Cerebral palsy (CP) is a chronic childhood disorder with no effective cure. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP and disorders such as Alzheimer’s disease and multiple sclerosis. Targeting neuroinflammation can be a potent therapeutic strategy. However, delivering drugs across the blood-brain-barrier to the target cells for treating diffuse brain injury is a major challenge. Here, we show that systemically administered polyamidoamine dendrimers localize in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not healthy controls. We further demonstrate that dendrimer-based N-acetyl-L-cysteine (NAC) therapy for brain injury suppresses neuroinflammation and leads to a dramatic improvement in motor function in the CP kits. The well known and safe clinical profile for NAC when combined with dendrimer-based targeting, provides opportunities for clinical translation in the treatment of neuroinflammatory disorders in humans. The effectiveness of the dendrimer-NAC treatment, administered in the postnatal period for a prenatal insult, suggests a window of opportunity for treatment of CP in humans after birth.

Apart from sharing common ancestry with chordates, sea cucumbers exhibit a unique morphology and exceptional regenerative capacity. Here we present the complete genome sequence of an economically important sea cucumber, A. japonicus, generated using Illumina and PacBio platforms, to achieve an assembly of approximately 805 Mb (contig N50 of 190 Kb and scaffold N50 of 486 Kb), with 30,350 protein-coding genes and high continuity. We used this resource to explore key genetic mechanisms behind the unique biological characters of sea cucumbers. Phylogenetic and comparative genomic analyses revealed the presence of marker genes associated with notochord and gill slits, suggesting that these chordate features were present in ancestral echinoderms. The unique shape and weak mineralization of the sea cucumber adult body were also preliminarily explained by the contraction of biomineralization genes. Genome, transcriptome, and proteome analyses of organ regrowth after induced evisceration provided insight into the molecular underpinnings of visceral regeneration, including a specific tandem-duplicated prostatic secretory protein of 94 amino acids (PSP94)-like gene family and a significantly expanded fibrinogen-related protein (FREP) gene family. This high-quality genome resource will provide a useful framework for future research into biological processes and evolution in deuterostomes, including remarkable regenerative abilities that could have medical applications. Moreover, the multiomics data will be of prime value for commercial sea cucumber breeding programs.

Dendrimers have emerged as topical microbicides to treat vaginal infections. This study explores the in-vitro, in-vivo antimicrobial activity of PAMAM dendrimers, and the associated mechanism. Interestingly, topical cervical application of 500 µg of generation-4 neutral dendrimer (G4-PAMAM-OH) showed potential to treat the Escherichia coli induced ascending uterine infection in guinea pig model of chorioamnionitis. Amniotic fluid collected from different gestational sacs of infected guinea pigs post treatment showed absence of E. coli growth in the cultures plated with it. The cytokine level [tumor necrosis factor (TNFα) and interleukin (IL-6 and IL-1β)] in placenta of the G4-PAMAM-OH treated animals were comparable to those in healthy animals while these were notably high in infected animals. Since, antibacterial activity of amine-terminated PAMAM dendrimers is known, the activity of hydroxyl and carboxylic acid terminated PAMAM dendrimers was compared with it. Though the G4-PAMAM-NH2 shows superior antibacterial activity, it was found to be cytotoxic to human cervical epithelial cell line above 10µg / mL, while the G4-PAMAM-OH was non cytotoxic upto 1mg / mL concentration. Cell integrity, outer (OM) and inner (IM) membrane permeabilization assays showed that G4-PAMAM-OH dendrimer efficiently changed the OM permeability, while G4-PAMAM-NH2 and G3.5-PAMAM-COOH damaged both OM and IM causing the bacterial lysis. The possible antibacterial mechanism are; G4-PAMAM-NH2 acts as polycation binding to the polyanionic lipopolysaccharide in E. coli, the G4-PAMAM-OH forms hydrogen bonds with the hydrophilic O-antigens in E. coli membrane and the G3.5-PAMAM-COOH acts as a polyanion, chelating the divalent ions in outer cell membrane of E. coli. This is the first study which shows that G4-PAMAM-OH dendrimer acts as an antibacterial agent.

Aim Understanding the interactions between nanomaterials and disease processes is crucial for designing effective therapeutic approaches. This article explores the unusual neuroinflammation targeting of dendrimers (with no targeting ligands) in the brain, with significant consequences for nanoscale materials in medicine. Method The in vivo biodistribution of fluorescent-labeled neutral generation-4-polyamidoamine dendrimers (~4 nm) in a rabbit model of cerebral palsy was explored following subarachnoid administration. Results These dendrimers, with no targeting ligands, were localizing in activated microglia and astrocytes (cells responsible for neuroinflammation), even in regions far moved from the site of injection, in newborn rabbits with maternal inflammation-induced cerebral palsy. Conclusion This intrinsic ability of dendrimers to localize inactivated microglia and astrocytes can enable targeted delivery of therapeutics in disorders such as cerebral palsy, Alzheimer’s and multiple sclerosis.

Local intravaginal drug therapy is preferred for treatment of ascending genital infections during pregnancy. In the present study, in-situ forming biodegradable hydrogel for sustained release of amoxicillin in the cervicovaginal region is described. A generation 4 poly(amidoamine) [G4-(NH2)64] dendrimer with peripheral thiopyridyl terminations is crosslinked with 8-arm polyethylene glycol (PEG) bearing thiol terminations. The hydrogels were formulated and tested in-vivo in pregnant guinea pig model for volume, retention times, biodegradation, tolerability and transport across fetal membrane. The physicochemical characterization of the hydrogels was carried out using differential calorimetry, SEM, and confocal imaging. The hydrogels offer antibacterial activity arising from sustained release of amoxicillin from gels. The in-vivo studies in guinea pig showed that 100-200 μL of gel sufficiently covered the cervicovaginal region with a residence time of at least 72 h and gel was primarily retained in the maternal tissues without crossing the fetal membranes into the fetus. The dendrimer gels were stable upto 72 h and the in-vivo biodegradation of gel occurred after 72 h and this correlated well with the in-vitro degradation pattern. The pH of the vagina was not altered upon application of the gel and none of the animals aborted upto 72 h after application of gel. The histological evaluation of the cervical tissues showed absence of edema in epithelial cell layer, no sloughing of the epithelial or superficial mucous layer, absence of necrosis and infiltration of inflammatory cells in the submucosal layers confirmed that tissues were tolerant to the gel. The immunohistofluorescence images showed the localization of the gel components on the superficial mucified epithelial layer. The crosslinking density and swelling of hydrogels was impacted by the polymer content and the 10 % hydrogels exhibited highest crosslink density. The in-vitro drug release studies carried out using Franz diffusion cells showed that amoxicillin release from 6 and 10 % gels was sustained for 240 h as compared to 3 % gels. As the polymer concentration increased to 10 % the release pattern from gels approached diffusion controlled mechanism with diffusional exponent n = 0.49. In conclusion, the biodegradable in-situ forming hydrogels of present study offer a therapeutic option to provide sustained localized delivery of amoxicillin intracervically to the pregnant woman for the treatment of ascending genital infections.

The polymorphisms of angiotensin-converting enzyme 2 (ACE2) gene have been suggested to be linked to increase risk of essential hypertension in multiple populations. However, the results are still debatable. To assess the association between ACE2 G8970A genetic polymorphism and essential hypertension, we conducted a meta-analysis of case-control studies across different ethnicity. PubMed, Embase, CBM, Wanfang and VIP databases were searched, and a total of 11 separate studies in females and nine separate studies in males met the inclusion criteria. Because ACE2 is on the X chromosome, data for each sex were analyzed separately. The selected studies contained 7,251 (4,472 females/2,779 males) hypertensive patients and 3,800 (2,161 females/1,639 males) normotensive controls. A statistically significant association was observed between the G8970A gene polymorphism and essential hypertension risk in female hypertensive group in the recessive genetic model (AA vs. GG+GA: P = 0.03, OR = 1.15, 95% CI = 1.02-1.30, P(heterogeneity) = 0.40, I(2) = 5%, fixed-effects model). Although no association was shown between the frequency of the A allele and the genetic susceptibility to essential hypertension in all male patients (A Allele: P = 0.38, OR = 1.10, 95% CI = 0.89-1.38, P(heterogeneity) = 0.02, I(2) = 56%, random-effects model), we found that the relationship between carrier of A allele and the essential hypertension risk in Han-Chinese male patients subgroup (A Allele: P = 0.006, OR = 1.21, 95% CI = 1.06–1.38, P(heterogeneity) = 0.10, I(2) = 44%, fixed-effects model). The current meta-analysis provided solid evidence suggesting that ACE2 gene polymorphism G8790A was probably a genetic risk factor for essential hypertension across different ethnic populations in female subjects and in Han-Chinese male subjects.

Reelin is an extracellular matrix (ECM) protein that is essential for neuron

Maternal intrauterine inflammation is implicated in neurodevelopmental disorders in the offspring. Serotonin is crucial for regulating maturation in the developing brain, and maternal inflammation may result in disruption of the serotonergic system in the perinatal period. Saline or endotoxin was injected intrauterine in pregnant rabbits term. Newborn rabbits underwent positron emission tomography (PET) imaging with a[ 11 C]methyl-L-tryptophan (AMT) to evaluate tryptophan metabolism in vivo. Decrease in standard uptake value for AMT and decrease in serotonin concentration was noted in the frontal and parietal cortices of endotoxin kits when compared with controls. In addition, a significant decrease in serotonin-immunoreactive fibers and decreased expression of serotonin transporter (5HTT) was measured in the somatosensory cortex. There was a three-fold increase in the number of apoptotic cells in the ventrobasal (VB) thalamus without loss of raphe serotonergic cell bodies in endotoxin kits when compared with controls. Glutamateric VB neurons projecting to somatosensory cortex transiently express 5HTT and store serotonin, regulating development of the somatosensory cortex. Intrauterine inflammation results in alterations in cortical serotonin and disruption of serotonin-regulated thalamocortical development in the newborn brain. This may be a common link in neurodevelopmental disorders resulting in impairment of the somatosensory system, such as cerebral palsy and autism.