Simvastatin Differentially Modulates Glial Functions in Cultured Cortical and Hypothalamic Astrocytes Derived from Interferon α/ß Receptor Knockout mice.

Astrocytes have key regulatory roles in central nervous system (CNS), integrating metabolic, inflammatory and synaptic responses. In this regard, type I interferon (IFN) receptor signaling in astrocytes can regulate synaptic plasticity. Simvastatin is a cholesterol-lowering drug that has shown anti-inflammatory properties, but its effects on astrocytes, a main source of cholesterol for neurons, remain to be elucidated. Herein, we investigated the effects of simvastatin in inflammatory and functional parameters of primary cortical and hypothalamic astrocyte cultures obtained from IFNα/ß receptor knockout (IFNα/ßR-/-) mice. Overall, simvastatin decreased extracellular levels of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), which were related to a downregulation in gene expression in hypothalamic, but not in cortical astrocytes. Moreover, there was an increase in anti-inflammatory interleukin-10 (IL-10) in both structures. Effects of simvastatin in inflammatory signaling also involved a downregulation of cyclooxygenase 2 (COX-2) gene expression as well as an upregulation of nuclear factor κB subunit p65 (NFκB p65). The expression of cytoprotective genes sirtuin 1 (SIRT1) and nuclear factor erythroid derived 2 like 2 (Nrf2) was also increased by simvastatin. In addition, simvastatin increased glutamine synthetase (GS) activity and glutathione (GSH) levels only in cortical astrocytes. Our findings provide evidence that astrocytes from different regions are important cellular targets of simvastatin in the CNS, even in the absence of IFNα/ßR, which was showed by the modulation of cytokine production and release, as well as the expression of cytoprotective genes and functional parameters.

Serum of COVID-19 patients changes neuroinflammation and mitochondrial homeostasis markers in hippocampus of aged rats.

Patients affected by COVID-19 present mostly with respiratory symptoms but acute neurological symptoms are also commonly observed. Furthermore, a considerable number of individuals develop persistent and often remitting symptoms months after infection, characterizing the condition called long-COVID. Since the pathophysiology of acute and persistent neurological manifestations is not fully established, we evaluated the expression of different genes in hippocampal slices of aged rats exposed to the serum of a post-COVID (sPC) individual and to the serum of patients infected by SARS-CoV-2 [Zeta (sZeta) and Gamma (sGamma) variants]. The expression of proteins related to inflammatory process, redox homeostasis, mitochondrial quality control and glial reactivity was determined. Our data show that the exposure to sPC, sZeta and sGamma differentially altered the mRNA levels of most inflammatory proteins and reduced those of antioxidant response markers in rat hippocampus. Furthermore, a decrease in the expression of mitochondrial biogenesis genes was induced by all serum samples, whereas a reduction in mitochondrial dynamics was only caused by sPC. Regarding the glial reactivity, S100B expression was modified by sPC and sZeta. These findings demonstrate that changes in the inflammatory response and a reduction of mitochondrial biogenesis and dynamics may contribute to the neurological damage observed in COVID-19 patients.

Zika Virus affects neurobehavioral development, and causes oxidative stress associated to blood-brain barrier disruption in a rat model of congenital infection.

Zika virus (ZIKV) is a mosquito-borne flavivirus associated with several neurodevelopmental outcomes after in utero infection. Here, we studied a congenital ZIKV infection model with immunocompetent Wistar rats, able to predict disabilities and that could pave the way for proposing new effective therapies. We identified neurodevelopmental milestones disabilities in congenital ZIKV animals. Also, on 22nd postnatal day (PND), blood-brain barrier (BBB) proteins disturbances were detected in the hippocampus with immunocontent reduction of ß_Catenin, Occludin and Conexin-43. Besides, oxidative stress imbalance on hippocampus and cortex were identified, without neuronal reduction in these structures. In conclusion, even without pups' microcephaly-like phenotype, congenital ZIKV infection resulted in neurobehavioral dysfunction associated with BBB and oxidative stress disturbances in young rats. Therefore, our findings highlighted the multiple impact of the congenital ZIKV infection on the neurodevelopment, which reinforces the continuity of studies to understand the spectrum of this impairment and to provide support to future treatment development for patients affected by congenital ZIKV.

Differential proteomics of Zika virus (ZIKV) infection reveals molecular changes potentially involved in immune system evasion by a Brazilian strain of ZIKV.

Zika virus (ZIKV) is an arbovirus that was responsible for multiple outbreaks from 2007 to 2015. It has been linked to cases of microcephaly in Brazil in 2015, among other neurological disorders. Differences among strains might be the reason for different clinical outcomes of infection. To evaluate this hypothesis, we performed a comparative proteomic analysis of Vero cells infected with the African strain MR766 (ZIKVAFR) and the Brazilian strain 17 SM (ZIKVBR). A total of 550 proteins were identified as differentially expressed in ZIKVAFR- or ZIKVBR-infected cells compared to the control. The main findings included upregulation of immune system pathways (neutrophil degranulation and adaptive/innate immune system) and potential activation of immune-system-related pathways by ZIKVAFR (mTOR, JAK-STAT, NF-κB, and others) compared with the ZIKVBR/control. In addition, phagocytosis by macrophages and engulfment of leukocytes were activated in ZIKVAFR infection. An in vivo analysis using an immunocompetent C57BL/6N mouse model identified interstitial pneumonia with neutrophil infiltration in the lungs only in mice infected with ZIKVBR at 48 hours postinfection, with a significant amount of virus detected. Likewise, only animals infected with ZIKVBR had viral material in the cytoplasm of lung macrophages. These results suggest that activation of the immune system by ZIKVAFR infection may lead to faster viral clearance by immune cells.

Autogenous dentin combined with mesenchymal stromal cells as an alternative alveolar bone graft: an in vivo study.

OBJECTIVE: Considering the chemical and structural properties of dentin, this study was aimed at evaluating the effect of dentin matrix alone or combined with mesenchymal stromal cells (MSC) on postextraction alveolar bone regeneration. MATERIAL AND METHODS: Wistar rats were subjected to tooth extraction with osteotomy and allocated into groups according to the graft inserted: (1) Gelita-Spon®, (2) Bio-Oss®, (3) Dentin, (4) MSC, (5) Dentin/MSC, and (6) Control. Maxillae were analyzed by means of hematoxylin and eosin (H&E) staining, immunohistochemical (IHC) analysis, microcomputed tomography (micro-CT), and scanning electron microscopy (SEM). Serum levels of calcium and phosphorus were quantified. RESULTS: The Bio-Oss group showed less bone than Gelita-Spon and Dentin/MSC; no other significant differences were seen in H&E analysis. The Bio-Oss group showed higher expression of collagen type I compared to the Dentin and Dentin/MSC groups and also higher osteocalcin expression than the Dentin/MSC group. There was a tendency of higher expression of osteopontin in the MSC, Dentin, and Dentin/MSC groups and higher VEGF in the MSC group. On micro-CT analysis, the Bio-Oss and the Dentin/MSC groups exhibited greater bone volume than the Control. Serum calcium and phosphorus levels did not significantly differ between the groups. SEM analysis depicted particles of Bio-Oss and dentin in the respective groups, as well as significant cellularity in the MSC group. CONCLUSION: Autogenous nondemineralized dentin is an alternative for alveolar bone grafting, which can be improved by combination with MSC. CLINICAL RELEVANCE: This work provides support for the clinical applicability of dentin graft alone or combined with MSC.

Possible Occupational Infection of Healthcare Workers with Monkeypox Virus, Brazil.

We evaluated epidemiologic and molecular characteristics of monkeypox virus (MPXV) infections sampled from 2 healthcare nurses. Five days after collecting samples from an infected patient, the nurses showed typical MPXV manifestations; quantitative PCR and whole-genome sequencing confirmed MPXV infection, most likely transmitted through contact with fomites.

Effect of hyaluronic acid on paracrine signaling of osteoblasts from mesenchymal stromal cells: potential impact on bone regeneration.

OBJECTIVES: This study evaluated hyaluronic acids (HA) with different molecular weights as potential matrices for tissue-engineered bone grafting and their possible influence on the paracrine mechanisms of adipose-derived mesenchymal stromal cells. MATERIAL AND METHODS: Murine adipose mesenchymal stromal cells (mASCs) on the fourth passage were seeded in 96-well plates, osteoinduced for 27 days and exposed for 3 days to low (HA-LW) and high/low molecular weight (HA-HLW) at previously defined concentrations. Cytokines IGF-1, VEGF, FGF-2, and BMP-2 were evaluated by quantification in the supernatant. RESULTS: Greater expression of growth factors was observed in groups with HA-HLW compared to HA-LW. Results indicated that differentiated cells secreted fewer cytokines, namely VEGF, FGF, and BMP-2 than undifferentiated mASCs (p < 0.05). IGF-1 showed its greatest expression in the mASC HA-LW group (p < 0.05). CONCLUSIONS: The application of HA-HLW as cell matrix in tissue engineering did not compromise mASC paracrine effect. Also, the association of HA-HLW matrix and mASCs resulted in greater expression of osteogenic growth factors. Longer periods of cell differentiation seemed to negatively affect their capacity for local paracrine stimulation. CLINICAL RELEVANCE: The use of HA-HLW as matrix for undifferentiated ASCs can be positive for bone regeneration, favoring its application as cell matrix in bone grafting procedures.

Combining canine mesenchymal stromal cells and hyaluronic acid for cartilage repair.

Cell therapy and tissue engineering have been intensively researched for repair of articular cartilage. In this study, we investigated the chondrogenic potential of canine adipose-derived mesenchymal stromal cells (ASCs) combined to high molecular weight hyaluronic acid (HA) in vitro, and their therapeutic effect in dogs with chronic osteoarthritis (OA) associated with bilateral hip dysplasia. Canine ASCs were characterized after conventional 2D culture or 3D culture in HA, showing adequate immunophenotype, proliferation and trilineage differentiation, as well as chondrogenesis after cultivation in HA. ASC/HA constructs were used to treat 12 dogs with OA, sequentially assigned to control, ASC and ASC/HA groups. Animals were examined for clinical, orthopedic and radiological parameters. Lameness at walk and pain on manipulation were reduced in the ASC group and mainly in the ASC/HA group. Range of motion and detection of crepitus on hip rotation and abduction improved similarly in all groups. For articular edema, muscle atrophy, Norberg angle values and radiographic analyses, there were no variations throughout the period. These results indicate that ASC/HA constructs are safe and may be an effective therapeutic tool in treating canine chronic osteoarthritis, which should be confirmed with larger studies and additional clinical parameters.

Adipogenic Mesenchymal Stem Cells and Hyaluronic Acid as a Cellular Compound for Bone Tissue Engineering.

This study investigates the applicability of adipose mesenchymal stem cells (mADSCs) and hyaluronic acid (HA) as a cellular compound for bone tissue engineering. A critical bone defect was created on each femur of 25 rats in vivo, receiving the following 5 graft treatments: I-Control-defect; II-HA; III-mADSCs; IV-mADSCs+HA; and V-previously osteoinduced mADSCs+HA. Evaluation using microcomputed tomography, histomorphometry, and RT-PCR analysis was performed 23 days after implantation. Microcomputed tomography analysis indicated higher means of bone contact surface (BCS) and bone surface density (BSD) for the mADSCs+HA group compared with Control and the HA groups (P < 0.05). Histomorphometric findings showed higher means of bone regeneration in the mADSCs+HA compared with HA and Control groups (P < 0.05). The RT-PCR ratios showed no difference in type 1 collagen (Col1A) gene expression or osteopontin (OP) gene expression, whereas for the osteonectin gene (ON) higher means were found in the HA and mADSCs osteoin+HA groups (P < 0.05). These results suggest that a combination of HA and mADSCs without prior osteoinduction might be applicable for bone tissue regeneration.

Short-Term Protocols to Obtain Insulin-Producing Cells from Rat Adipose Tissue: Signaling Pathways and In Vivo Effect.

Studies using mesenchymal stromal cells (MSCs) as a source of insulin-secreting cells (IPCs) are a promising path in the pursuit for diabetes therapy. Here, we investigate three short-term differentiation protocols in order to generate IPCs from autologous adipose-derived stromal cells (ADSCs) with an expressive insulin-secreting profile in vitro and in vivo, as well as the signaling pathways involved in the chosen differentiation protocols. We extracted and cultured ADSCs and differentiated them into IPCs, using three different protocols with different inductors. Afterwards, the secretory profile was analyzed and IPCs differentiated in exendin-4/activin A medium, which presented the best secretory profile, was implanted in the kidney subcapsular region of diabetic rats. All protocols induced the differentiation, but media supplemented with exendin-4/activin A or resveratrol induced the expression and secretion of insulin more efficiently, and only the exendin-4/activin-A-supplemented medium generated an insulin secretion profile more like ß-cells, in response to glucose. The PI3K/Akt pathway seems to play a negative role in IPC differentiation; however, the differentiation of ADSCs with exendin-4/activin A positively modulated the p38/MAPK pathway. Resveratrol medium activated the Jak/STAT3 pathway and generated IPCs apparently less sensitive to insulin and insulin-like receptors. Finally, the implant of IPCs with the best secretory behavior caused a decrease in hyperglycemia after one-week implantation in diabetic rats. Our data provide further information regarding the generation of IPCs from ADSCs and strengthen evidence to support the use of MSCs in regenerative medicine, specially the use of exendin-4/activin A to produce rapid and effectively IPCs with significant in vivo effects.

Peripheral Levels of AGEs and Astrocyte Alterations in the Hippocampus of STZ-Diabetic Rats.

Diabetic patients and streptozotocin (STZ)-induced diabetes mellitus (DM) models exhibit signals of brain dysfunction, evidenced by neuronal damage and memory impairment. Astrocytes surrounding capillaries and synapses modulate many brain activities that are connected to neuronal function, such as nutrient flux and glutamatergic neurotransmission. As such, cognitive changes observed in diabetic patients and experimental models could be related to astroglial alterations. Herein, we investigate specific astrocyte changes in the rat hippocampus in a model of DM induced by STZ, particularly looking at glial fibrillary acidic protein (GFAP), S100B protein and glutamate uptake, as well as the content of advanced glycated end products (AGEs) in serum and cerebrospinal fluid (CSF), as a consequence of elevated hyperglycemia and the content of receptor for AGEs in the hippocampus. We found clear peripheral alterations, including hyperglycemia, low levels of proinsulin C-peptide, elevated levels of AGEs in serum and CSF, as well as an increase in RAGE in hippocampal tissue. We found specific astroglial abnormalities in this brain region, such as reduced S100B content, reduced glutamate uptake and increased S100B secretion, which were not accompanied by changes in GFAP. We also observed an increase in the glucose transporter, GLUT-1. All these changes may result from RAGE-induced inflammation; these astroglial alterations together with the reduced content of GluN1, a subunit of the NMDA receptor, in the hippocampus may be associated with the impairment of glutamatergic communication in diabetic rats. These findings contribute to understanding the cognitive deficits in diabetic patients and experimental models.

Effect of metformin in hypothalamic astrocytes from an immunocompromised mice model.

Astrocytes are glial cells that play key roles in neuroinflammation, which is a common feature in diabetic encephalopathy and aging process. Metformin is an antidiabetic compound that shows neuroprotective properties, including in inflammatory models, but astroglial signaling pathways involved are still poorly known. Interferons α/ß are cytokines that participate in antiviral responses and the lack of their signaling increases susceptible to viral infections. Here, we investigated the effects of metformin on astrocytes from hypothalamus, a crucial brain region related to inflammatory processes. Astrocyte cultures were derived from interferon α/ß receptor knockout (IFNα/ßR-/-) and wild-type (WT) mice. Metformin did not change the expression of glial fibrillary acidic protein but caused an anti-inflammatory effect by decreasing pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß), as well as increasing gene expression of anti-inflammatory proteins interleukin-10 and Nrf2 (nuclear factor erythroid derived 2 like 2). However, nuclear factor κB p65 and cyclooxygenase 2 were downregulated in WT astrocytes and upregulated in IFNα/ßR-/- astrocytes. AMP-activated protein kinase (AMPK), a molecular target of metformin, was upregulated only in WT astrocytes, while sirtuin 1 increased in both mice models. The expression of inducible nitric oxide synthase was decreased in WT astrocytes and heme oxygenase 1 was increased in IFNα/ßR-/- astrocytes. Although loss of IFNα/ßR-mediated signaling affects some effects of metformin, our results support beneficial roles of this drug in hypothalamic astrocytes. Moreover, paradoxical response of metformin may involve AMPK. Thus, metformin can mediate glioprotection due its effects on age-related disorders in non-diabetic and diabetic encephalopathy individuals.

Treadmill exercise induces hippocampal astroglial alterations in rats.

Physical exercise effects on brain health and cognitive performance have been described. Synaptic remodeling in hippocampus induced by physical exercise has been described in animal models, but the underlying mechanisms remain poorly understood. Changes in astrocytes, the glial cells involved in synaptic remodeling, need more characterization. We investigated the effect of moderate treadmill exercise (20 min/day) for 4 weeks on some parameters of astrocytic activity in rat hippocampal slices, namely, glial fibrillary acidic protein (GFAP), glutamate uptake and glutamine synthetase (GS) activities, glutathione content, and S100B protein content and secretion, as well as brain-derived neurotrophic factor (BDNF) levels and glucose uptake activity in this tissue. Results show that moderate treadmill exercise was able to induce a decrease in GFAP content (evaluated by ELISA and immunohistochemistry) and an increase in GS activity. These changes could be mediated by corticosterone, whose levels were elevated in serum. BDNF, another putative mediator, was not altered in hippocampal tissue. Moreover, treadmill exercise caused a decrease in NO content. Our data indicate specific changes in astrocyte markers induced by physical exercise, the importance of studying astrocytes for understanding brain plasticity, as well as reinforce the relevance of physical exercise as a neuroprotective strategy.

Glioprotective effects of resveratrol in hypothalamic astrocyte cultures obtained from interferon receptor knockout (IFNα/ßR-/-) mice.

Astrocytes play essential roles in the central nervous system (CNS), such as the regulation of glutamate metabolism, antioxidant defenses, and inflammatory/immune responses. Moreover, hypothalamic astrocytes seem to be crucial in the modulation of inflammatory processes, including those related to type I interferon signaling. In this regard, the polyphenol resveratrol has emerged as an important glioprotective molecule to regulate astrocyte functions. Therefore, this study aimed to investigate the immunomodulatory and protective effects of resveratrol in hypothalamic astrocyte cultures obtained from mouse depleted of type I interferon receptors (INF-α/ß-/-), a condition that can impair immune and inflammatory functions. Resveratrol upregulated glutamate transporter and glutamine synthetase gene expression, as well as modulated the release of wide range of cytokines and genes involved in the control of inflammatory response, besides the expression of adenosine receptors, which display immunomodulatory functions. Resveratrol also increased genes associated with redox balance, mitochondrial processes, and trophic factors signaling. The putative genes associated with glioprotective effects of resveratrol, including nuclear factor erythroid derived 2 like 2 (Nrf2), heme oxygenase 1 (HO-1), sirtuin 1 (SIRT1), and phosphoinositide 3-kinase (PI3K)/Akt, were further upregulated by resveratrol. Thus, our data show that resveratrol was able to modulate key genes associated with glial functionality and inflammatory response in astrocyte cultures derived from IFNα/ßR-/- mice. These data are in agreement with previous results, reinforcing its glioprotective effects even in hypothalamic astrocytes with altered inflammatory and immune signaling. Finally, this polyphenol can prepare astrocytes to better respond to injuries, including those associated with neuroimmunology defects.

Nano-scaled surfaces and sustainable-antibiotic-release from polymeric coating for application on intra-osseous implants and trans-mucosal abutments.

Multifunctional surfaces may display the potential to accelerate and promote the healing process around dental implants. However, the initial cellular biocompatibility, molecular activity, and the release of functionalized molecules from these novel surfaces require extensive investigation for clinical use. Aiming to develop and compare innovative surfaces for application in dental implants, the present study utilized titanium disks, which were treated and divided into four groups: machined (Macro); acid-etched (Micro); anodized-hydrophilic surface (TNTs); and anodized surface coated with a rifampicin-loaded polymeric layer (poly(lactide-co-glycolide), PLGA) (TNTsRIMP). The samples were characterized regarding their physicochemical properties and the cumulative release of rifampicin (RIMP), investigated at different pH values. Additionally, differentiated osteoblasts from mesenchymal cells were used for cell viability and qRT-PCR analysis. Antibacterial properties of each surface treatment were investigated against Staphylococcus epidermidis. TNTsRIMP demonstrated controlled drug release for up to 7 days in neutral pH environments. Osteogenic cell cultures indicated that all the evaluated surfaces showed biocompatibility. The TNTs group revealed up-regulated values for bone-related gene quantification in 7 days, followed by the TNTsRIMP group. Furthermore, the antibiotic-functionalized surface revealed effectiveness to inhibit S. epidermidis and stimulate promising conditions for osteogenic cell behavior. Characteristics such as nanomorphology and hydrophilicity were determinants for the up-regulated quantification of osteogenic biomarkers related to early bone maturation, encouraging application in intra-osseous implant surfaces; in addition, antibiotic-functionalized surfaces demonstrated significant higher antibacterial properties compared to the other groups. Our findings suggest that polymeric-antibiotic-loaded coating might be applied for the prevention of early infections, favoring its application in multifunctional surfaces for intra- and/or trans-mucosal components of dental implants, while, hydrophilic nanotextured surfaces promoted optimistic properties to stimulate early bone-related cell responses, favoring its application in bone-anchored surfaces.

Preserving the B-cell compartment favors operational tolerance in human renal transplantation.

Transplanted individuals in operational tolerance (OT) maintain long-term stable graft function after completely stopping immunosuppression. Understanding the mechanisms involved in OT can provide valuable information about pathways to human transplantation tolerance. Here we report that operationally tolerant individuals display quantitative and functional preservation of the B-cell compartment in renal transplantation. OT exhibited normal numbers of circulating total B cells, naive, memory and regulatory B cells (Bregs) as well as preserved B-cell receptor repertoire, similar to healthy individuals. In addition, OT also displayed conserved capacity to activate the cluster of differentiation 40 (CD40)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in Bregs, in contrast, with chronic rejection. Rather than expansion or higher activation, we show that the preservation of the B-cell compartment favors OT.

SARS-CoV-2-Induced Amyloidgenesis: Not One, but Three Hypotheses for Cerebral COVID-19 Outcomes.

The main neuropathological feature of Alzheimer's disease (AD) is extracellular amyloid deposition in senile plaques, resulting from an imbalance between the production and clearance of amyloid beta peptides. Amyloid deposition is also found around cerebral blood vessels, termed cerebral amyloid angiopathy (CAA), in 90% of AD cases. Although the relationship between these two amyloid disorders is obvious, this does not make CAA a characteristic of AD, as 40% of the non-demented population presents this derangement. AD is predominantly sporadic; therefore, many factors contribute to its genesis. Herein, the starting point for discussion is the COVID-19 pandemic that we are experiencing and how SARS-CoV-2 may be able to, both directly and indirectly, contribute to CAA, with consequences for the outcome and extent of the disease. We highlight the role of astrocytes and endothelial cells in the process of amyloidgenesis, as well as the role of other amyloidgenic proteins, such as fibrinogen and serum amyloid A protein, in addition to the neuronal amyloid precursor protein. We discuss three independent hypotheses that complement each other to explain the cerebrovascular amyloidgenesis that may underlie long-term COVID-19 and new cases of dementia.

Why antidiabetic drugs are potentially neuroprotective during the Sars-CoV-2 pandemic: The focus on astroglial UPR and calcium-binding proteins.

We are living in a terrifying pandemic caused by Sars-CoV-2, in which patients with diabetes mellitus have, from the beginning, been identified as having a high risk of hospitalization and mortality. This viral disease is not limited to the respiratory system, but also affects, among other organs, the central nervous system. Furthermore, we already know that individuals with diabetes mellitus exhibit signs of astrocyte dysfunction and are more likely to develop cognitive deficits and even dementia. It is now being realized that COVID-19 incurs long-term effects and that those infected can develop several neurological and psychiatric manifestations. As this virus seriously compromises cell metabolism by triggering several mechanisms leading to the unfolded protein response (UPR), which involves endoplasmic reticulum Ca2+ depletion, we review here the basis involved in this response that are intimately associated with the development of neurodegenerative diseases. The discussion aims to highlight two aspects-the role of calcium-binding proteins and the role of astrocytes, glial cells that integrate energy metabolism with neurotransmission and with neuroinflammation. Among the proteins discussed are calpain, calcineurin, and sorcin. These proteins are emphasized as markers of the UPR and are potential therapeutic targets. Finally, we discuss the role of drugs widely prescribed to patients with diabetes mellitus, such as statins, metformin, and calcium channel blockers. The review assesses potential neuroprotection mechanisms, focusing on the UPR and the restoration of reticular Ca2+ homeostasis, based on both clinical and experimental data.

Zika Virus Envelope Domain III Recombinant Protein Delivered With Saponin-Based Nanoadjuvant From Quillaja brasiliensis Enhances Anti-Zika Immune Responses, Including Neutralizing Antibodies and Splenocyte Proliferation.

Nanoadjuvants that combine immunostimulatory properties and delivery systems reportedly bestow major improvements on the efficacy of recombinant, protein-based vaccines. Among these, self-assembled micellar formulations named ISCOMs (immune stimulating complexes) show a great ability to trigger powerful immunological responses against infectious pathogens. Here, a nanoadjuvant preparation, based on saponins from Quillaja brasiliensis, was evaluated together with an experimental Zika virus (ZIKV) vaccine (IQB80-zEDIII) and compared to an equivalent vaccine with alum as the standard adjuvant. The preparations were administered to mice in two doses (on days zero and 14) and immune responses were evaluated on day 28 post-priming. Serum levels of anti-Zika virus IgG, IgG1, IgG2b, IgG2c, IgG3 were significantly increased by the nanoadjuvant vaccine, compared to the mice that received the alum-adjuvanted vaccine or the unadjuvanted vaccine. In addition, a robust production of neutralizing antibodies and in vitro splenocyte proliferative responses were observed in mice immunized with IQB80-zEDIII nanoformulated vaccine. Therefore, the IQB80-zEDIII recombinant preparation seems to be a suitable candidate vaccine for ZIKV. Overall, this study identified saponin-based delivery systems as an adequate adjuvant for recombinant ZIKV vaccines and has important implications for recombinant protein-based vaccine formulations against other flaviviruses and possibly enveloped viruses.