome properties attenuate production of other cytokines, which are essential for host defense. In this review, we analyzed the effect of anti-inflammasome agents on the production of cytokines which are not regulated by inflammasome and involving in initial immune responses. As a result, the infiammasome inhibitors are put into three categories: non-effector, stimulator, or inhibitor of cytokine production. Even the stimulator of cytokine production ameliorated symptoms resulting from inflammasome activation in mouse models. Thus, we suggest ideal immune modulators targeting inflammasomes in order to enhance cytokine production while inhibiting cytokine maturation.

Antifatigue,Antioxidant and Immunoregulatory Effects of Peptides Hydrolyzed from Manchurian Walnut(Juglans mandshurica Maxim.) on Mice

The Manchurian walnut(Juglans mandshurica Maxim.) is rich in proteins, whereas this resource has not been used efficiently. The antifatigue, antioxidative and immunoregulatory effects of Manchurian walnut hydrolysate peptides(MWHPs)were evaluated in this study. MWHPs with a degree of hydrolysis of 32.23% were ultrafiltered and divided into three fractions,namely, high(> 10 k Da), medium(3–10 kDa), and low molecular weight(< 3 kDa), and then fed to mice continuously at doses of 200, 400 or 800 mg/(kg·d). The antifatigue, antioxidative, and immunoregulatory effects of the peptides were tested on the second and fourth weeks of MWHP administration. Results showed that low-molecular-weight MWHPs exerted significant antifatigue(prolonging swimming time, elevating liver glycogen contents, and reducing lactic acid contents), antioxidative(enhancing superoxide dismutase(SOD), GSH-Px, and catalase(CAT) activities and reducing malondialdehyde(MDA) content), and immunoregulatory(raising the immune-organ index and promoting T-lymphocyte proliferation and s Ig A secretion in the intestinal tract) effects. This research indicates that MWHPs have potential applications in health care and may be developed as a base for new functional foods.

Radiotherapy as an immune checkpoint blockade combination strategy for hepatocellular carcinoma

In the immune oncology era,the clinical efficacy of immune checkpoint inhibitors(ICIs)against most solid cancers is well known.In hepatocellular carcinoma,the recent success of combination therapy with targeting agents has accelerated the search for novel combination strategies.Radiotherapy(RT),an attractive modality,can be combined with ICIs,which act as strong modulators of the tumor immune microenvironment.Herein,we discuss immune modulation caused by radiation and the current trials of RT-ICI combination treatment as well as future perspectives.

Role of β-microseminoprotein from prostate cancer initiationto recurrence: A mini-review

Medline/Pubmed articles relevant to this topic were considered using the search terms ?-microseminoprotein, MSMB, prostate secretory protein of 94 amino acids and PSP94. Full articles were retrieved when the abstract was considered relevant. In addition, other data related to this topic including our own are discussed. Summary of fi ndings-?-microseminoprotein(MSMB) is increasingly being considered as a marker for prostatecancer, as reduced levels have been associated with the disease. Here we review various aspects of this protein including its biological and physiological variants, binding proteins and immune modulation; its importance as a marker for biochemical recurrence of prostate cancer; prostate cancer related splice variants and its therapeutic utility. Two of the most important properties of MSMB are related to anticancer functions and immune modulation. Predominant expression of two(short and full-length) splice variants of MSMB has been observed from normal prostate and several other tissues. In benign prostate hyperplasia the short isoform is dominant, constituting 98% of this isoform, whereas in prostate cancer 96% constitute the fulllength isoform. The MSMB promoter single nucleotide polymorphism rs10993994 with the C allele functions as an activated cyclic adenosine monophosphate response element binding protein binding site. This C variant of rs10993994 could be responsible for the production of splice variants under variable conditions. MSMB has binding motifs to a few known proteins including immunoglobulin G and several Cysteine-rich secretory proteins family proteins. MSMB bound to these proteins is considered as immune modulating. Use of MSMB as a urinary marker for detecting aggressive prostate cancers that could resist radiation and surgical treatments, seems possible, but needs further investigation. The ratio of MSMB splice variants could also be a possible approach in understanding prostate cancers, with higher ratios indicating severe disease.

STUDY ON THE MECHANISM OF ESCAPING IMMUNE SURVEILLANCE IN HUMAN GLIOMAS

Objective: To study mechanisms by which human gliomas may escape immune surveillance Methods: The effect of supernatant (SN) obtained from cultured media of malignant glioma cell lines on the proliferation of phytohemagglutinin p stimulated peripheral blood lymphocytes (PBLs) from healthy subjects and patients with gliomas was examined by MTT assay The immunosuppressive factor which might be existed in the SN was identified by neutralization method with specific antibodies and Northern blot hybridization of glioma cells In addition, the cellular immunity of patients with gliomas and relevant hormone and catecholamine were determined Results: It was found that the malignant glioma cells could release an immunosuppressive factor in an autocrine fashion which was further identified as the transforming growth factor β 2 (TGF β 2) It was also demonstrated that the plasma levels of norepinephrine in glioma patients were significantly reduced and correlated well with the suppression of the patients' own cellular immunity Conclusions: Two distinct mechanisms by which human gliomas may evade immune surveillance: 1 The secretion of an immunosuppressive factor which was identified as TGF β 2; 2 The dysfunction of Neuro Immune modulation in the presence of cerebral gliomas

Tweaking the immune system as an adjuvant for the treatment of retinal degenerations

Blinding diseases such as photoreceptor degenerations are debilitating conditions that severely impair daily lives of affected patients.This group of diseases are amenable to photoreceptor replacement therapies and recent transplantation studies provided proof-of-principle for functional recovery at the retinal and behavioral level,though the actual mechanism of repair still needs further investigations.The immune system responds in several ways upon photoreceptor engraftment,resulting in T-cell and macrophage infiltrations and,consequently,decrease in graft survival.Most studies on the role of the immune system suggest a detrimental effect in a therapeutic setting.Conversely,the opposite idea wherein the immune system can be activated towards a protective state was also explored in other experimental paradigms.Here,Neves and colleagues explored the potential of cross-species studies and,to a certain extent,the concept of a protective immune system in retinal degeneration and therapy.Mesencephalic astrocyte-derived neurotrophic factor(MANF)was identified in this study as a novel factor that,by modulating the immune system,can slow down photoreceptor degeneration and improve transplantation outcome.

Historical evolution,overview,and therapeutic manipulation of costimulatory molecules

Co-stimulatory molecules are key mediators in the regulation of immune responses and knowledge of its different families,structure,and functions has improved in recent decades.Understanding the role of co-stimulatory molecules in pathological processes has allowed the development of strategies to modulate cellular functions.Currently,modulation of co-stimulatory and co-inhibitory molecules has been applied in clinical applications as therapeutic targets in diseases and promising results have been achieved.

Treatment of Multiple Sclerosis

Background: A new method of immune-based therapies has been made and applied on multiple sclerosis patients in last decades. Some of these treatments have a high efficacy and reasonable side effects. In slowing disease progression, present treatments have significant limitations, but often associated with significant adverse effects of immunosuppression, with having a bit low capability to counter the disability. Methods: This is a review meta-analysis of treatment of multiple sclerosis. Results: Thus a valuable aim for multiple sclerosis clinical research is to introduce more effective therapies. Conclusion: It is absolutely necessary to increase the individualized therapy planes development in respect to make better planes to disease-modifying treatments.

Probiotics intervention in colorectal cancer:From traditional approaches to novel strategies

The intestine harbors a large population of microorganisms that interact with epithelial cells to maintain host healthy physiological status.These intestinal microbiota engage in the fermentation of non-digestible nutrients and produce beneficial metabolites to regulate host homeostasis,metabolism,and immune response.The disruption of microbiota,known as dysbiosis,has been implicated in many intestinal diseases,including colorectal cancer(CRC).As the third most common cancer and the second leading cause of cancer-related death worldwide,CRC poses a significant health burden.There is an urgent need for novel interventions to reduce CRC incidence and improve clinical outcomes.Modulating the intestinal microbiota has emerged as a promising approach for CRC prevention and treatment.Current research efforts in CRC probiotics primarily focus on reducing the incidence of CRC,alleviating treatment-related side effects,and potentiating the efficacy of anticancer therapy,which is the key to successful translation to clinical practice.This paper aims to review the traditional probiotics and new interventions,such as next-generation probiotics and postbiotics,in the context of CRC.The underlying mechanisms of probiotic anti-cancer effects are also discussed,including the restoration of microbial composition,reinforcement of gut barrier integrity,induction of cancer cell apoptosis,inactivation of carcinogens,and modulation of host immune response.This paper further evaluates the novel strategy of probiotics as an adjuvant therapy in boosting the efficacy of chemotherapy and immunotherapy.Despite all the promising findings presented in studies,the evaluation of potential risks,optimization of delivery methods,and consideration of intra-patient variability of gut microbial baseline must be thoroughly interpreted before bench-to-bedside translation.

Meningeal lymphatic vasculature,a general target for glioblastoma therapy?

Glioblastoma(GBM)causes nearly universal mortality as a result of the failure of conventional therapies including surgical resection,targeted radiation therapy,and chemotherapy.An increasingly important treatment option is combining immunotherapy with other therapies in both preclinical and clinical studies.The central nervous system(CNS)has been historically considered an immune privileged area,but increasing evidence,including the recent rediscovery of meningeal lymphatic vessels(MLVs),has overturned this notion.MLVs are populated by multiple immune cells and connect the CNS to the periphery by draining cerebrospinal fluid with soluble CNS antigens and immune cells into cervical lymph nodes.In the past few years,more and more studies have indicated that MLVs are involved in the regulation of inflammation and the immune response in the pathogenesis of various CNS diseases including GBM.Here,we explore the critical interlinkages between MLVs and GBM therapies including chemotherapy,radiotherapy and immunotherapy,and propose the meningeal lymphatic vasculature as a general target for GBM therapy.

Exploring the modulatory role of bovine lactoferrin on the microbiome and the immune response in healthy and Shiga toxin‑producing E.coli challenged weaned piglets

Background Post-weaned piglets suffer from F18+Escherichia coli(E.coli)infections resulting in post-weaning diar-rhoea or oedema disease.Frequently used management strategies,including colistin and zinc oxide,have contrib-uted to the emergence and spread of antimicrobial resistance.Novel antimicrobials capable of directly interacting with pathogens and modulating the host immune responses are being investigated.Lactoferrin has shown promising results against porcine enterotoxigenic E.coli strains,both in vitro and in vivo.Results We investigated the influence of bovine lactoferrin(bLF)on the microbiome of healthy and infected weaned piglets.Additionally,we assessed whether bLF influenced the immune responses upon Shiga toxin-producing E.coli(STEC)infection.Therefore,2 in vivo trials were conducted:a microbiome trial and a challenge infection trial,using an F18+STEC strain.BLF did not affect theα-andβ-diversity.However,bLF groups showed a higher relative abundance(RA)for the Actinobacteria phylum and the Bifidobacterium genus in the ileal mucosa.When analysing the immune response upon infection,the STEC group exhibited a significant increase in F18-specific IgG serum levels,whereas this response was absent in the bLF group.Conclusion Taken together,the oral administration of bLF did not have a notable impact on theα-andβ-diversity of the gut microbiome in weaned piglets.Nevertheless,it did increase the RA of the Actinobacteria phylum and Bifi-dobacterium genus,which have previously been shown to play an important role in maintaining gut homeostasis.Furthermore,bLF administration during STEC infection resulted in the absence of F18-specific serum IgG responses.

Lobe-specific modulation of B16MET melanoma lung metastases by nephrilin peptide

Aim:Nephrilin peptide modulates systemic immune responses to trauma in contexts characterized by simultaneous inflammation and immunosuppression.This study explores the possibility that nephrilin peptide may modulate lung metastasis,which also occurs in an environment of concurrent inflammation and immunosuppression.Methods:B16MET melanoma cells were injected via the tail vein of mice and the development of lung metastases was recorded in animals treated with nephrilin peptide or vehicle by subcutaneous bolus injection daily for three weeks.In a separate experiment,nephrilin was administered by subcutaneous bolus injection for seven days to study the biodistribution of peptide and possible changes to plasma cytokine levels.Results:Nephrilin significantly suppressed B16MET lung metastases.Suppression was more effective in deep lobes with the poorest access to circulation:accessory>inferior>middle>superior.In a separate biodistribution study in mice,nephrilin showed similar biodistribution levels in kidney,liver,brain,and left lung,but significantly higher accumulation in the lobes of the right lung in a gradient that matched its effectiveness in suppressing metastases(accessory>inferior>middle).The latter environments were also characterized by significantly higher local concentrations of succinate,a proxy for lower levels of oxygenation.Conclusion:Nephrilin accumulates preferentially in the deep lobes of the right lung in mice and inhibits B16MET right lung metastases in a lobe-specific manner.

Engineering white blood cell membrane-camouflaged nanocarriers for inflammation-related therapeutics

White blood cells(WBCs)play essential roles against inflammatory disorders,bacterial infections,and cancers.Inspired by nature,WBC membrane-camouflaged nanocarriers(WBC-NCs)have been developed to mimic the“dynamic”functions of WBCs,such as transendothelial migration,adhesion to injured blood vessels,etc,which make them promising for diverse medical applications.WBC-NCs inherit the cell membrane antigens of WBCs,while still exhibiting the robust inflammation-related therapeutic potential of synthetic nanocarriers with excellent(bio)physicochemical performance.This review summarizes the proposed concept of cell membrane engineering,which utilizes physical engineering,chemical modification,and biological functionalization technologies to endow the natural cell membrane with abundant functionalities.In addition,it highlights the recent progress and applications of WBC-NCs for inflammation targeting,biological neutralization,and immune modulation.Finally,the challenges and opportunities in realizing the full potential of WBC-NCs for the manipulation of inflammation-related therapeutics are discussed.

Immune modulatory function of abundant immune-related microRNAs in microvesicles from bovine colostrum

Colostrum provides essential nutrients and immunologically active factors that are beneficial to newborns.Our previous work demonstrated that milk contains large amounts of miRNA that is largely stored in milk-derived microvesicles(MVs).In the present study,we found that the MVs from colostrum contain signifi cantly higher levels of several immune-related miRNAs.We hypothesized that the colostrum MVs may transfer the immune-related miR-NAs into cells,which contribute to its immune modulatory feature.We isolated colostrum MVs by ultracentrifugation and demonstrated several immune modulation features associated with miRNAs.We also provide evidence that the physical structure of milk-derived MVs is essential for transfer miRNAs and following immune modulation effect.Moreover,we found that colostrum powder-derived MVs also contains higher levels of immune-related miRNAs that display similar immune modulation effects.Taken together,these results show that MV-containing immunerelated miRNAs may be a novel mechanism by which co-lostrum modulates body immune response.

A double-blind,randomized,placebo-and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis

Background:Benvitimod cream,a novel synthetic small molecule,was effective in treating mild-to-moderate plaque psoriasis.We conducted a phase III clinical trial to assess the efficacy and safety of benvitimod cream in patients with mild-to-moderate plaque psoriasis.Methods:We randomly assigned 686 patients(2:1:1)to receive 1%benvitimod cream,0.005%calcipotriol ointment or placebo twice a day for 12 weeks.The primary efficacy end points were the percentage of patients with a 75%or greater reduction from baseline in the psoriasis area and severity index(PASI 75)score and with a score of 0 or 1 in static physician’s global assessment(sPGA)at week 12.Results:The results showed that 50.4%of patients in the benvitimod group achieved PASI 75,which was significantly higher than that in the calcipotriol(38.5%,P<0.05)and placebo(13.9%,P<0.05)groups.The proportion of patients achieving an sPGA score 0 or 1 was 66.3%in the benvitimod group and 63.9%in the calcipotriol group,which were both significantly higher than that in the placebo group(34%,P<0.05).In the long-term follow-up study,50.8%of patients experienced recurrence.After retreatment with 1%benvitimod,73.3%of patients achieved an sPGA score of 0 or 1 again at week 52.Adverse events included application site irritation,follicular papules,and contact dermatitis.No systemic adverse reactions were reported.Conclusion:During this 12-week study,benvitimod cream was demonstrated with high effectiveness and safety in patients with mild-to-moderate plaque psoriasis.

Effects of Sodium Copper Chlorophyllin on Mesenchymal Stem Cell Function in Aplastic Anemia Mice

Objective： To investigate the effects of sodium copper chlorophyllin （SCC） on the proliferation, differentiation and immunomodulatory function of mesenchymal stem cells （MSCs） from mice with aplastic anemia. Methods： A mouse model of aplastic anemia was established by exposure of BALB/c mice to sublethal doses of 5.0 Gy Co60 γ radiation, followed by transplantation of 2 × 108 lymph node cells from DBA/2 donor mice within 4 h after radiation. Aplastic anemic BALB/c mice were randomly divided into six groups： the treated groups, which received 25, 50, or 100 mg/kg/day SCC, respectively; a positive control group treated with cyclosporine A （CsA）; and an untreated model control group （model group）; while, the non-irradiated mice as the normal control group. SCC or CsA were administered by gastrogavage for 20 days, starting on day 4 after irradiation. Peripheral blood cells were counted and colony-forming fibroblasts （CFU-F） in the bone marrow were assayed. The ability of MSCs to form calcium nodes after culture in osteoinductive medium was also observed. The immunosuppressive effect of MSCs on T lymphocytes was analyzed by enzyme-linked immunosorbent assay and flow cytometry, to evaluate the efficacy of SCC in mice with aplastic anemia. Results： Peripheral blood white cell and platelet counts were increased by medium and high SCC doses, compared with the untreated control. CFU-Fs were also increased compared with the untreated control, and the numbers of calcium nodes in MSCs in osteoinductive medium were elevated in response to SCC treatment. The percentage of Forkhead box protein 3 （FOXP3^＋） T cells was increased in T celI-MSC cocultures, and the cytokine transforming growth factor 131 was up-regulated in SCC-treated groups. Conclusion： The results of this study suggest that SCC not only promotes the proliferation and differentiation of MSCs, but also improves their immunoregulatory capacity in mice with apiastic anemia.

Mechanism of traditional Chinese medicine in the treatment of allergic rhinitis

Objective To review the major progress in mechanism of traditional Chinese medicine （TCM） in the treatment of allergic rhinitis （AR）. Methods Contents about the treatment mechanism of TCM in the therapy of AR in this article were obtained from 22 original articles and reviews published in Chinese- and English-language journals. All of the references were searched by use of Pubmed （1997-2012）. Results AR is one of the most common and most serious public health problems in children and young people. Many AR patients were worried about the possible adverse effects of synthetic drugs they were taking. Thus, they seek complementary and alternative therapy, such as TCM. TCM emphasized on the importance of holistic convalescence, not just the disease itself. The favorable safety profile of TCM makes well-acceptance by the general population. In the recent decade, more and more studies of TCM for AR are developed. These studies indicated that the treatment of allergic disorders with TCM therapy including herbal medicines and acupuncture are of safety and efficacy. The mechanism of TCM in the treatment of AR has been discussed. It has been reported that a number of the herbs in the Chinese herbal formulae used in the treatment possess anti-allergic, anti-inflammatory or immune modulation activity. Such function include the inhibition of the release or the activity of mast cell mediators （such as histamine）, inhibition the induction of inflammation reaction by chemical agents, and down regulation of serum （immunoglobulin E） IgE levels or the activity of lymphocyte and/or macrophage. Conclusions TCM are frequently used concurrently to improve the clinical efficacy. This review is focuses on the description of the actions mechanism of Chinese medicine＇s approach relevant to the treatment of AR.

Effective intrahepatic CD8＋ T-cell immune responses are induced by low but not high numbers of antigen-expressing hepatocytes

Liver infections with hepatotropic viruses, such as hepatitis B virus and hepatitis C virus are accompanied by viral persistence and immune failure. CD8＋ T cells are crucial mediators of the intrahepatic antiviral immune response. Chronic infections of the liver and other organs correlate with T-cell exhaustion. It was previously suggested that high antigen load could result in T-cell exhaustion. We aimed at elucidating the impact of different intrahepatic antigen loads on the quality of CD8＋ T-cell-mediated immunity by employing an infection-free transgenic mouse model expressing ovalbumin （Ova） as the target antigen. Adoptive transfer of OT-I cells induced a transient intrahepatic immune response toward both high and low Ova levels. However, antigen clearance was achieved only in mice expressing low antigen levels. In contrast, T cells exposed to high antigen levels underwent exhaustion and became depleted, causing antigen persistence. Moreover, when functional T cells were exposed to high intrahepatic antigen levels, a complete transition toward exhaustion was observed. Thus, this study shows that the antigen expression level in the liver correlates inversely with T-cell immunity in vivo and governs the efficiency of immune responses upon antigen presentation.