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Spinal cord injury (SCI) is characterized by a complex and prolonged injury process that exacerbates the damage induced by the primary injury and inhibits the potential for regeneration. SCI frequently results in the devastating loss of neurological functions and thus has serious consequences on patient quality of life. Current treatments are limited and focus on early interventions for the acute management of complications. Therefore, the development of novel treatments targeting ongoing injury processes is required to improve SCI outcomes. We aimed to systematically review studies published in the last 10 years that examined experimental treatments with neuroregenerative and neuroprotective capabilities for the improvement of SCI. We analyzed treatments from 44 studies that were identified through a systematic literature search using three databases: PubMed, Web of Science and EMBASE (searched through Ovid). We performed a meta-analysis for Basso-Beattie-Bresnahan (BBB) locomotion test data and collected immunohistochemistry results to demonstrate neuroregenerative and neuroprotective properties of the treatments, respectively. The two treatments that illustrated the most significant improvements in functional recovery using the BBB test were the combined use of tetrahedral framework nucleic acid (tFNA) with neural stem cells (NSCs) and Fortasyn® Connect (FC) supplementation. Both treatments also attenuated secondary injury processes as demonstrated through immunohistochemistry. Combined tFNA with NSCs and FC supplementation are promising treatments for the improvement of SCI as they both demonstrate neuroregenerative and neuroprotective properties. Further pre-clinical testing is required to validate and determine the long-term efficacies of these treatments for the improvement of SCI. [ABSTRACT FROM AUTHOR]

Drought stress restricts plant growth and development by altering metabolic activity and biological functions. However, plants have evolved several cellular and molecular mechanisms to overcome drought stress. Drought tolerance is a multiplex trait involving the activation of signaling mechanisms and differentially expressed molecular responses. Broadly, drought tolerance comprises two steps: stress sensing/signaling and activation of various parallel stress responses (including physiological, molecular, and biochemical mechanisms) in plants. At the cellular level, drought induces oxidative stress by overproduction of reactive oxygen species (ROS), ultimately causing the cell membrane to rupture and stimulating various stress signaling pathways (ROS, mitogen-activated-protein-kinase, Ca2+, and hormone-mediated signaling). Drought-induced transcription factors activation and abscisic acid concentration co-ordinate the stress signaling and responses in cotton. The key responses against drought stress, are root development, stomatal closure, photosynthesis, hormone production, and ROS scavenging. The genetic basis, quantitative trait loci and genes of cotton drought tolerance are presented as examples of genetic resources in plants. Sustainable genetic improvements could be achieved through functional genomic approaches and genome modification techniques such as the CRISPR/Cas9 system aid the characterization of genes, sorted out from stress-related candidate single nucleotide polymorphisms, quantitative trait loci, and genes. Exploration of the genetic basis for superior candidate genes linked to stress physiology can be facilitated by integrated functional genomic approaches. We propose a third-generation sequencing approach coupled with genome-wide studies and functional genomic tools, including a comparative sequenced data (transcriptomics, proteomics, and epigenomic) analysis, which offer a platform to identify and characterize novel genes. This will provide information for better understanding the complex stress cellular biology of plants. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding nucleic acids that can regulate post-transcriptional gene expression by binding to complementary sequences of target mRNA. Evidence showed that dysregulated miRNA expression may be associated with neurological conditions such as Alzheimer's disease (AD). In this study, we combined the results of two independent systematic reviews aiming to unveil the co-expression network of miRNAs and proteins in brain tissues of AD patients. Twenty-eight studies including a total of 113 differentially expressed miRNAs (53 of them validated by qRT-PCR), and 26 studies including a total of 196 proteins differentially expressed in AD brains compared to healthy age matched controls were selected. Pathways analyses were performed on the results of the two reviews and 39 common pathways were identified. A further bioinformatic analysis was performed to match miRNA and protein targets with an inverse relation. This revealed 249 inverse relationships in 28 common pathways, representing new potential targets for therapeutic intervention. A meta-analysis, whenever possible, revealed miR-132-3p and miR-16 as consistently downregulated in late-stage AD across the literature. While no inverse relationships between miR-132-3p and proteins were found, miR-16′s inverse relationship with CLOCK proteins in the circadian rhythm pathway is discussed and therapeutic targets are proposed. The most significant miRNA dysregulated pathway highlighted in this review was the hippo signaling pathway with p = 1.66 × 10−9. Our study has revealed new mechanisms for AD pathogenesis and this is discussed along with opportunities to develop novel miRNA-based drugs to target these pathways. [ABSTRACT FROM AUTHOR]

The incidence of spinal cord injury (SCI) is ever-growing, resulting in life-changing neurological deficits which can have devastating long-term impacts on a person's quality of life. There is an unmet clinical need for a treatment which will prevent progression of the injury, allowing improved axonal regeneration and functional recovery to occur. The initial mechanical insult, followed by a cascade of secondary mechanisms, leads to the exacerbation and remodelling of the lesion site, thus inhibiting neurological recovery. Oedema rapidly accumulates following SCI and contributes to the detrimental pathophysiology and worsens functional outcomes. This study systematically reviewed the current experimental treatments being explored in the field of SCI, which specifically target oedema. Abiding by PRISMA guidelines and strict inclusion criteria, 14 studies were identified and analysed from three online databases (PubMed, Web of Science and EMBASE). As a result, we identified three key modalities which attenuate oedema: selective inhibition of the main water channel protein, aquaporin 4 (AQP4), modulation of inflammation and surgical interventions. Collectively, however, they all result in the downregulation of AQP4, which crucially leads to a reduction in oedema and improved functional outcomes. We concluded that trifluoperazine (TFP), a calmodulin kinase inhibitor which prevents the cell-surface localisation of AQP4, was the most efficacious treatment, significantly eliminating oedema within 7 days of administration. To date, this study is the most concise analysis of current experimental treatments for oedema, exposing its molecular mechanisms and assessing potential therapeutic pathways for future research. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) represents one of the leading causes of mortality and morbidity worldwide, placing an enormous socioeconomic burden on healthcare services and communities around the world. Survivors of TBI can experience complications ranging from temporary neurological and psychosocial problems to long-term, severe disability and neurodegenerative disease. The current lack of therapeutic agents able to mitigate the effects of secondary brain injury highlights the urgent need for novel target discovery. This study comprises two independent systematic reviews, investigating both microRNA (miRNA) and proteomic expression in rat models of severe TBI (sTBI). The results were combined to perform integrated miRNA-protein co-expression analyses with the aim of uncovering the potential roles of miRNAs in sTBI and to ultimately identify new targets for therapy. Thirty-four studies were included in total. Bioinformatic analysis was performed to identify any miRNA–protein associations. Endocytosis and TNF signalling pathways were highlighted as common pathways involving both miRNAs and proteins found to be differentially expressed in rat brain tissue following sTBI, suggesting efforts to find novel therapeutic targets that should be focused here. Further high-quality investigations are required to ascertain the involvement of these pathways and their miRNAs in the pathogenesis of TBI and other CNS diseases and to therefore uncover those targets with the greatest therapeutic potential. [ABSTRACT FROM AUTHOR]

CNS neurons are generally incapable of regenerating their axons after injury due to several intrinsic and extrinsic factors, including the presence of axon growth inhibitory molecules. One such potent inhibitor of CNS axon regeneration is Reticulon (RTN) 4 or Nogo-A. Here, we focused on RTN3 as its contribution to CNS axon regeneration is currently unknown. We found that RTN3 expression correlated with an axon regenerative phenotype in dorsal root ganglion neurons (DRGN) after injury to the dorsal columns, a well-characterised model of spinal cord injury. Overexpression of RTN3 promoted disinhibited DRGN neurite outgrowth in vitro and dorsal column axon regeneration/sprouting and electrophysiological, sensory and locomotor functional recovery after injury in vivo. Knockdown of protrudin, however, ablated RTN3-enhanced neurite outgrowth/axon regeneration in vitro and in vivo. Moreover, overexpression of RTN3 in a second model of CNS injury, the optic nerve crush injury model, enhanced retinal ganglion cell (RGC) survival, disinhibited neurite outgrowth in vitro and survival and axon regeneration in vivo, an effect that was also dependent on protrudin. These results demonstrate that RTN3 enhances neurite outgrowth/axon regeneration in a protrudin-dependent manner after both spinal cord and optic nerve injury. [ABSTRACT FROM AUTHOR]

Reference 1 Thomas C.N., Thompson A.M., Ahmed Z., Blanch R.J. Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model. Retinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model. The authors wish to add that "pre- and post-procedural analgesia was administered to all animals undergoing procedures". [Extracted from the article]

Key pathological features of cerebral small vessel disease (cSVD) include impairment of the blood brain barrier (BBB) and the progression of white matter lesions (WMLs) amongst other structural lesions, leading to the clinical manifestations of cSVD. The function of endothelial cells (ECs) is of major importance to maintain a proper BBB. ECs interact with several cell types to provide structural and functional support to the brain. Oligodendrocytes (OLs) myelinate axons in the central nervous system and are crucial in sustaining the integrity of white matter. The interplay between ECs and OLs and their precursor cells (OPCs) has received limited attention yet seems of relevance for the study of BBB dysfunction and white matter injury in cSVD. Emerging evidence shows a crosstalk between ECs and OPCs/OLs, mediated by signaling through the Wingless and Int-1 (WNT)/β-catenin pathway. As the latter is involved in EC function (e.g., angiogenesis) and oligodendrogenesis, we reviewed the role of WNT/β-catenin signaling for both cell types and performed a systematic search to identify studies describing a WNT-mediated interplay between ECs and OPCs/OLs. Dysregulation of this interaction may limit remyelination of WMLs and render the BBB leaky, thereby initiating a vicious neuroinflammatory cycle. A better understanding of the role of this signaling pathway in EC–OL crosstalk is essential in understanding cSVD development. [ABSTRACT FROM AUTHOR]

Neurotrophic factors (NTF) secreted by Schwann cells in a sciatic nerve (SN) graft promote retinal ganglion cell (RGC) axon regeneration after either transplantation into the vitreous body of the eye or anastomosis to the distal stump of a transected optic nerve. In this study, we investigated the neuroprotective and growth stimulatory properties of SN grafts in which Schwann cells had been killed (acellular SN grafts, ASN) or remained intact (cellular SN grafts, CSN). We report that both intravitreal (ivit) implanted and optic nerve anastomosed CSN promote RGC survival and when simultaneously placed in both sites, they exert additive RGC neuroprotection. CSN and ASN were rich in myelin-associated glycoprotein (MAG) and axon growth-inhibitory ligand common to both the central nervous system (CNS) and peripheral nervous system (PNS) myelin. The penetration of the few RGC axons regenerating into an ASN at an optic nerve transection (ONT) site is limited into the proximal perilesion area, but is increased >2-fold after ivit CSN implantation and increased 5-fold into a CSN optic nerve graft after ivit CSN implantation, potentiated by growth disinhibition through the regulated intramembranous proteolysis (RIP) of p75NTR (the signalling trans-membrane moiety of the nogo-66 trimeric receptor that binds MAG and associated suppression of RhoGTP). Mϋller cells/astrocytes become reactive after all treatments and maximally after simultaneous ivit and optic nerve CSN/ASN grafting. We conclude that simultaneous ivit CSN plus optic nerve CSN support promotes significant RGC survival and axon regeneration into CSN optic nerve grafts, despite being rich in axon growth inhibitory molecules. RGC axon regeneration is probably facilitated through RIP of p75NTR, which blinds axons to myelin-derived axon growth-inhibitory ligands present in optic nerve grafts. [ABSTRACT FROM AUTHOR]

Caspase-2 is the most evolutionarily conserved member of the mammalian caspase family and has been implicated in both apoptotic and non-apoptotic signaling pathways, including tumor suppression, cell cycle regulation, and DNA repair. A myriad of signaling molecules is associated with the tight regulation of caspase-2 to mediate multiple cellular processes far beyond apoptotic cell death. This review provides a comprehensive overview of the literature pertaining to possible sophisticated molecular mechanisms underlying the multifaceted process of caspase-2 activation and to highlight its interplay between factors that promote or suppress apoptosis in a complicated regulatory network that determines the fate of a cell from its birth and throughout its life. [ABSTRACT FROM AUTHOR]

Closed-globe injury can cause visual loss in military and civilian populations, with retinal cell death, including retinal ganglion cell (RGC) degeneration, leading to irreversible blindness. RGC and optic nerve (ON) degeneration after eye or head injury is termed traumatic optic neuropathy (TON). There are currently no treatments for RGC loss, therefore novel therapeutics to prevent RGC death or promote axonal regeneration are a priority. We investigated necroptotic signaling mechanisms in a rat blunt ocular injury model. After bilateral blunt trauma, protein expression and retinal localization of necroptosis pathway members (receptor interacting protein kinase 1, RIPK1; receptor interacting protein kinase 3, RIPK3; and mixed lineage kinase domain like pseudokinase, MLKL) were assessed by Western blot and immunohistochemistry (IHC), and potent necroptosis inhibitor Necrostatin-1s (Nec-1s) was delivered by intravitreal injection to one eye and vehicle to the contralateral eye. RGC and photoreceptor survival were assessed by cell counting and outer nuclear layer (ONL) thickness measurements on histology. The neuroprotective effects of Nec-1s were assessed in primary retinal culture by βIII-tubulin+ RGC cell counts. MLKL protein expression were upregulated at 48 h after injury and MLKL immunolocalised to retinal binding protein with multiple splice (RBPMS)+ RGC, inner nuclear cells and ONL cells, specifically at the retinal injury site. RIPK3 expression did not increase but RIPK3 co-immunolocalised with RBPMS+ RGC in intact and injured retinae. In vitro, a Nec-1s concentration of 0.01 pg/µL was RGC neuroprotective. In the blunt ocular injury rat model, Nec-1s prevented RGC death at the center of the impact site but did not protect against ONL thinning or provide functional restitution. RGC degeneration in our blunt ocular injury model is site-specific, with necroptosis driving death at the center of the focal impact site. [ABSTRACT FROM AUTHOR]

There are contradictory reports on the role of the serine/threonine kinase isoform glycogen synthase kinase-3β (GSK3β) after injury to the central nervous system (CNS). Some report that GSK3 activity promotes axonal growth or myelin disinhibition, whilst others report that GSK3 activity prevents axon regeneration. In this study, we sought to clarify if suppression of GSK3β alone and in combination with the cellular-stress-induced factor RTP801 (also known as REDD1: regulated in development and DNA damage response protein), using translationally relevant siRNAs, promotes retinal ganglion cell (RGC) survival and neurite outgrowth/axon regeneration. Adult mixed retinal cell cultures, prepared from rats at five days after optic nerve crush (ONC) to activate retinal glia, were treated with siRNA to GSK3β (siGSK3β) alone or in combination with siRTP801 and RGC survival and neurite outgrowth were quantified in the presence and absence of Rapamycin or inhibitory Nogo-A peptides. In in vivo experiments, either siGSK3β alone or in combination with siRTP801 were intravitreally injected every eight days after ONC and RGC survival and axon regeneration was assessed at 24 days. Optimal doses of siGSK3β alone promoted significant RGC survival, increasing the number of RGC with neurites without affecting neurite length, an effect that was sensitive to Rapamycin. In addition, knockdown of GSK3β overcame Nogo-A-mediated neurite growth inhibition. Knockdown of GSK3β after ONC in vivo enhanced RGC survival but not axon number or length, without potentiating glial activation. Knockdown of RTP801 increased both RGC survival and axon regeneration, whilst the combined knockdown of GSK3β and RTP801 significantly increased RGC survival, neurite outgrowth, and axon regeneration over and above that observed for siGSK3β or siRTP801 alone. These results suggest that GSK3β suppression promotes RGC survival and axon initiation whilst, when in combination with RTP801, it also enhanced disinhibited axon elongation. [ABSTRACT FROM AUTHOR]

After injury to the spinal cord, edema contributes to the underlying detrimental pathophysiological outcomes that lead to worsening of function. Several related membrane proteins called aquaporins (AQPs) regulate water movement in fluid transporting tissues including the spinal cord. Within the cord, AQP1, 4 and 9 contribute to spinal cord injury (SCI)-induced edema. AQP1, 4 and 9 are expressed in a variety of cells including astrocytes, neurons, ependymal cells, and endothelial cells. This review discusses some of the recent findings of the involvement of AQP in SCI and highlights the need for further study of these proteins to develop effective therapies to counteract the negative effects of SCI-induced edema. [ABSTRACT FROM AUTHOR]