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Hypertension is a major harbinger of cardiovascular morbidity and mortality. It predisposes to higher rates of myocardial infarction, chronic kidney failure, stroke, and heart failure than most other risk factors. By 2025, the prevalence of hypertension is projected to reach 1.5 billion people. The pathophysiology of this disease is multifaceted, as it involves nitric oxide and endothelin dysregulation, reactive oxygen species, vascular smooth muscle proliferation, and vessel wall calcification, among others. With the advent of new biomolecular techniques, various studies have elucidated a gaping hole in the etiology and mechanisms of hypertension. Indeed, epigenetics, DNA methylation, histone modification, and microRNA-mediated translational silencing appear to play crucial roles in altering the molecular phenotype into a hypertensive profile. Here, we critically review the experimentally determined associations between microRNA (miRNA) molecules and hypertension pharmacotherapy. Particular attention is given to the epigenetic mechanisms underlying the physiological responses to antihypertensive drugs like candesartan, and other relevant drugs like clopidogrel, aspirin, and statins among others. Furthermore, how miRNA affects the pharmaco-epigenetics of hypertension is especially highlighted. [ABSTRACT FROM AUTHOR]

Neonatal Encephalopathy (NE) is a major cause of lifelong disability and neurological complications in affected infants. Identifying novel diagnostic biomarkers in this population may assist in predicting MRI injury and differentiate neonates with NE from those with low-cord pH or healthy neonates and may help clinicians make real-time decisions. To compare the microRNA (miRNA) profiles between neonates with NE, healthy controls, and neonates with low cord pH. Moreover, miRNA concentrations were compared to brain injury severity in neonates with NE. This is a retrospective analysis of miRNA profiles from select samples in the biorepository and data registry at the University of Florida Health Gainesville. The Firefly miRNA assay was used to screen a total of 65 neurological miRNA targets in neonates with NE (n = 36), low cord pH (n = 18) and healthy controls (n = 37). Multivariate statistical techniques, including principal component analysis and orthogonal partial least squares discriminant analysis, and miRNA Enrichment Analysis and Annotation were used to identify miRNA markers and their pathobiological relevance. A set of 10 highly influential miRNAs were identified, which were significantly upregulated in the NE group compared to healthy controls. Of these, miR-323a-3p and mir-30e-5p displayed the highest fold change in expression levels. Moreover, miR-34c-5p, miR-491-5p, and miR-346 were significantly higher in the NE group compared to the low cord pH group. Furthermore, several miRNAs were identified that can differentiate between no/mild and moderate/severe injury in the NE group as measured by MRI. MiRNAs represent promising diagnostic and prognostic tools for improving the management of NE. [ABSTRACT FROM AUTHOR]

Background: Amidst growing concern about the safety of sport-related repetitive subconcussive head impacts (RSHI), biofluid markers may provide sensitive, informative, and practical assessment of the effects of RSHI exposure. Objective: This scoping review aimed to systematically examine the extent, nature, and quality of available evidence from studies investigating the effects of RSHI on biofluid markers, to identify gaps and to formulate guidelines to inform future research. Methods: PRISMA extension for Scoping Reviews guidelines were adhered to. The protocol was pre-registered through publication. MEDLINE, Scopus, SPORTDiscus, CINAHL, PsycINFO, Cochrane Library, OpenGrey, and two clinical trial registries were searched (until March 30, 2022) using descriptors for subconcussive head impacts, biomarkers, and contact sports. Included studies were assessed for risk of bias and quality. Results: Seventy-nine research publications were included in the review. Forty-nine studies assessed the acute effects, 23 semi-acute and 26 long-term effects of RSHI exposure. The most studied sports were American football, boxing, and soccer, and the most investigated markers were (in descending order): S100 calcium-binding protein beta (S100B), tau, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), phosphorylated tau (p-tau), ubiquitin C-terminal hydrolase L1 (UCH-L1), and hormones. High or moderate bias was found in most studies, and marker-specific conclusions were subject to heterogeneous and limited evidence. Although the evidence is weak, some biofluid markers—such as NfL—appeared to show promise. More markedly, S100B was found to be problematic when evaluating the effects of RSHI in sport. Conclusion: Considering the limitations of the evidence base revealed by this first review dedicated to systematically scoping the evidence of biofluid marker levels following RSHI exposure, the field is evidently still in its infancy. As a result, any recommendation and application is premature. Although some markers show promise for the assessment of brain health following RSHI exposure, future large standardized and better-controlled studies are needed to determine biofluid markers' utility. Key Points: This is the first systematically conducted review focused on scoping biofluid markers in sport-related repetitive subconcussive head impact (RSHI) research, identifying a significant body of evidence not previously featured in relevant systematic reviews. The scoping review identified critical limitations of the current research in the field, including lack of impact monitoring and failure to sufficiently control for confounding variables such as concussion history and the effect of exercise. Findings reveal that the current evidence base is largely heterogeneous, limiting any firm conclusions at this stage. Despite limited and heterogeneous evidence, some markers appeared to show promise in detecting the effects of subconcussive head impacts. [ABSTRACT FROM AUTHOR]

Previously, we showed that Satureja Khuzestanica Jamzad essential oil (SKEO) and its major component, carvacrol (CAR), 5-isopropyl-2-methylphenol, has anti-inflammatory, anti-apoptotic, and anti-edematous properties after experimental traumatic brain injury (TBI) in rats. CAR, predominantly found in Lamiaceae family (Satureja and Oregano), is lipophilic, allowing diffusion across the blood–brain barrier (BBB). These experiments test the hypothesis that acute treatment with CAR after TBI can attenuate oxidative stress and BBB permeability associated with CAR's anti-edematous traits. Rats were divided into six groups and injured using Marmarou weight drop: Sham, TBI, TBI + Vehicle, TBI + CAR (100 and 200 mg/kg) and CAR200-naive treated rats. Intraperitoneal injection of vehicle or CAR was administered thirty minutes after TBI induction. 24 h post-injury, brain edema, BBB permeability, BBB-related protein levels, and oxidative capacity were measured. Data showed CAR 200 mg/kg treatment decreased brain edema and prevented BBB permeability. CAR200 decreased malondialdehyde (MDA) and reactive oxygen species (ROS) and increased superoxide dismutase (SOD) and total antioxidative capacity (T-AOC), indicating the mechanism of BBB protection is, in part, through antioxidant activity. Also, CAR 200 mg/kg treatment suppressed matrix metalloproteinase-9 (MMP-9) expression and increased ZO-1, occludin, and claudin-5 levels. These data indicate that CAR can promote antioxidant activity and decrease post-injury BBB permeability, further supporting CAR as a potential early therapeutic intervention that is inexpensive and more readily available worldwide. However, more experiments are required to determine CAR's long-term impact on TBI pathophysiology. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a multidimensional damage, and currently, no FDA-approved medicine is available. Multiple pathways in the cell are triggered through a head injury (e.g., calpain and caspase activation), which truncate tau and generate variable fragment sizes (MW 400–45,000 K). In this study, we used an open-head TBI mouse model generated by controlled cortical impact (CCI) and collected ipsilateral (IC) and contralateral (CC) mice htau brain cortices at one (D1) three (D3), and seven (D7) days post-injury. We implemented immunological (antibody-based detection) and peptidomic approaches (nano-reversed-phase liquid chromatography/tandem mass spectrometry) to investigate proteolytic tau peptidome (low molecular weight (LMW) < 10 K)) and pathological phosphorylation sites (high-molecular-weight (HMW); > 10 K) derived from CCI-TBI animal models. Our immunoblotting analysis verified tau hyperphosphorylation, HMW, and HMW breakdown products (HMW-BDP) formation of tau (e.g., pSer202, pThr181, pThr231, pSer396, and pSer404), following CCI-TBI. Peptidomic data revealed unique sequences of injury-dependent proteolytic peptides generated from human tau protein. Among the N-terminal tau peptides, EIPEGTTAEEAGIGDTPSLEDEAAGHVTQA (a.a. 96–125) and AQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARM (a.a. 91–127). Examples of tau C-terminal peptides identified include NVSSTGSIDMVDSPQLATLADEVSASLAKQGL (a.a. 410–441) and QLATLADEVSASLAKQGL (a.a. 424–441). Our peptidomic bioinformatic tools showed the association of proteases, such as CAPN1, CAPN2, and CTSL; CASP1, MMP7, and MMP9; and ELANE, GZMA, and MEP1A, in CCI-TBI tau peptidome. In clinical trials for novel TBI treatments, it might be useful to monitor a subset of tau peptidome as targets for biomarker utility and use them for a "theranostic" approach. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes progressive dysfunction that induces biochemical and metabolic changes that lead to cell death. Nevertheless, there is no definitive FDA-approved therapy for TBI treatment. Our previous immunohistochemical results indicated that the cost-effective natural Iranian medicine, Satureja khuzistanica Jamzad essential oil (SKEO), which consists of 94.16% carvacrol (CAR), has beneficial effects such as reducing neuronal death and inflammatory markers, as well as activating astrocytes and improving neurological outcomes. However, the molecular mechanisms of these neuroprotective effects have not yet been elucidated. This study investigated the possible mechanisms involved in the anti-inflammatory and anti-apoptotic properties of SKEO and CAR after TBI induction. Eighty-four male Wistar rats were randomly divided into six groups: Sham, TBI, TBI + Vehicle, TBI + CAR (100 and 200 mg/kg), and TBI + SKEO (200 mg/kg) groups. After establishing the "Marmarou" weight drop model, diffuse TBI was induced in the rat brain. Thirty minutes after TBI induction, SKEO & CAR were intraperitoneally injected. One day after TBI, injured rats exhibited significant brain edema, neurobehavioral dysfunctions, and neuronal apoptosis. Western blot results revealed upregulation of the levels of cleaved caspase-3, NFκB p65, and Bax/Bcl-2 ratio, which was attenuated by CAR and SKEO (200 mg/kg). Furthermore, the ELISA results showed that CAR treatment markedly prevents the overproduction of the brain pro-inflammatory cytokines, including IL-1β, TNF-α, and IL-6. Moreover, the neuron-specific enolase (NSE) immunohistochemistry results revealed the protective effect of CAR and SKEO on post-TBI neuronal death. The current study revealed that the possible neuroprotective mechanisms of SKEO and CAR might be related to (at least in part) modulating NF-κB regulated inflammation and caspase-3 protein expression. It also suggested that CAR exerts more potent protective effects than SKEO against TBI. Nevertheless, the administration of SKEO and CAR may express a novel therapeutic approach to ameliorate TBI-related secondary phase neuropathological outcomes. [ABSTRACT FROM AUTHOR]

Introduction: The power Doppler is a useful tool in the evaluation of pediatric acute scrotal pain. Nonetheless, it may have some inherent limitations in scrotal vascularization analysis, potentially causing unnecessary surgery. The microvascular imaging ultrasound (MicroV) is an innovative Doppler technique able to improve the detection of very low flow. This retrospective study aims to compare both power Doppler and MicroV in the evaluation of a pediatric population with early-stage scrotal pain onset, first in testis vascularization analysis, and second in their diagnostic performances. Materials and methods: 69 patients met the following inclusion criteria, age < 18-year-old, a clinical diagnosis of acute scrotal disease, pain onset ≤ 6 h, ultrasound examination (including B-mode, power Doppler, and MicroV), 3-months follow-up. For both power Doppler and MicroV, through a defined vascularization scale, it was evaluated the agreement in vascularization detection, and the sensitivity and specificity in US diagnostic abilities. Results: Retrospective diagnoses were of 8 testicular torsion, 15 orchi-epididymitis, and 46 children with other scrotal conditions. Power Doppler provided inconclusive US evaluation in 37.68% of the cases, while MicroV only in the 1.45% (p < 0.0001). Testicular torsion and orchi-epididymitis were identified, respectively, with MicroV in 100% (sensitivity, specificity, PPV, NPV, and accuracy of 100%) and 80% of patients (80% sensitivity, 100% specificity and PPV, 94.73% NPV, 95.65% accuracy); with power Doppler the identification was, respectively, of 87.5% (87.5% sensitivity, 100% specificity and PPV, 98.38% NPV and accuracy) and of 73.3% (73.33% sensitivity, 98.14% specificity, 91.66% PPV, 92.98% NPV, 92.75% accuracy). Conclusions: Our findings indicate that MicroV is a reliable technique in vascularization detection of pediatric testes, being able also to detect vascularization in healthy testicles with no-flow at power Doppler examination. Moreover, MicroV could be a valuable ally in the US diagnostic of children with early-stage scrotal pain onset. [ABSTRACT FROM AUTHOR]

The use of methamphetamine (METH) is a growing worldwide epidemic that bears grave societal implications. METH is known to exert its neurotoxic effects on the dopaminergic and serotonergic systems of the brain. In addition to this classical studied mechanism of damage, findings from our laboratory and others have shown that acute METH treatment and mechanical injury, i.e. traumatic brain injury (TBI), share common cell injury mechanism(s). Since neuro-inflammation is a signature event in TBI, we hypothesize that certain cytokine levels might also be altered in rat brain exposed to an acute METH insult. In this study, using a cytokine antibody array chip, we evaluated the serum levels of 19 cytokines in rats 24 h after exposure to a 40 mg/kg acute regimen of METH. Data were compared to rats subjected to experimental TBI using the controlled cortical impact (CCI) injury model and saline controls. Sandwich ELISA method was used to further validate some of the findings obtained from the antibody cytokine array. We confirmed that three major inflammatory-linked cytokines (IL-1β, IL-6, and IL-10) were elevated in the METH and TBI groups compared to the saline group. Such finding suggests the involvement of an inflammatory process in these brain insults, indicating that METH use is, in fact, a stressor to the immune system where systemic involvement of an altered cytokine profile may play a major role in mediating chemical brain injury after METH use. [ABSTRACT FROM AUTHOR]

Degradomics is a proteomics sub-discipline whose goal is to identify and characterize protease-substrate repertoires. With the aim of deciphering and characterizing key signature breakdown products, degradomics emerged to define encryptic biomarker neoproteins specific to certain disease processes. Remarkable improvements in structural and analytical experimental methodologies as evident in research investigating cellular behavior in neuroscience and cancer have allowed the identification of specific degradomes, increasing our knowledge about proteases and their regulators and substrates along with their implications in health and disease. A physiologic balance between protein synthesis and degradation is sought with the activation of proteolytic enzymes such as calpains, caspases, cathepsins, and matrix metalloproteinases. Proteolysis is essential for development, growth, and regeneration; however, inappropriate and uncontrolled activation of the proteolytic system renders the diseased tissue susceptible to further neurotoxic processes. In this article, we aim to review the protease-substrate repertoires as well as emerging therapeutic interventions in spinal cord injury at the degradomic level. Several protease substrates and their breakdown products, essential for the neuronal structural integrity and functional capacity, have been characterized in neurotrauma including cytoskeletal proteins, neuronal extracellular matrix glycoproteins, cell junction proteins, and ion channels. Therefore, targeting exaggerated protease activity provides a potentially effective therapeutic approach in the management of protease-mediated neurotoxicity in reducing the extent of damage secondary to spinal cord injury. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) and traumatic spinal cord injury (SCI), collectively termed neurotrauma, are two parallel neurological conditions that can cause long-lasting neurological impairment and other comorbidities in patients, while at the same time, can create a high burden to society. To date, there are still no FDA-approved therapeutic interventions for either TBI or SCI. Recent advances in proteomic technologies, including tandem mass spectrometry, as well as imaging mass spectrometry, have enabled new approaches to study the differential proteome in TBI and SCI with the use of either animal disease models and/or biosamples from clinical observational studies. Thus, the applications of state-of-the-art proteomic method hold promises in shedding light on identifying clinically useful neurotrauma 'biomarkers' and/or in identifying distinct and, otherwise, unobvious systems pathways or 'key drivers' that can be further exploited as new therapeutic intervention targets. [ABSTRACT FROM AUTHOR]

A major consequence of traumatic brain injury (TBI) is the rapid proteolytic degradation of structural cytoskeletal proteins. This process is largely reflected by the interruption of axonal transport as a result of extensive axonal injury leading to neuronal cell injury. Previous work from our group has described the extensive degradation of the axonally enriched cytoskeletal αII-spectrin protein which results in molecular signature breakdown products (BDPs) indicative of injury mechanisms and to specific protease activation both in vitro and in vivo. In the current study, we investigated the integrity of βII-spectrin protein and its proteolytic profile both in primary rat cerebrocortical cell culture under apoptotic, necrotic, and excitotoxic challenge and extended to in vivo rat model of experimental TBI (controlled cortical impact model). Interestingly, our results revealed that the intact 260-kDa βII-spectrin is degraded into major fragments (βII-spectrin breakdown products (βsBDPs)) of 110, 108, 85, and 80 kDa in rat brain (hippocampus and cortex) 48 h post-injury. These βsBDP profiles were further characterized and compared to an in vitro βII-spectrin fragmentation pattern of naive rat cortex lysate digested by calpain-2 and caspase-3. Results revealed that βII-spectrin was degraded into major fragments of 110/85 kDa by calpain-2 activation and 108/80 kDa by caspase-3 activation. These data strongly support the hypothesis that in vivo activation of multiple protease system induces structural protein proteolysis involving βII-spectrin proteolysis via a specific calpain and/or caspase-mediated pathway resulting in a signature, protease-specific βsBDPs that are dependent upon the type of neural injury mechanism. This work extends on previous published work that discusses the interplay spectrin family (αII-spectrin and βII-spectrin) and their susceptibility to protease proteolysis and their implication to neuronal cell death mechanisms. [ABSTRACT FROM AUTHOR]

Stroke is the second leading cause of death worldwide and a major cause of long-term severe disability representing a global health burden and one of the highly researched medical conditions. Nanostructured material synthesis and engineering have been recently developed and have been largely integrated into many fields including medicine. Recent studies have shown that nanoparticles might be a valuable tool in stroke. Different types, shapes, and sizes of nanoparticles have been used for molecular/biomarker profiling and imaging to help in early diagnosis and prevention of stroke and for drug/RNA delivery for improved treatment and neuroprotection. However, these promising applications have limitations, including cytotoxicity, which hindered their adoption into clinical use. Future research is warranted to fully develop and effectively and safely translate nanoparticles for stroke diagnosis and treatment into the clinic. This work will discuss the emerging role of nanotheragnostics in stroke diagnosis and treatment applications. [ABSTRACT FROM AUTHOR]

The role of amyloid-β (Aβ) neuropathology and its significant changes in biofluids after traumatic brain injury (TBI) is still debated. We used ultrasensitive digital ELISA approach to assess amyloid-β1-42 (Aβ42) concentrations and time-course in cerebrospinal fluid (CSF) and in plasma of patients with severe TBI and investigated their relationship to injury characteristics, neurological status and clinical outcome. We found decreased CSF Aβ42 levels in TBI patients acutely after injury with lower levels in patients who died 6 months post-injury than in survivors. Conversely, plasma Aβ42 levels were significantly increased in TBI with lower levels in patients who survived. A trend analysis showed that both CSF and plasma Aβ42 levels strongly correlated with mortality. A positive correlation between changes in CSF Aβ42 concentrations and neurological status as assessed by Glasgow Coma Scale (GCS) was identified. Our results suggest that determination of Aβ42 may be valuable to obtain prognostic information in patients with severe TBI as well as in monitoring the response of the brain to injury. [ABSTRACT FROM AUTHOR]

Stroke is the second leading cause of death worldwide and the third leading cause of death in the USA. A clinically useful biomarker for the diagnosis of stroke does not currently exist. Biomarkers could improve stroke care by allowing early diagnosis by non-expert clinical providers, serial monitoring of patients, and rapid assessment of severity of brain injury. With the introduction of highly advanced multidimensional separation techniques coupled with high throughput genomics/proteomics platforms, several components of the pathophysiological and biochemical pathways have been elucidated in the areas of brain trauma. A major outcome of these approaches is the discovery of biomarkers that would have important applications in diagnosis, prognosis, and even development of experimental neuroprotective drugs that have been used in different paradigms of brain injury. In this paper, we reviewed the recent advances of current and novel brain injury protein biomarkers and their utilities in different models of brain injury with an emphasis on stroke, an area that has been understudied. This will include the utility of neuroproteomics/neurosystems biology analysis as a novel discipline leading to the identification of novel biomarkers that can reach the pipeline of bench side. Additionally, an outline of biomarker-based management of traumatic brain injury and stroke patient assessments of therapeutic interventions has been included. Finally, comparison of current biomarker occurrence between preclinical models and biomarker data from human clinical studies for stroke has been summarized. [ABSTRACT FROM AUTHOR]

Abuse of the club drugs Methamphetamine (Meth) and Ecstasy (MDMA) is an international problem. The seriousness of this problem is the result of what appears to be programmed cell death (PCD) occurring within the brain following their use. This follow up study focused on determining which cell types, neurons and/or glial cells, were affected in the brains of drug-injected rats. Two proteolytic enzyme families involved in PCD, calpains and caspases, were previously shown to be activated and to degrade the brain cytoskeletal associated protein αII-spectrin. Using methods employed and confirmed in traumatic brain injury (TBI) studies, rat brain tissues were examined, 24 and 48 h after Meth and MDMA exposure, for the activation of calpain-1 and caspase-3, and their subsequent αII-spectrin cleavage breakdown products (SBDPs), SBDP145, and SBDP120, respectively. Based upon our previous studies we know that activated calpain-1 and caspase-3 were up-regulated after drug use as were the levels of their cleaved SBDPs, SBDP145, and SBDP120, respectively, which is indicative of PCD. Here we show that activated calpain-1 and caspase-3 increases could be localized to neurons in the cortex where the products of their cleaved targets were found to be concentrated, particularly, to the axonal regions. These findings support the hypothesis that calpains and caspases mediate PCD in cortical neurons following club drug abuse and, more importantly, appear to contribute to the neuropathology suffered by abusers. [ABSTRACT FROM AUTHOR]

The original version of this article unfortunately contained a typographical error on Author’s name “Firas Kobessiy”. This should be corrected as “Firas Kobeissy”. [ABSTRACT FROM AUTHOR]

The crucial biological role of proteases has been visible with the development of degradomics discipline involved in the determination of the proteases/substrates resulting in breakdown-products (BDPs) that can be utilized as putative biomarkers associated with different biological-clinical significance. In the field of cancer biology, matrix metalloproteinases (MMPs) have shown to result in MMPs-generated protein BDPs that are indicative of malignant growth in cancer, while in the field of neural injury, calpain-2 and caspase-3 proteases generate BDPs fragments that are indicative of different neural cell death mechanisms in different injury scenarios. Advanced proteomic techniques have shown a remarkable progress in identifying these BDPs experimentally. In this work, we present a bioinformatics-based prediction method that identifies protease-associated BDPs with high precision and efficiency. The method utilizes state-of-the-art sequence matching and alignment algorithms. It starts by locating consensus sequence occurrences and their variants in any set of protein substrates, generating all fragments resulting from cleavage. The complexity exists in space O(mn) as well as in O(Nmn) time, where N, m, and n are the number of protein sequences, length of the consensus sequence, and length per protein sequence, respectively. Finally, the proposed methodology is validated against βII-spectrin protein, a brain injury validated biomarker. [ABSTRACT FROM AUTHOR]

Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research. [ABSTRACT FROM AUTHOR]