The aim of this study was to gain insight into the bacterial composition and dynamics in a mineral water treatment system (MWTS). The bacterial community of a full-scale mineral water treatment plant in the Maofeng Mountain, South China, was studied using high-throughput sequencing combined with cultivation-based techniques in both the dry and wet season. Overall, adenosine tri-phosphate (ATP) concentration (6.47 × 10-11 - 3.32 × 10-8 M) and heterotrophic plate counts (HPC) (3 - 1.29 × 103 CFU/mL) of water samples in the wet season were lower than those (ATP concentration 5.10 × 10-11 - 6.96 × 10-8 M, HPC 2 - 1.97 × 103 CFU/mL) in the dry season throughout the whole MWTS. The microbial activity and biomass of water samples obviously changed along with treatment process. All 300 isolates obtained using cultivation-based techniques were distributed in 5 phyla, 7 classes, and 19 genera. Proteobacteria accounted for 55.7% (167) of the total isolates, among which predominant genus was Pseudomonas (19.3%). Illumina sequencing analysis of 16s rRNA genes revealed 15 bacterial phyla (relative abundance >0.1%) as being identified in all water samples. Among these, Proteobacteria constituted the dominant bacteria microbiota in all water samples. A large shift in the proportion of Bacteroidetes, Actinobacteria, and Firmicutes was obtained during the treatment process, with the proportion of Bacteroidetes, Actinobacteria decreasing sharply, whereas that of Firmicutes increased and predominated in the final water product. The core microbiome, which was still present in whole MWTS comprised several genera including Pseudomonas, Acinetobacter, Clostridium, and Mycobacterium, that contain species that are opportunistic pathogens, suggesting a potential threat for mineral water microbiology safety. This study is the first to investigate the bacterial community of a full-scale mineral water treatment plant in China. The results provided data regarding the bacteria composition and dynamics in an MWTS, which will contribute to the beneficial manipulation of the mineral water microbiome.

Weissella genus from Leuconostocaceae family forms a group of Gram-positive lactic acid bacteria (LAB) that mostly reside in fermented foods and some have been isolated from the environment and vertebrates including humans. Currently there are 23 recognized species, 16 complete and 37 draft genome assemblies for this genus. Weissella hellenica has been found in various sources and is characterized by their probiotic and bacteriocinogenic properties. Despite its widespread importance, little attention has been paid to genomic characterization of this species with the availability of draft assembly of two species in the public database so far. In this manuscript, we identified W. hellenica 0916-4-2 from fermented kimchi and completed its genome sequence. Comparative genomic analysis identified 88 core genes that had interspecies mean amino acid identity of more than 65%. Whole genome phylogenetic analysis showed that three W. hellenica strains clustered together and the strain 0916-4-2 was close to strain WiKim14. In silico analysis for the secondary metabolites biosynthetic gene cluster showed that Weissella are far less producers of secondary metabolites compared to other members of Leuconostocaceae. The availability of the complete genome of W. hellenica 0916-4-2 will facilitate further comparative genomic analysis of Weissella species, including studies of its biotechnological potential and improving the nutritional value of various food products.

Infection and life-long residence in the human nervous system is central to herpes simplex virus (HSV) pathogenesis. Access is gained through innervating axonal projections of sensory neurons. This distinct mode of entry separates the viral genome from tegument proteins, including the potent transactivator of viral IE genes, VP16. This, in turn, promotes a balance between lytic and latent infection which underlies the ability of the virus to invade, disseminate, and set up a large reservoir of latent infections. In the mouse ocular model, TG neurons marked as either "latent" or "lytic" at 48 h postinfection indicated that these programs were selected early and were considered distinct and mutually exclusive. More recently, a temporal analysis of viral program selection revealed a default latent-like state that begins at ~18 h postinfection and in individual neurons, precedes entry into the viral lytic cycle. Studies using refined viral mutants demonstrated that transition out of this latent program depended upon the transactivation function of VP16. Pursuit of the apparent incongruity between the established leaky-late kinetics of VP16 expression with a "preimmediate-early" function led to the discovery of an unrecognized regulatory feature of the HSV-1 VP16 promoter near/downstream of its TATA box. Among three potential sites identified was a putative Egr-1/Sp1 site. Here, we report that a refined mutation of this site, while having no impact on replication in cultured cells or cornea, resulted in ~100-fold reduction in lytic infection in TG in vivo. Notably, the HSV-2 VP16 promoter has 13 direct tandem-repeats upstream of its TATA box forming multiple potential overlapping Egr-1/Sp1 sites. Thus, despite different structures, these promoters might share function in directing the preimmediate-early VP16 protein expression. To test this, the HSV-1 VP16 promoter/5'UTR was replaced by the HSV-2 VP16 promoter/5'UTR in the HSV-1 backbone. Compared to the genomically repaired isolate, the HSV-2 VP16 promoter/5'UTR (1) accelerated the transition into the lytic cycle, and enhanced (2) virulence, and (3) entry into the lytic cycle following a reactivation stressor. These gain-of-function phenotypes support the hypothesis that the VP16 promoter regulates the latent/lytic boundary in neurons and that the HSV-1 and HSV-2 promoter/5'UTRs encode distinct thresholds for this transition.

Plant growth promoting rhizobacteria (PGPR) are beneficial microorganisms that can be utilized to improve plant responses against biotic and abiotic stresses. In this study, 74 halotolerant bacterial isolates were isolated from rhizosphere and endorhizosphere of durum wheat (Triticum turgidum subsp. durum) plants cultivated in saline environments in the Ghor region near the east of the Dead Sea. 16S rDNA partial sequences and phylogenetic analysis of 62 isolates showed clear clustering of the isolates into three phyla: Firmicutes (61.3%), Proteobacteria (29.0%), and Actinobacteria (9.7%). At the genus level, the majority of them were grouped within the Bacillus, Oceanobacillus, and Halomonas genera. The isolates, which possessed plant growth promoting traits including nitrogen fixation, ACC deaminase activity, auxin production, inorganic phosphate solubilization and siderophore production, were selected. The effect of the inoculation of selected PGPR strains on growth of salt sensitive and salt tolerant durum wheat genotypes under high salt stress conditions was evaluated. Six halotolerant PGPR strains were able to improve survival in inoculated plants under high salinity stress conditions as reflected in higher germination percentages and seedling root growth when compared with non-inoculated plants. Furthermore, three halotolerant PGPR strains were able to improve durum wheat tolerance to water deficit stress. In addition, antagonistic effect in four halotolerant PGPR strains against an aggressive pathogenic isolate of Fusarium culmorum that causes crown rot disease was observed in a dual culture assay. In conclusion, the halotolerant PGPR strains described in this study might have great potential to improve durum wheat productivity under different stress conditions.

The objective of this experiment was to determine if dosing pre-weaned calves with enriched ruminal microbiota alters the rumen microbial environment and growth performance. Twenty Holstein bull calves were removed from their dam at birth, fed 3.8 L colostrum within 4 h after birth, and housed individually. Calves were fed pasteurized milk 3×/d from 0 to 7 weeks of age and offered a texturized calf starter ad libitum at 6 days of age. A randomized complete block design with repeated measures and a 2 × 2 factorial arrangement of treatments was used to evaluate responses. Treatments were administered by stomach intubation once per week from 3 to 6 weeks of age and included: 50 mL autoclaved rumen fluid (RF), 50 mL bacterial-enriched RF (BE), 50 mL protozoal-enriched RF (PE); or 50 mL of each BE and PE inoculum. A rumen content composite was collected from 4 rumen fistulated, lactating cows and used to create the inocula. BE inocula were microscopically confirmed to be free of ciliate protozoa before inoculation, while PE contained 2.9 ± 2.2 × 105 protozoa/mL. RF was collected from the calves once per week before 50 mL of the inoculum was administered. Animal performance (e.g., weight gain and dry matter intake) was not altered by inocula type. All calves were microscopically free of rumen ciliates before inoculum administration and calves that did not receive PE remained ciliate-free. Ciliate protozoa were observed in RF from 6, 8, and 6 PE treated calves (n = 10) at weeks 4, 5, and 6, respectively. Ruminal NH3 was lower in PE treated calves (3.3 vs. 6.8 ± 1.0 mM), while ruminal butyrate molar percent was greater in BE treated calves (10.8 vs. 8.3 ± 0.8). Rumen bacterial diversity measures did not differ by treatment at 3-6 weeks. Individual calf bacterial communities from treated calves became temporarily similar to the inocula at 4 weeks of age, but these communities diverged from the inocula at 5 weeks. This study provides new information about two types of rumen-derived inocula and insight into the challenges of directing the rumen microbial environment in the pre-weaned calf.

"Candidatus Liberibacter asiaticus" (CLas), one of the causal agents of citrus Huanglongbing (HLB), secretes proteins with functions that are largely unknown. In this study, we demonstrated that CLIBASIA_00460, one of the CLas-encoded Sec-dependent presecretory proteins, might contribute to the phytopathogenicity of CLas. CLIBASIA_00460 was conserved in CLas strains and expressed at a significantly higher level in citrus than in Asian citrus psyllid. Agrobacteria-mediated transient expression in Nicotiana benthamiana epidermal cells showed that the mature CLIBASIA_00460 (m460) without the putative Sec-dependent signal peptide was localized in multiple cellular compartments including nucleus at 25°C, but that nuclear accumulation was greatly decreased as the temperature rose to 32°C. When overexpressed via a Potato virus X (PVX)-based expression vector in N. benthamiana, m460 induced no local symptoms, but tiny necrotic spots were scattered on the systemic leaves. However, NLS-m460, which contains the SV40 nuclear localization sequence (NLS) at the N-terminus to promote nuclear import of m460, caused chlorosis and necrosis in the local leaves and severe necrosis in the systemic leaves. Taken together, these data suggest that CLIBASIA_00460 represented a novel virulence factor of CLas, and that nuclear localization of this protein was temperature dependent and positively correlated with its pathogenicity in planta.

Salicornia bigelovii is a promising halophytic crop for saline soils in semi-arid regions. This study was designed to characterize isolates of endophytic actinobacteria from S. bigelovii roots and evaluate the effects associated with plant growth promotion. Twenty-eight endophytic isolates obtained from surface-sterilized roots of S. bigelovii were initially selected based on their production of 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase in vitro in a chemically defined medium. Application of Micromonospora chalcea UAE1, possessing the highest ACC deaminase activity, to S. bigelovii seedlings significantly enhanced the plant growth under gnotobiotic and greenhouse conditions. This was clear from the increases in the dry weight and length of both shoot and root, and seed yield compared to the non-ACC deaminase-producing isolate Streptomyces violaceorectus, or control treatment. The growth promotion was also supported by significant increases in the content of photosynthetic pigments and the levels of auxins, but significant decreases in the levels of ACC in planta. Under greenhouse conditions, M. chalcea recovered from inside the inoculated roots in all samplings (up to 12 weeks post inoculation), suggesting that the roots of healthy S. bigelovii are a suitable habitat for the endophytic actinobacterial isolates. Pure cultures of M. chalcea were not capable of producing auxins, gibberellic acid, cytokinins or polyamines in vitro. This indicates that the growth promotion is most likely to be due to the reduction of the endogenous levels of the stress hormone ethylene. Our findings suggest that growth and yields of S. bigelovii can be enhanced by the field application of the endophyte M. chalcea UAE1. This study is the first to report potential endophytic non-streptomycete actinobacteria to promote the growth of halophytic plants in semi-arid zones under greenhouse conditions.

One of the primary targets of immune checkpoint inhibition is the negative immune regulatory molecule CTLA-4. Immune-related adverse events are commonly observed following CTLA-4 inhibition in melanoma treatment, and a spectrum of these conditions are also observed in individuals with germline haploinsufficiency of CTLA4. Here we describe a heterozygous de novo missense variant of CTLA4 in a young girl with childhood-onset autoimmune hepatitis and polyarthritis, the latter responding to treatment with CTLA-4-Ig fusion protein. This variant lay within the highly conserved MYPPPY motif of CTLA-4: a critical structural determinant of ligand binding, which is also bound by the anti-CTLA-4 monoclonal antibody ipilimumab. Within the spectrum of CTLA4 variants reported, missense variants in the MYPPPY motif were overrepresented when compared to variants within a control population, highlighting the physiological importance of this motif in both the genetic and pharmacological regulation of autoimmunity and anti-tumor immunity.

In rheumatoid arthritis(RA) pathogenesis, activated RA fibroblast-like synoviocytes (RA-FLSs) exhibit similar proliferative features as tumor cells and subsequent erosion to cartilage will eventually lead to joint destruction. Therefore, it is imperative to search for compounds, which can effectively inhibit the abnormal activation of RA-FLSs, and retard RA progression.3'3-Diindolylmethane (DIM), the major product of the acid-catalyzed oligomerization of indole-3-carbinol from cruciferous vegetables, has been reported to be functionally relevant to inhibition of migration, invasion and carcinogenesis in some solid tumors. In this study, we explored the anti-proliferation, anti-metastasis and anti-inflammation effects of DIM on RA-FLSs as well as the underlying molecular mechanisms. To do this, primary RA-FLSs were isolated from RA patients and an animal model. Cell proliferation, migration and invasion were measured using CCK-8, scratch, and Transwell assays, respectively. The effects of DIM on Matrix metalloproteinases (MMPs) and some inflammatory factors mRNA and key molecules such as some inflammatory factors and those involved in aberrantly-activated signaling pathway in response to tumor necrosis factor α(TNF-α), a typical characteristic mediator in RA-FLS, were quantitatively measured by real-time PCR and western blotting. Moreover, the effect of DIM on adjuvant induced arthritis(AIA) models was evaluated with C57BL/6 mice in vivo. The results showed that DIM inhibited proliferation, migration and invasion of RA-FLS in vitro. Meanwhile, DIM dramatically suppressed TNF-α-induced increases in the mRNA levels of MMP-2, MMP-3, MMP-8, and MMP-9; as well as the proinflammatory factors IL-6, IL-8, and IL-1β. Mechanistic studies revealed that DIM is able to suppress phosphorylated activation not only of p38, JNK in MAPK pathway but of AKT, mTOR and downstream molecules in the AKT/mTOR pathway. Moreover, DIM treatment decreased expression levels of proinflammatory cytokines in the serum and alleviated arthritis severity in the knee joints of AIA mice. Taken together, our findings demonstrate that DIM could inhibit proliferation, migration and invasion of RA-FLSs and reduce proinflammatory factors induced by TNF-α in vitro by blocking MAPK and AKT/mTOR pathway and prevent inflammation and knee joint destruction in vivo, which suggests that DIM might have therapeutic potential for RA.

Upon antigen recognition, naïve B cells undergo rapid proliferation followed by differentiation to specialized antibody secreting cells (ASCs), called plasma cells. Increased circulating plasma cells are reported in patients with B cell-associated malignancies, chronic graft-vs.-host disease, and autoimmune disorders. Our aim was to optimize an RNAi-based method that efficiently and reproducibly knocks-down genes of interest in human primary peripheral B cells for the targeted analysis of ASC differentiation. The unique contributions of transcriptional diversity in species-specific regulatory networks and the mechanisms of gene function need to be approached directly in human B cells with tools to hone our basic inferences from animal models to human biology. To date, methods for gene knockdown in human primary B cells, which tend to be more refractory to transfection than immortalized B cell lines, have been limited by losses in cell viability and ineffective penetrance. Our single-step siRNA nucleofector-based approach for human primary naïve B cells demonstrates reproducible knockdown efficiency (~40-60%). We focused on genes already known to play key roles in murine ASC differentiation, such as interferon regulatory factor 4 (IRF4) and AID. This study reports a validated non-viral method of siRNA delivery into human primary B cells that can be applied to study gene regulatory networks that control human ASC differentiation.

Human leukocyte antigen (HLA) alleles have a high degree of polymorphism, which determines their peptide-binding motifs and subsequent T-cell receptor recognition. The simplest way to understand the cross-presentation of peptides by different alleles is to classify these alleles into supertypes. A1 and A3 HLA supertypes are widely distributed in humans. However, direct structural and functional evidence for peptide presentation features of key alleles (e.g., HLA-A*30:01 and -A*30:03) are lacking. Herein, the molecular basis of peptide presentation of HLA-A*30:01 and -A*30:03 was demonstrated by crystal structure determination and thermostability measurements of complexes with T-cell epitopes from influenza virus (NP44), human immunodeficiency virus (RT313), and Mycobacterium tuberculosis (MTB). When binding to the HIV peptide, RT313, the PΩ-Lys anchoring modes of HLA-A*30:01, and -A*30:03 were similar to those of HLA-A*11:01 in the A3 supertype. However, HLA-A*30:03, but not -A*30:01, also showed binding with the HLA*01:01-favored peptide, NP44, but with a specific structural conformation. Thus, different from our previous understanding, HLA-A*30:01 and -A*30:03 have specific peptide-binding characteristics that may lead to their distinct supertype-featured binding peptide motifs. Moreover, we also found that residue 77 in the F pocket was one of the key residues for the divergent peptide presentation characteristics of HLA-A*30:01 and -A*30:03. Interchanging residue 77 between HLA-A*30:01 and HLA-A*30:03 switched their presented peptide profiles. Our results provide important recommendations for screening virus and tumor-specific peptides among the population with prevalent HLA supertypes for vaccine development and immune interventions.

Background: IL-17A has effects on several cell types and is a therapeutic target in several inflammatory diseases. IL-17F shares 50% homology and biological activities with IL-17A. It is now of interest to target both cytokines. The objective was to compare the IL-17A and IL-17F effect on cytokine production by RA synoviocytes, and to extend to other cells. Methods: Cells (RA synoviocytes, psoriasis skin fibroblasts, endothelial cells, myoblasts, and hepatocytes) were cultured in the presence or not of: IL-17A, IL-17F, TNF, IL-1β alone or their combinations, IL-17A/TNF, IL-17A/IL-1β, IL-17A/TNF/IL-1β, IL-17F/TNF, IL-17F/IL-1β, and IL-17F/TNF/IL-1β. All experiments were performed in parallel to reduce variability. After 48 h, supernatants were recovered and IL-6 and IL-8 levels were measured by ELISA. Results: IL-17A and IL-17F alone increased significantly IL-6 and IL-8 productions by synoviocytes, with a stronger effect for IL-17A. For IL-6 production, TNF or IL-1β alone had the largest effect on myoblasts (5-fold increase), while for IL-8 production, it was on skin fibroblasts (5-fold increase). The IL-17A/TNF synergistic increase was observed on all cells for IL-6; and for IL-8, except for endothelial cells. For IL-17F/TNF, except with endothelial cells, a synergistic effect was also observed, but less powerful than with IL-17A/TNF. IL-17A/IL-1β or IL-17F/IL-1β effect was cell-type dependent, with an additive effect for synoviocytes (1.6 and 2-fold increase, respectively for IL-6, and 1.8 and 2-fold increase, respectively for IL-8) and a synergistic effect for hepatocytes (3.8 and 4.2-fold increase, respectively for IL-6, and 6 and 2-fold increase, respectively for IL-8). The three-cytokine combination induced an additive effect for synoviocytes and a synergistic effect for skin fibroblasts. Conclusion: IL-17A and IL-17F acted similarly by inducing pro-inflammatory cytokine secretion, with a stronger response intensity with IL-17A. Their activities were potentiated by the combination with TNF and IL-1β, with an effect dependent on the cell type.

Salinization is one of the major causes of agricultural soil degradation worldwide. In arid and semi-arid regions with calcareous soils, phosphorus (P) deficiency further worsens the quality of salinized soils. Nonetheless, nutrient poor soils could be suitable of producing second-generation energy crops. Due to its high biomass production, Arundo donax L. (giant reed) is one of the most promising species for energy and second-generation biofuel production. A. donax can be propagated by micropropagation, an in vitro technique that produces high number of homogeneous plantlets. However, crop establishment is often compromised due to poor plantlet acclimatization to the soil environment. Arbuscular mycorrhizal fungi (AM) are components of soil-plant systems able to increase root phosphorus uptake and to confer the plant an increase tolerance to salinity with a consequent enhancement effect of plant growth and yield. In the present study, the relative importance of the early symbiosis establishment between AM fungi and A. donax micropropagated plantlets in the response to salt stress under low phosphorus availability was determined. A commercial inoculum which contained two different AM fungi species: Rhizophagus intraradices and Funneliformis mosseae was used. AM-symbionts (AM) and non-symbionts plants were grown at two phosphorus [2.5 μM (C) and 0.5 mM (P)] and three NaCl (1, 75 and 150 mM) concentrations in a room chamber under controlled conditions. After 5 weeks, AM root colonization was 60, 26 and 15% in 1, 75 and 150 mM NaCl-treated plants, respectively. At 1 and 75 mM NaCl, AM plants showed increased growth. In all saline treatments, AM plants had decreased Na+ uptake, Na+ root-to-shoot translocation, Na+/K+ ratio and increased P and K use efficiencies with respect to C and P plants. AM improved the nutritional status of A. donax plants by enhancing nutrient use efficiency rather than nutrient uptake. Increased phosphorus use efficiency in AM plants could have benefited ion (Na+ and K+) uptake and/or allocation and ultimately ameliorate the plant's response to saline conditions.

The tribe Geonomateae is a widely distributed group of 103 species of Neotropical palms which contains six ecologically important understory or subcanopy genera. Although it has been the focus of many studies, our understanding of the evolutionary history of this group, and in particular of the taxonomically complex genus Geonoma, is far from complete due to a lack of molecular data. Specifically, the previous Sanger sequencing-based studies used a few informative characters and partial sampling. To overcome these limitations, we used a recently developed Arecaceae-specific target capture bait set to undertake a phylogenomic analysis of the tribe Geonomateae. We sequenced 3,988 genomic regions for 85% of the species of the tribe, including 84% of the species of the largest genus, Geonoma. Phylogenetic relationships were inferred using both concatenation and coalescent methods. Overall, our phylogenetic tree is highly supported and congruent with taxonomic delimitations although several morphological taxa were revealed to be non-monophyletic. It is the first time that such a large genomic dataset is provided for an entire tribe within the Arecaceae. Our study lays the groundwork not only for detailed macro- and micro-evolutionary studies within the group, but also sets a workflow for understanding other species complexes across the tree of life.

Beta-actin (ACTB) loss-of-function mutations result in a pleiotropic developmental disorder of kidney. The present study aims to explore whether the common variants at the ACTB gene contribute to diabetic kidney disease (DKD) susceptibility in patients with type 2 diabetes mellitus (T2DM). From the baseline population of 20,340 diabetic patients, 1,510 DKD cases and 1,510 age-matched T2DM controls were selected. All subjects were Han Chinese. Three tagging single nucleotide polymorphisms (SNPs), rs852423, rs852426, and rs2966449, at the ACTB gene were genotyped. Logistic regression was performed to estimate the association with DKD. SNPs, rs852426 and rs2966449, were significantly associated with DKD [additive model; odds ratio (OR), 1.217 and 1.151; P = 0.001 and 0.018, respectively]. The association of rs852426 with DKD still remained statistically significant after Bonferroni correction and particularly significant in the population older than 70 years rather than the 70 years or younger (P = 0.047 for heterogeneity test). Furthermore, the association of rs852426 with DKD was observed in populations of male and females without smoking, drinking, and with duration for T2DM 10-20 years. The association of rs2966449 with DKD was also found in the populations older than 70 years, male, not smoking, not drinking, and with duration for T2DM over 20 years. The estimated glomerular filtration rate (eGFR) levels of the individuals with TT or CC genotypes of rs2966449 were significantly lower than that of TC genotype in DKD cases (P = 0.021). The present study provides evidence that the ACTB variants, i.e., rs852426 and rs2966449, may confer the genetic susceptibility to DKD in a Han Chinese population.

Exercise is an effective strategy to reduce obesity-induced oxidative stress. The purpose of this study was to compare the effects of two training modalities (moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT)) on the pro/antioxidant status of different tissues in obese Zucker rats.

Alzheimer's disease (AD) is the most common type of dementia, with increasing prevalence and no disease-modifying treatment available yet. There is increasing evidence-from interventions targeting mitochondria-that may shed some light on new strategies for the treatment of AD. Previously, using senescence-accelerated OXYS rats that simulate key characteristics of sporadic AD, we have shown that treatment with mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) from age 12 to 18 months (that is, during active progression of AD-like pathology)-via improvement of mitochondrial function-prevented the neuronal loss and synaptic damage, enhanced neurotrophic supply, and decreased amyloid-β 1-42 protein levels and tau hyperphosphorylation in the hippocampus. In the present study, we continued to explore the mechanisms of the anti-AD effects of SkQ1 in an OXYS rat model through deep RNA sequencing (RNA-seq) and focused upon the cell-specific gene expression alterations in the hippocampus. According to RNA-seq results, OXYS rats had 1,159 differentially expressed genes (DEGs) relative to Wistar rats (control), and 6-month treatment with SkQ1 decreased their number twofold. We found that 10.5% of all DEGs in untreated (control) OXYS rats were associated with mitochondrial function, whereas SkQ1 eliminated differences in the expression of 76% of DEGs (93 from 122 genes). Using transcriptome approaches, we found that the anti-AD effects of SkQ1 are associated with an improvement of the activity of many signaling pathways and intracellular processes. SkQ1 changed the expression of genes in neuronal, glial, and endothelial cells, and these genes are related to mitochondrial function, neurotrophic and synaptic activity, calcium processes, immune and cerebrovascular systems, catabolism, degradation, and apoptosis. Thus, RNA-seq analysis yields a detailed picture of transcriptional changes during the development of AD-like pathology and can point to the molecular and genetic mechanisms of action of the agents (including SkQ1) holding promise for the prevention and treatment of AD.

In prevention studies of metabolic syndrome (MetS), Ang-(1-7) has shown to improve the insulin signaling. We evaluated the HPβCD/Ang-(1-7) treatment on lipid metabolism, renin-angiotensin system (RAS) components, oxidative stress, and insulin pathway in the liver and gastrocnemius muscle and hepatic steatosis in rats with established MetS. After 7 weeks of high-fat (FAT) or control (CT) diets, rats were treated with cyclodextrin (HPβCD) or HPβCD/Ang-(1-7) in the last 6 weeks. FAT-HPβCD/empty rats showed increased adiposity index and body mass, gene expression of ACE/ANG II/AT1R axis, and oxidative stress. These results were accompanied by imbalances in the insulin pathway, worsening of liver function, hyperglycemia, and dyslipidemia. Oral HPβCD/Ang-(1-7) treatment decreased ACE and AT1R, increased ACE2 gene expression in the liver, and restored thiobarbituric acid reactive substances (TBARS), catalase (CAT), superoxide dismutase (SOD), insulin receptor substrate (Irs-1), glucose transporter type 4 (GLUT4), and serine/threonine kinase 2 (AKT-2) gene expression in the liver and gastrocnemius muscle improving hepatic function, cholesterol levels, and hyperglycemia in MetS rats. Overall, HPβCD/Ang-(1-7) treatment restored the RAS components, oxidative stress, and insulin signaling in the liver and gastrocnemius muscle contributing to the establishment of blood glucose and lipid homeostasis in MetS rats.

The neutrophil recruiting cytokine Interleukin-17A (IL-17A) is a key component in vascular dysfunction and arterial hypertension. Moreover, IL-17A has a central role for the vascular infiltration of myeloid cells into the arterial wall in Angiotensin II-induced vascular inflammation. The intention of our study was to analyze the impact of T cell-derived IL-17A on hypertension, vascular function, and inflammation.

Glioblastoma (GBM) is one of most malignancy tumors worldwide. Temozolomide (TMZ) is an important chemotherapy drug in GBM therapy. However, acquired TMZ-resistance frequently happens in GBM therapy and leads to high percentage of GBM recurrence. In our study, we demonstrated that Snail is upregulated in recurrent GBM tumors, and promotes the GBM cells resistant to TMZ induced apoptosis. Enhanced expression of Snail compromises the apoptosis induced by TMZ, and increases the cell migration and invasion. Reversely, depletion of Snail by siRNA has the opposite effects. In addition, we confirmed that the expression of Snail is modulated by STAT3 activation, since phospho-STAT3 level is relatively higher in recurrent GBM tumors and TMZ resistant cells. Knockdown of STAT3 turns down the expression of Snail in protein and mRNA level, and thereby sensitized the resistant GBM cells to TMZ treatment. Interestingly, the activation of STAT3 in GBM resistant cells is modulated by IL-6 secretion. Suppression of IL-6 abandons the STAT3 activation, and reduces its binding with Snail promoter. Inhibition of IL-6 by its antibody enhanced the killing effects of TMZ both in vivo and in vitro. Overall, our results provided a rational to overcome the TMZ resistant in GBM treatment by targeting IL-6-STAT3-Snail pathway.