Potent Protection Research Articles

Marginal diversity analysis of conservation of Chinese domestic duck breeds

The present study aimed to systematically evaluate the genetic diversity of Chinese domestic duck breeds and ensure the most effective allocation and usage of conservation funds. We first performed an analysis of DNA genetic distance in 21 duck breeds by measuring short tandem repeats. Then, we calculated the extinction probability, contribution rate, and marginal diversity for each breed. The results showed that the extinction rate of the Zhongshan duck, Guangxi duck, and Ji’an duck were the highest at 0.67, 0.59, and 0.59, respectively, and that of the Linwu duck, Jinding duck, and Gaoyou duck were the lowest at 0.15, 0.18, and 0.19, respectively. The current diversity of populations was 7.72 and the expected diversity in five hundred years is 5.14 ± 1.15. The marginal diversity of the Chinese Muscovy duck was the largest (−2.20), accounting for 42.61% of the expected diversity, followed by the Guangxi duck (−0.49, 9.44%), whereas the Jinding duck was the smallest (−0.12; 2.32%). The protection potency of the Chinese Muscovy duck was the largest (0.61), followed by Guangxi duck (0.29), whereas the Jinding duck was the smallest (0.02). This study provides a reference for determining the conservation priority of Chinese domestic duck breeds or genetic resources.

N-Benzyl-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) with Hybrid Structure as a Candidate for a Broad-Spectrum Antiepileptic Drug

In our recent studies, we identified compound N-benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide (AS-1) as a broad-spectrum hybrid anticonvulsant which showed potent protection across the most important animal acute seizure models such as the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (s.c. PTZ) test, and the 6-Hz (32 mA) test in mice. Therefore, AS-1 may be recognized as a candidate for new anticonvulsant effective in different types of human epilepsy with a favorable safety margin profile determined in the rotarod test in mice. In the aim of further pharmacological evaluation of AS-1, in the current study, we examined its activity in the 6-Hz (44 mA) test, which is known as the model of drug-resistant epilepsy. Furthermore, we determined also the antiseizure activity in the kindling model of epilepsy induced by repeated injection of pentylenetetrazole (PTZ) in mice. As a result, AS-1 revealed relatively potent protection in the 6-Hz (44 mA) test, as well as delayed the progression of kindling induced by repeated injection of PTZ in mice at doses of 15 mg/kg, 30 mg/kg, and 60 mg/kg. Importantly, the isobolographic analysis showed that a combination of AS-1 and valproic acid (VPA) at the fixed ratio of 1:1 displayed a supra-additive (synergistic) interaction against PTZ-induced seizures in mice. Thus, AS-1 may be potentially used in an add-on therapy with VPA. Moreover, incubation of zebrafish larvae with AS-1 substantially decreased the number, cumulative but not the mean duration of epileptiform-like events in electroencephalographic assay. Finally, the in vitro ADME-Tox studies revealed that AS-1 is characterized by a very good permeability in the parallel artificial membrane permeability assay test, excellent metabolic stability on human liver microsomes (HLMs), no significant influence on CYP3A4/CYP2D6 activity, and moderate inhibition of CYP2C9 in a concentration of 10 μM, as well as no hepatotoxic properties in HepG2 cells (concentration of 10 μM).

Comparison of adjuvants to optimize influenza neutralizing antibody responses

Seasonal influenza vaccines represent a positive intervention to limit the spread of the virus and protect public health. Yet continual influenza evolution and its ability to evade immunity pose a constant threat. For these reasons, vaccines with improved potency and breadth of protection remain an important need. We previously developed a next-generation influenza vaccine that displays the trimeric influenza hemagglutinin (HA) on a ferritin nanoparticle (NP) to optimize its presentation. Similar to other vaccines, HA-nanoparticle vaccine efficacy is increased by the inclusion of adjuvants during immunization. To identify the optimal adjuvants to enhance influenza immunity, we systematically analyzed TLR agonists for their ability to elicit immune responses. HA-NPs were compatible with nearly all adjuvants tested, including TLR2, TLR4, TLR7/8, and TLR9 agonists, squalene oil-in-water mixtures, and STING agonists. In addition, we chemically conjugated TLR7/8 and TLR9 ligands directly to the HA-ferritin nanoparticle. These TLR agonist-conjugated nanoparticles induced stronger antibody responses than nanoparticles alone, which allowed the use of a 5000-fold-lower dose of adjuvant than traditional admixtures. One candidate, the oil-in-water adjuvant AF03, was also tested in non-human primates and showed strong induction of neutralizing responses against both matched and heterologous H1N1 viruses. These data suggest that AF03, along with certain TLR agonists, enhance strong neutralizing antibody responses following influenza vaccination and may improve the breadth, potency, and ultimately vaccine protection in humans.

Antiaging activity, molecular docking, and prediction of percutaneous absorption parameters of quinoline–hydrazone hybrids

The application of antiaging agents can contribute to the prevention and control of skin photoaging. In the current research, nine quinoline–hydrazone hybrids were synthesized to obtain biologically active compounds as possible antiaging agents. The compounds were tested through a comprehensive in vitro evaluation of antielastase, anticollagenase, and antihyaluronidase activities along with the determination of their potential to quench reactive oxygen species (ROS) by the ORAC method. The selected hybrids were subsequently tested on human dermal fibroblasts (HDF) to reveal possible UVB photoprotective activity. The most potent antiaging protection of all the prepared compounds was shown by the trihydroxylated quinoline–hydrazones 5 and 9, which showed the best collagenase inhibition (IC50 = 39.4 and 45.6 µM, respectively). Compound 5 also showed activity against elastase and hyaluronidase (IC50 = 164.2 and 318.8 µM, respectively). The molecular docking results suggest that the difference of inhibition between 5 and 9 is principally attributed to the hydrogen bonds interactions in the residues His218 and His228, and Zn atom in collagenase, Val216 in elastase and Tyr75 in hyaluronidase. In addition, compounds 5 and 9 were able to significantly protect human skin cells from UVB radiation in vitro. These compounds significantly decreased UVB-induced MMP-1 and ROS production and inhibited the suppression of type I procollagen synthesis in cultured HDF. The in silico dermatopharmacokinetic parameters showed promising results. Therefore, our study presented promising results for antiaging drug discovery, focusing on quinoline–hydrazone hybrids as dual inhibitors of skin aging-related enzymes, antioxidants, and inhibitors of the biological effects of UVB irradiation.

Pre-clinical study of protective potency of candidate recombinant live pertussis vaccine for intranasal administration

The aim of present research is studying of protective potency of candidate recombinant live pertussis vaccine (RLPV) for intranasal administration.Materials and methods. Two methods of protective potency assessment, based on mice survival estimating, were used: after intracerebral administration of B.pertussis 18323 bacteria and after intranasal administration of virulent Bordetella spp. bacteria (B.pertussis, B.parapertussis and B.bronchiseptica) to immunized mice.Results. An ingenious method of pertussis vaccine protective potency assessment due to mucosal immunity is suggested. Protective potency of constructed RLPV estimated in two tests of intracerebral and intranasal administration was higher than market image drug of DTP vaccine. RLPV provided protection from infection in mice after administration of both wild type and recombinant Bordetella spp. bacteria.Conclusion. Examined recombinant live pertussis vaccine (RLPV) for intranasal administration has significant protective potential and could be recommended for using in clinical trials.

Development and evaluation of candidate subunit vaccine and novel antitoxin against botulinum neurotoxin serotype E

ABSTRACTBotulinum neurotoxins (BoNTs) are among the most toxic proteins. Vaccination is an effective strategy to prevent botulism. To generate a vaccine suitable for human use, a recombinant non-His-tagged isoform of the Hc domain of botulinum neurotoxin serotype E (rEHc) was expressed in Escherichia coli and purified by sequential chromatography. The immunogenicity of rEHc was evaluated in mice and dose- and time-dependent immune responses were observed in both antibody titers and protective potency. Then, the pilot-scale expression and purification of rEHc were performed, and its immunological activity was characterized. Our results showed rEHc has good immunogenicity and can elicit strong protective potency against botulinum neurotoxin serotype E (BoNT/E) in mice, indicating that rEHc is an effective botulism vaccine candidate. Further, we developed a novel antitoxin against BoNT/E by purifying F(abʹ)2 from pepsin-digested serum IgG of rEHc-inoculated horses. The protective effect of the F(abʹ)2 antitoxin was determined in vitro and in vivo. The results showed that our F(abʹ)2 antitoxin can prevent botulism in BoNT/E-challenged mice and effectively alleviate the progression of paralysis caused by BoNT/E to achieve therapeutic effects. Therefore, our results provide valuable experimental data for the production of a novel antitoxin, which is a promising candidate for the treatment of BoNT/E-induced botulism.

Evaluating the protective potency of Acacia hydaspica R. Parker on histological and biochemical changes induced by Cisplatin in the cardiac tissue of rats

BackgroundIncrease oxidative trauma is the main cause behind Cisplatin (CP) induced cardiotoxicity which restricts its clinical application as anti-neoplastic prescription. Acacia hydaspica is a natural shrub with diverse bioactivities. Acacia hydaspica ethyl acetate extract (AHE) ameliorated drug-induced cardiotoxicity in animals with anti-oxidative mechanisms. Current study aimed to evaluate the protective potential of A. hydaspica against cisplatin-induced myocardial injury.MethodsRats were indiscriminately distributed into six groups (n = 6). Group 1: control; Groups 2: Injected with CP (7.5 mg/kg bw, i.p, single dose) on day 16; Group 3: Treated for 21 days with AHE (400 mg/kg b.w, oral); Group 4: Received CP injection on day 16 and treated with AHE for 5 days post injection; Group 5: Received AHE (400 mg/kg b.w/day, p.o.) for 21 days and CP (7.5 mg/kg b.w., i.p.) on day 16; Group 6: Treated with silymarin (100 mg/kg b.w., p.o.) after 1 day interval for 21 days and CP injection (7.5 mg/kg b.w., i.p.) on day 16. On 22nd day, the animals were sacrificed and their heart tissues were removed. Cisplatin induced cardiac toxicity and the influence of AHE were evaluated by examination of serum cardiac function markers, cardiac tissue antioxidant enzymes, oxidative stress markers and histology.ResultsCP inoculation considerably altered cardiac function biomarkers in serum and diminished the antioxidant enzymes levels, while increased oxidative stress biomarkers in cardiac tissues AHE treatment attenuated CP-induced deteriorations in creatine kinase (CK), Creatine kinase isoenzymes MB (CK-MB), cardiac Troponin I (cTNI) and lactate dehydrogenase (LDH) levels and ameliorated cardiac oxidative stress markers as evidenced by decreasing lipid peroxidation, H2O2 and NO content along with augmentation in phase I and phase II antioxidant enzymes. Additionally, CP inoculation also induced morphological alterations which were ameliorated by AHE. In pretreatment group more significant protection was observed compared to post-treatment group indicating preventive potential of AHE. The protective potency of AHE was comparable to silymarin.ConclusionResults demonstrate that AHE attenuated CP induce cardiotoxicity. The polyphenolic metabolites and antioxidant properties of AHE might be responsible for its protective influence.

Syngeneic B16-F1 cells are more efficient than allogeneic Cloudman cells as antigen source in DC-based vaccination in the B16-F1 murine melanoma model

A major obstacle to obtaining relevant results in cancer vaccination has been the lack of identification of immunogenic antigens. Dendritic cell (DC)-based cancer vaccines used preventively may afford protection against tumor inoculation, but the effect of antigen choice on anti-tumor protection is not clear. When using irradiated syngeneic tumor cells to load DCs, tumor self-antigens are provided, including tumor-associated antigens (TAAs) and neoantigens generated by tumor mutations. On the other hand, allogeneic tumor cells could only supply shared TAAs. To assess the advantages of each source in protective vaccination, we analyzed in C57BL/6 mice the effect of loading DCs with irradiated syngeneic B16-F1 or allogeneic Cloudman melanoma cells; both cell lines were characterized by whole exome sequencing and RNAseq. Tumor cell components from the two irradiated cell lines were efficiently internalized by DCs, and transported to MHC-class II positive tubulovesicular compartments (MIICs). DCs loaded with allogeneic irradiated Cloudman cells (DC-ApoNecALLO) induced a partially effective anti-melanoma protection, although Cloudman and B16-F1 cells share the expression of melanocyte differentiation antigens (MDAs), cancer-testis antigens (CTAs) and other TAAs. DCs loaded with syngeneic B16-F1 cells (DC-ApoNecSYN) established a more potent and long-lasting protection and induced a humoral anti-B16F1 response, thus suggesting that neoepitopes are needed for inducing long-lasting protection.

Design and evaluation of a multi-epitope assembly peptide vaccine against Acinetobacter baumannii infection in mice.

To design a multi-epitope assembly peptide (MEP) of Acinetobacter baumannii and evaluate its immunogenicity and protective immunity in Balb/c mice. The T- and B-cell epitopes of outer membrane proteins FilF and NucAb from A. baumannii were predicted and identified by using bioinformatics software and immunological tests. Peptides with predicted high adhesin probability from A. baumannii Ata protein was used as the backbone, two B-cell epitopes and one CD4+ T-cell epitope from FilF were linked to the N-terminal of the backbone, and two B-cell epitopes and one CD4+ T-cell epitope from NucAb were linked to the C-terminal of the backbone to construct the MEP. The gene of the MEP was expressed in E. coli BL21, and its immunogenicity and protective efficacy were evaluated in Balb/c mice. A recombinant protein with a molecular weight of about 37 kDa was successfully purified, and was identified as the recombinant multi-epitope assembly peptide (rMEP) by Western blot analysis. The animal tests showed that the rMEP was highly immunogenic and could induce high levels of IgG antibody and provide potent protection (88.9%) against lethal doses of A. baumannii. This is the first report of the design and study of a rMEP vaccine against A. baumannii. The results indicate that the rMEP is a promising vaccine candidate for the control of infections caused by A. baumannii.

Transcutaneous immunization of recombinant Staphylococcal enterotoxin B protein using a dissolving microneedle provides potent protection against lethal enterotoxin challenge

Staphylococcal enterotoxin B (SEB) produced by the Staphylococcus aureus bacteriumis most commonly associated with food poisoning and is known to also cause toxic shock syndrome. Currently, no approved vaccine or specific drug is available to treat SEB intoxication. In this study, we fabricated dissolving microneedles (MNs) loaded with recombinant SEB (rSEB) protein, and evaluated its characteristics, including dissolution profile, protein particle size, insertion depth, antigen retention time in vivo, and skin irritation. Our results showed that rSEB protein-loaded dissolving MNs made of chondroitin sulfate (2%) and trehalose (0.8%) could easily penetrate into the mouse skin within 5 min. The rSEB particle size was unchanged before and after MN fabrication. The skin penetration depth of the MNs was 260 µm. Moreover, the MNs also significantly extended the antigen retention time in vivo. rSEB protein-loaded dissolving MNs also triggered slight erythema at the beginning of administration, but this erythema disappeared within a few hours. More importantly, we investigated the immunogenicity and protective efficacy of rSEB protein-loaded dissolving MNs. Challenge studies in mice revealed that mice in full-dose MN group had a high level of SEB specific antibody response thatprovided100% protection against a lethal SEB toxin challenge. However, there was only 60% protection observed in mice that were in the half-dose MN (dose sparing) group. We also determined the pathological alterations in the tissues of the immunized mice. Taken together, these dissolving MNs may present a promising transcutaneous immunization strategy for treating SEB intoxication.

Designed DNA-Encoded IL-36 Gamma Acts as a Potent Molecular Adjuvant Enhancing Zika Synthetic DNA Vaccine-Induced Immunity and Protection in a Lethal Challenge Model.

Identification of novel molecular adjuvants which can boost and enhance vaccine-mediated immunity and provide dose-sparing potential against complex infectious diseases and for immunotherapy in cancer is likely to play a critical role in the next generation of vaccines. Given the number of challenging targets for which no or only partial vaccine options exist, adjuvants that can address some of these concerns are in high demand. Here, we report that a designed truncated Interleukin-36 gamma (IL-36 gamma) encoded plasmid can act as a potent adjuvant for several DNA-encoded vaccine targets including human immunodeficiency virus (HIV), influenza, and Zika in immunization models. We further show that the truncated IL-36 gamma (opt-36γt) plasmid provides improved dose sparing as it boosts immunity to a suboptimal dose of a Zika DNA vaccine, resulting in potent protection against a lethal Zika challenge.

Development of bivalent compounds as potential neuroprotectants for Alzheimer's disease.

In our efforts to further investigate the impact of the spacer and membrane anchor to the neuroprotective activities, a series of bivalent compounds that contain cholesterol and extended spacers were designed, synthesized and biologically characterized. Our results support previous studies that incorporation of a piperazine ring into the spacer significantly improved the protective potency of bivalent compounds in MC65 cell model. Spacer length beyond 21 atoms does not add further benefits with 21MO being the most potent one with an EC50 of 81.86 ± 11.91 nM. Our results also demonstrated that bivalent compound 21MO suppressed the production of mitochondria reactive oxygen species. Furthermore, our results confirmed that both of the spacer and membrane anchor moiety are essential to metal binding. Collectively, the results provide further evidence and information to guide optimization of such bivalent compounds as potential neuroprotectants for Alzheimer's disease.

Irisin pretreatment ameliorates intestinal ischemia/reperfusion injury in mice through activation of the Nrf2 pathway

Intestinal ischemia/reperfusion (I/R) injury is a serious clinical event that may induce intestinal mucosal injury, whose major underlying mechanisms include reactive oxygen species (ROS) generation, release of inflammatory mediators and induction of apoptosis. Irisin is considered an agent with potent protection against many pathological injures. The aim of this study was to investigate the protective effect of irisin pretreatment on intestinal injury and explore its underlying mechanisms in a mouse model of intestinal I/R injury as well as a cell model (IEC-6 cell) of hypoxia/reoxygenation (H/R). The results showed that irisin pretreatment ameliorated I/R and H/R-induced injury in vivo and in vitro. In addition, irisin reduced the levels of tumor necrosis factor (TNF)-α, interleukin(IL)-1β and interleukin(IL)-6 in the intestine. Compared with the I/R group, irisin pretreatment effectively reduced malondialdehyde (MDA) and myeloperoxidase (MPO) levels, but increased superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the intestine, and significantly reduced oxidative stress. Furthermore, irisin pretreatment downregulated Bax and cleaved Caspase-3 at the protein level, and increased Bcl-2 protein amounts, significantly reducing apoptosis in the intestine of I/R mice. Moreover, both in vivo and in vitro results showed that irisin pretreatment significantly upregulated nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein. Meanwhile, Nrf2 siRNA treatment partially abrogated the protective effects of irisin pretreatment on H/R induced cellular damage, inflammatory response, oxidative stress, and apoptosis in IEC-6 cells. These findings suggest that irisin pretreatment improves I/R-induced intestinal inflammatory response, reduces oxidative stress and inhibits apoptosis, which could be, at least partially, associated with Nrf2 pathway activation.

MF59 adjuvant enhances the immunogenicity and protective immunity of the OmpK/Omp22 fusion protein from Acineterbacter baumannii through intratracheal inoculation in mice.

Acinetobacter baumannii (A baumannii) is an emerging nosocomial pathogenic bacterium which leads to hospital infections. The increase in drug-resistant A baumannii strains makes it difficult to control by using common antibiotics. The development of effective vaccines is an alternative means to avoid A baumannii infections. In the present study, Balb/c mice were inoculated intratracheally with 30μg of OmpK/Omp22 fusion protein alone or OmpK/Omp22 formulated with MF59 adjuvant. After two times of boosting at day 14 and 21, the antigen-specific antibody levels and the protective immunity against A baumannii challenge were evaluated. The results showed that the OmpK/Omp22 formulated with MF59 immunized mice produced much higher level of antigen-specific antibodies compared to mice immunized with OmpK/Omp22 alone (P<0.01). Mice immunized with 30μg of OmpK/Omp22 formulated with MF59 also provided more potent protection post-challenge, which showed lower bacterial loads in the blood and lung tissue, lower level of blood inflammatory cytokines and higher survival rate (83.3%) than mice immunized with OmpK/Omp22 alone (P<0.001). In conclusion, this study demonstrated that OmpK/Omp22 fusion protein adjuvanted with MF59 induced superior immune response and better protection than OmpK/Omp22 alone through intratracheal inoculation in mice.

TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells

Mutations in the polycystins cause autosomal dominant polycystic kidney disease (ADPKD). Here we show that transmembrane protein 33 (TMEM33) interacts with the ion channel polycystin-2 (PC2) at the endoplasmic reticulum (ER) membrane, enhancing its opening over the whole physiological calcium range in ER liposomes fused to planar bilayers. Consequently, TMEM33 reduces intracellular calcium content in a PC2-dependent manner, impairs lysosomal calcium refilling, causes cathepsins translocation, inhibition of autophagic flux upon ER stress, as well as sensitization to apoptosis. Invalidation of TMEM33 in the mouse exerts a potent protection against renal ER stress. By contrast, TMEM33 does not influence pkd2-dependent renal cystogenesis in the zebrafish. Together, our results identify a key role for TMEM33 in the regulation of intracellular calcium homeostasis of renal proximal convoluted tubule cells and establish a causal link between TMEM33 and acute kidney injury.

The Protective Buddha: On the Cosmological Logic of Paritta

AbstractParitta — ritual chanting — is a central institution in Theravāda Buddhism, with deep roots in all historical forms of Buddhism in Asia. Nevertheless, no study provides a convincing framework for how the protective potency of the Buddha and his words is understood. Earlier strands of scholarship highlighted the psychological aspects of ritual chanting that were thought to have a positive effect on participants. Later scholars emphasized the role of paritta in the training of monks. These studies do not explain “how paritta works,” that is, for example, why, according to the views encapsulated in the texts themselves, bringing the Buddha to mind can act against demons or change reality. This article offers a close reading of the central texts of the genre in order to conceptualize the metaphysical understanding they employ. It thus provides insights regarding the unique ontological position and cosmological function of the Buddha according to the texts.

Adeno-Associated Virus as an Effective Malaria Booster Vaccine Following Adenovirus Priming.

An ideal malaria vaccine platform should potently induce protective immune responses and block parasite transmission from mosquito to human, and it should maintain these effects for an extended period. Here, we have focused on vaccine development based on adeno-associated virus serotype 1 (AAV1), a viral vector widely studied in the field of clinical gene therapy that is able to induce long-term transgene expression without causing toxicity in vivo. Our results show the potential utility of AAV1 vectors as an extremely potent booster vaccine to induce durable immunity when combined with an adenovirus-priming vaccine in a rodent malaria model. We generated a series of recombinant AAV1s and human adenovirus type 5 (AdHu5) expressing either Plasmodium falciparum circumsporozoite protein (PfCSP) or P25 (Pfs25) protein. Heterologous two-dose immunization with an AdHu5-prime and AAV1-boost (AdHu5-AAV1) elicited robust and durable PfCSP- or Pfs25-specific functional antibodies over 280 days. Regarding protective efficacy, AdHu5-AAV1 PfCSP achieved high sterile protection (up to 80% protection rate) against challenge with transgenic Plasmodium berghei sporozoites expressing PfCSP. When examining transmission-blocking (TB) efficacy, we found that immunization with AdHu5-AAV1 Pfs25 maintained TB activity in vivo against transgenic P. berghei expressing Pfs25 for 287 days (99% reduction in oocyst intensity, 85% reduction in oocyst prevalence). Our data indicate that AAV1-based malaria vaccines can confer potent and durable protection as well as TB efficacy when administered following an AdHu5 priming vaccine, supporting the further evaluation of this regimen in clinical trials as a next-generation malaria vaccine platform.

Vaccine vectors: the bright side of cytomegalovirus.

Cytomegaloviruses (CMVs) present singular features that are particularly advantageous for human vaccine development, a current medical need. Vaccines that induce neutralizing antibodies are among the most successful and efficacious available. However, chronic and persistent human infections, pathogens with high variability of exposed proteins, as well as tumors, highlight the need for developing novel vaccines inducing strong and long-lasting cellular immune responses mediated by effector or effector memory CD8+ cytotoxic T lymphocytes. CMVs induce the most potent CD8+ T lymphocyte response to a pathogen known in each of their hosts, maintain and even increase it for life for selected antigens, in what is known as the ever growing inflationary memory, and maintain an effector memory status due to recent and repeated antigen stimulation that endows these inflationary T lymphocytes with superior and faster protective potency. In addition to these CMV singularities, this family of viruses has two more common favorable features: they can superinfect an already infected host, which is needed in face of the high CMV prevalence, and they can harbor very large segments of foreign DNA at many different genomic sites. All these properties endow CMVs with a singular potential to be used as human vaccine vectors. Current developments with most of the recombinant CMV-based vaccine candidates that have been tested in animal models against clinically relevant viral and bacterial infections and for their use in tumor immunotherapy are reviewed herein. Since CMV vectors should be designed to avoid the risk of disease in immunocompromised individuals, special attention is also paid to attenuated vectors. Taken together, the results support the future use of CMV-based vaccine vectors to induce protective CD8+ T lymphocyte responses in humans, mainly against viral infections and as anti-tumor vaccines.

TGFα preserves oligodendrocyte lineage cells and improves white matter integrity after cerebral ischemia

Transforming growth factor α (TGF-α) has been reported to play important roles in neurogenesis and angiogenesis in the injured brain. The present study characterizes a novel role for TGFα in oligodendrocyte lineage cell survival and white matter integrity after ischemic stroke. Three days after transient (60 min) middle cerebral artery occlusion (tMCAO), TGFα expression was significantly increased in microglia/macrophages and neurons. Expression of the receptor of TGFα—epidermal growth factor receptor (EGFR)—was increased in glial cells after ischemia, including in oligodendrocyte lineage cells. TGFα knockout enlarged brain infarct volumes and exacerbated cell death in oligodendrocyte precursor cells (OPCs) and oligodendrocytes three days after tMCAO. TGFα-deficient mice displayed long-term exacerbation of sensorimotor deficits after tMCAO, and these functional impairments were accompanied by loss of white matter integrity and impaired oligodendrocyte replacement. In vitro studies confirmed that 5 or 10 ng/mL TGFα directly protected OPCs and oligodendrocytes against oxygen and glucose deprivation (OGD)-induced cell death, but exerted no effects on OPC differentiation. Further studies identified STAT3 as a key transcription factor mediating the effects of TGFα on OPCs and oligodendrocytes. In conclusion, TGFα provides potent oligodendrocyte protection against cerebral ischemia, thereby maintaining white matter integrity and improving neurological recovery after stroke.

Saccharomyces boulardii CNCM I-745 Modulates the Fecal Bile Acids Metabolism During Antimicrobial Therapy in Healthy Volunteers.

Saccharomyces boulardii CNCM I-745 (SB) is a probiotic yeast used to lower the incidence of antibiotic-associated Clostridium difficile (C. difficile) infection, though its mechanism of action remains unclear. Cholic acid is a primary bile acid, which triggers the germination and promotes the growth of C. difficile. The intestinal microbiota transforms primary into secondary bile acids. This study examined (1) the antimicrobial-induced alteration of fecal bile acid content, and (2) whether the concomitant administration of SB influences this transformation. This is an ancillary work from a randomized study, which revealed that SB modulates fecal microbiota dysbiosis during antibiotic treatment. Healthy subjects were randomly assigned to (1) SB only, (2) amoxicillin-clavulanate (AC), (3) SB plus AC, or (4) no treatment. We analyzed fecal concentrations of BA by high performance liquid chromatography/tandem mass spectrometry. Compared to the untreated or the SB-treated groups, AC decreased the percentage of fecal secondary BA significantly (days 3 and 7). When SB and AC were administered concomitantly, this decrease in secondary BA was no longer significant. Following treatment with AC, a significant peak of fecal CA was measured on days 3 and 7, which was prevented by the concomitant administration of SB. AC administered to healthy volunteers altered the microbial transformation of primary BA, decreased secondary BA, and increased CA. The latter was prevented by the concomitant administration of SB and AC, suggesting a potent mechanism protection conferred by SB against post-antimicrobial C. difficile infection.Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01473368.