How Can We Improve Vaccination Response in Old People? Part I: Targeting Immunosenescence of Innate Immunity Cells

Vaccination, being able to prevent millions of cases of infectious diseases around the world every year, is the most effective medical intervention ever introduced. However, immunosenescence makes vaccines less effective in providing protection to older people. Although most studies explain that this is mainly due to the immunosenescence of T and B cells, the immunosenescence of innate immunity can also be a significant contributing factor. Alterations in function, number, subset, and distribution of blood neutrophils, monocytes, and natural killer and dendritic cells are detected in aging, thus potentially reducing the efficacy of vaccines in older individuals. In this paper, we focus on the immunosenescence of the innate blood immune cells. We discuss possible strategies to counteract the immunosenescence of innate immunity in order to improve the response to vaccination. In particular, we focus on advances in understanding the role and the development of new adjuvants, such as TLR agonists, considered a promising strategy to increase vaccination efficiency in older individuals.     

Postischemic Neuroprotection of Aminoethoxydiphenyl Borate Associates Shortening of Peri-Infarct Depolarizations

Brain stroke is a highly prevalent pathology and a main cause of disability among older adults. If not promptly treated with recanalization therapies, primary and secondary mechanisms of injury contribute to an increase in the lesion, enhancing neurological deficits. Targeting excitotoxicity and oxidative stress are very promising approaches, but only a few compounds have reached the clinic with relatively good positive outcomes. The exploration of novel targets might overcome the lack of clinical translation of previous efficient preclinical neuroprotective treatments. In this study, we examined the neuroprotective properties of 2-aminoethoxydiphenyl borate (2-APB), a molecule that interferes with intracellular calcium dynamics by the antagonization of several channels and receptors. In a permanent model of cerebral ischemia, we showed that 2-APB reduces the extent of the damage and preserves the functionality of the cortical territory, as evaluated by somatosensory evoked potentials (SSEPs). While in this permanent ischemia model, the neuroprotective effect exerted by the antioxidant scavenger cholesteronitrone F2 was associated with a reduction in reactive oxygen species (ROS) and better neuronal survival in the penumbra, 2-APB did not modify the inflammatory response or decrease the content of ROS and was mostly associated with a shortening of peri-infarct depolarizations, which translated into better cerebral blood perfusion in the penumbra. Our study highlights the potential of 2-APB to target spreading depolarization events and their associated inverse hemodynamic changes, which mainly contribute to extension of the area of lesion in cerebrovascular pathologies.     

I2-Imidazoline Ligand CR4056 Improves Memory,Increases ApoE Expression and Reduces BBB Leakage in 5xFAD Mice

Recent evidence suggests that I2-imidazoline ligands have neuroprotective properties in animal models of neurodegeneration, such as Alzheimer’s disease (AD). We recently demonstrated that the I2-ligand BU224 reversed memory impairments in AD transgenic mice and this effect was not because of reductions in amyloid-β (Aβ) deposition. In this study, our aim was to determine the therapeutic potential of the powerful analgesic I2-imidazoline ligand CR4056 in the 5xFAD model of AD, since this ligand has been proven to be safely tolerated in humans. Sub-chronic oral administration of CR4056 (30 mg/kg for 10 days) led to an improvement in recognition memory in 6-month-old 5xFAD mice, but not in wild-type littermates, without affecting Aβ levels or deposition. Our results also revealed a change in the profile of microglia by CR4056, resulting in a suppression of pro-inflammatory activated microglia, but increased the density of astrocytes and the expression of ApoE, which is mainly produced by these glial cells. In addition, CR4056 restored fibrinogen extravasation, affecting the distribution of markers of astrocytic end feet in blood vessels. Therefore, these results suggest that CR4056 protects against Aβ-mediated neuroinflammation and vascular damage, and offers therapeutic potential at any stage of AD.     

Effects of Sedentarism and Treadmill Training in Mechanical Properties of Muscles of Ovariectomized Rats with High-Fat Diet

The aim of this study is to evaluate the ability of physical training in the maintenance of muscle strength in rats with HFD （high-fat diet） after OVX （ovariectomy）. Eighty Wistar rats are at eight weeks of age and weight 200 g which divided into 8 groups （n = 10） and treated for 12 weeks： GA： OVX ＋ ND （normal diet）, GB： OVX ＋ ND ＋ training, GC： sham ＋ ND, GD： sham ＋ ND ＋ training, GE： OVX ＋ HFD, GF： OVX ＋ HFD ＋ training, GG： sham ＋ HFD and GH： sham ＋ HFD ＋ training. HFD consists of standard ration for rats with addition of 30% lipids. In training groups, physical training five training/week was conducted on a treadmill with adaptation period of three weeks up to 18 m/s for one hour, training were performed for 12 weeks. The sedentary animals remained in individual box. To analyze the effects of training and diet, tensile strength tests of the gastrocnemius muscles were conducted： the speed of 0.1 mm/min. Analysis of variance was performed to compare groups. The mean （SD） obtained for the maximum load （N） were： GA 57.77 （6.89）, GB 62.74 （5.07）, GC 49.45 （6.06）, GD 59.42 （5.26） and GE 55.58 （4.72）, GF 62.50 （4.56）, GG 58.35 （4.54） and GH 56.67 （5.87）, respectively. There were no differences for maximum load between surgeries （p = 0.004） and between treatments （p = 0.000）. Differences were found also for the relationship surgery diet treatment （p = 0.007）. For the variable stiffness （N/mm）, there were not statistically significant differences： GA 5.03 （0.72）, GB 5.08 （1.09）, GC 5.17 （0.53）, GD 5.35 （0.80）, GE 5.52 （1.20）, GF 5.36 （1.07）, GG 4.83 （1.03） and GH 5.40 （0.73）. For the toughness （N/mm）, there were differences between treatments （p = 0.010） and the ratio diet treatment （p = 0.024）： GA 455.00 （107.21）, GB 541.96 （126.80）, GC 394.97 （84.67）, GD 566.90 （157.07）; GE 424.63 （113.03）, GF 478.07 （106.03）; GG 517.44 （98.65?     

Metal–Organic Gel‐Derived FexOy/Nitrogen‐Doped Carbon Films for Enhanced Lithium Storage

The development of cost‐effective and flexible electrodes is demanding in the field of energy storage. Herein, flexible Fe_xO_y/nitrogen‐doped carbon films (Fe_xO_y/NC‐MOG) are prepared by facile electrospinning of Fe‐based metal–organic gels (MOGs) followed by high‐temperature carbonization. This approach allows the even mixing of fragile coordination polymers with polyacrylonitrile into flexible films while reserving the structural characteristics of coordination polymers. After thermal treatment, Fe_xO_y/NC‐MOG films possess uniformly distributed Fe_xO_y nanoparticles and larger accessible surface areas than traditional Fe_xO_y‐NC films without MOG. Taking advantage of the unique structure, Fe_xO_y/NC‐MOG exhibits a superior rate performance (449.8 mA h g^?1 at 5000 mA g^–1) and long cycle life (629.3 mA h g^–1 after 500 cycles at 1000 mA g^–1) when used as additive‐free anodes in lithium‐ion batteries.     

Insights into the Pharmacokinetics and In Vitro Cell-Based Studies of the Imidazoline I2 Receptor Ligand B06

The impact of neurodegenerative diseases (ND) is becoming unbearable for humankind due to their vast prevalence and the lack of efficacious treatments. In this scenario, we focused on imidazoline I₂ receptors (I₂-IR) that are widely distributed in the brain and are altered in patients with brain disorders. We took the challenge of modulating I₂-IR by developing structurally new molecules, in particular, a family of bicyclic α-iminophosphonates, endowed with high affinity and selectivity to these receptors. Treatment of two murine models, one for age-related cognitive decline and the other for Alzheimer’s disease (AD), with representative compound B06 ameliorated their cognitive impairment and improved their behavioural condition. Furthermore, B06 revealed beneficial in vitro ADME-Tox properties. The pharmacokinetics (PK) and metabolic profile are reported to de-risk B06 for progressing in the preclinical development. To further characterize the pharmacological properties of B06, we assessed its neuroprotective properties and beneficial effect in an in vitro model of Parkinson’s disease (PD). B06 rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine (6-OHDA) and showed a crucial anti-inflammatory effect in a cellular model of neuroinflammation. This research reveals B06 as a putative candidate for advancing in the difficult path of drug discovery and supports the modulation of I₂-IR as a fresh approach for the therapy of ND.     

Selective Coloration of Melanin Nanospheres through Resonant Mie Scattering

Black melanin inks are prepared to selectively exhibit colors under strong light, inspired by human hair. High absorbance of melanin suppresses multiple scattering, causing resonant Mie scattering predominant. Various colors can be developed as the resonant wavelength dictated by nanosphere diameter. Therefore, the melanin inks can be used to encrypt and selectively disclose multicolor patterns for anticounterfeiting applications.