Therapeutic potential of Bergenin in the management of neurological-based diseases and disorders.

Originally sourced from plants, Bergenin has been used as a medicinal compound in traditional medicine for centuries, and anecdotal reports suggest a wide range of therapeutic uses. Naturally-occurring and lab-synthesized Bergenin, as well as some of its related compounds, have been shown in in vivo and in vitro studies to alter activity of several enzymes and proteins critical in cellular functioning, including reelin, GSK-3ß, Lingo-1, Ten-4, GP-43, Aß 1-42, P-tau, SOD1,2, GPx, Glx1, NQO1, HO1, PPAR-É£, BDNF, VEGF, and STAT6. Additionally, Bergenin alters levels of several cytokines, such as IL-6, IL-1ß, TNF-α, and TGF-ß. Behavioral and cellular effects of Bergenin have been shown to involve PI3K/Akt, NF-κB, PKC, Nrf2, and Sirt1/FOXO3a pathways. These pathways, enzymes, and proteins have been shown to be important in normal neurological functioning, and/or dysfunctions in these pathways and proteins have been shown to be important in several neuro-based disorders or diseases, which suggests that Bergenin could be therapeutic in management of neuropsychiatric conditions or neurological disorders. In preclinical studies, Bergenin has been shown to be useful for the management of Alzheimer's disease, Parkinson's disease, anxiety, depression, addiction, epilepsy, insomnia, stroke, and potentially, state control. Our review aims to summarize current evidence supporting the conclusion that Bergenin could play a role in treating various neuro-based disorders and that future studies should be conducted to evaluate the mechanisms by which Bergenin could exert its therapeutic effects.

Unexplored power of CRISPR-Cas9 in neuroscience, a multi-OMICs review.

The neuroscience and neurobiology of gene editing to enhance learning and memory is of paramount interest to the scientific community. The advancements of CRISPR system have created avenues to treat neurological disorders by means of versatile modalities varying from expression to suppression of genes and proteins. Neurodegenerative disorders have also been attributed to non-canonical DNA secondary structures by affecting neuron activity through controlling gene expression, nucleosome shape, transcription, translation, replication, and recombination. Changing DNA regulatory elements which could contribute to the fate and function of neurons are thoroughly discussed in this review. This study presents the ability of CRISPR system to boost learning power and memory, treat or cure genetically-based neurological disorders, and alleviate psychiatric diseases by altering the activity and the irritability of the neurons at the synaptic cleft through DNA manipulation, and also, epigenetic modifications using Cas9. We explore and examine how each different OMIC techniques can come useful when altering DNA sequences. Such insight into the underlying relationship between OMICs and cellular behaviors leads us to better neurological and psychiatric therapeutics by intelligently designing and utilizing the CRISPR/Cas9 technology.

Deep brain stimulation (DBS) as a therapeutic approach in gait disorders: What does it bring to the table?

Gait deficits are found in various degenerative central nervous system conditions, and are particularly a hallmark of Parkinson's disease (PD). While there is no cure for such neurodegenerative disorders, Levodopa is considered as the standard medication in PD patients. Often times, the therapy of severe PD consists of deep brain stimulation (DBS) of the subthalamic nucleus. Earlier research exploring the effect of gait have reported contradictory results or insufficient efficacy. A change in gait includes various parameters, such as step length, cadence, Double-stance phase duration which may be positively affected by DBS. DBS could also be effective in correcting the levodopa-induced postural sway abnormalities. Moreover, during normal walking, interaction among the subthalamic nucleus and cortex -essential regions which exert a role in locomotion- are coupled. However, during the freezing of gait, the activity is desynchronized. The mechanisms underlying DBS-induced neurobehavioral improvements in such scenarios requires further study. The present review discusses DBS in the context of gait, the benefits associated with DBS compared to standard pharmacotherapy options, and provides insights into future research.

Aging, testosterone, and neuroplasticity: friend or foe?

Neuroplasticity or neural plasticity implicates the adaptive potential of the brain in response to extrinsic and intrinsic stimuli. The concept has been utilized in different contexts such as injury and neurological disease. Neuroplasticity mechanisms have been classified into neuroregenerative and function-restoring processes. In the context of injury, neuroplasticity has been defined in three post-injury epochs. Testosterone plays a key yet double-edged role in the regulation of several neuroplasticity alterations. Research has shown that testosterone levels are affected by numerous factors such as age, stress, surgical procedures on gonads, and pharmacological treatments. There is an ongoing debate for testosterone replacement therapy (TRT) in aging men; however, TRT is more useful in young individuals with testosterone deficit and more specific subgroups with cognitive dysfunction. Therefore, it is important to pay early attention to testosterone profile and precisely uncover its harms and benefits. In the present review, we discuss the influence of environmental factors, aging, and gender on testosterone-associated alterations in neuroplasticity, as well as the two-sided actions of testosterone in the nervous system. Finally, we provide practical insights for further study of pharmacological treatments for hormonal disorders focusing on restoring neuroplasticity.

Mechanisms of COVID-19-induced cerebellitis.

The COVID-19 pandemic caused by SARS-CoV2 has raised several important health concerns, not least increased mortality and morbidity. SARS-CoV2 can infect the central nervous system via hematogenous or transneuronal routes, acting through different receptors including ACE2, DPP4, and neuropilin 1 and cause several issues, including the focus here, cerebellitis. The cerebellum is an essential part of the CNS located adjacent to the brainstem with a complex micro and macroscopic structure. The cerebellum plays several physiological roles, such as coordination, cognition, and executive functioning. Damage to the cerebellum can lead to incoordination and ataxia. In our narrative review, we searched different databases from 2021 to 2022 with the keywords cerebellum and COVID-19; 247 studies were identified and reviewed, focusing on clinical studies and excluding non-clinical studies; 56 studies were finally included for analysis. SARS-CoV2 infection of the cerebellum can be seen to be assessed through many methods such as MRI, PET, CT, postmortem studies, and histological findings. These methodological studies have demonstrated that cerebellar infection with COVID-19 can bring about several sequelae: thrombosis, microbleed, hemorrhage, stroke, autoantibody production, ataxia, and widespread inflammation in the cerebellum. Such central effects are likely to exacerbate the known multiorgan effects of SARS-CoV2 and should also be considered as part of disease prognosis.

Engineering a novel immunogenic chimera protein utilizing bacterial infections associated with atherosclerosis to induce a deviation in adaptive immune responses via Immunoinformatics approaches.

Recent studies have established the role of bacteria including Streptococcus pneumoniae, Helicobacter pylori, Chlamydia pneumonia, Mycobacterium tuberculosis, and Porphyromonas gingivalis in the development of atherosclerosis. These bacteria contribute to plaque formation via promoting Th1 immune responses and speeding up ox-LDL formation. Hence, we employed computational reverse vaccinology (RV) approaches to deviate immune response toward Th2 via engineering a novel immunogenic chimera protein. Prominent atherogenic antigens from related bacteria were identified. Then, machine learning-based servers were employed for predicting CTL and HTL epitopes. We selected epitopes from a wide variety of HLAs. Then, a chimeric protein sequence containing TAT peptide, adjuvant, IL-10 inducer, and linker-separated epitopes was designed. The conformational structure of the vaccine was built via multiple-template homology modelling using MODELLER. The initial structure was refined and validated by Ramachandran plot. The vaccine was also docked with TLR4. After that, molecular dynamics (MD) simulation of the docked vaccine-TLR4 was conducted. Finally, the immune simulation of the vaccine was conducted via the C-ImmSim server. A chimera protein with 629 amino acids was built and, classified as a non-allergenic probable antigen. An improved ERRAT score of 80.95 for the refined structure verified its stability. Additionally, validation via the Ramachandran plot showed 98.09% of the residues were located in the most favorable and permitted regions. MD simulations showed the vaccine-TLR4 complex reached a stable conformation. Also, RMS fluctuations analysis revealed no sign of protein denaturation or unfolding. Finally, immune response simulations indicated a promising response by innate and adaptive immunity. In summary, we built an immunogenic vaccine against atherosclerosis and demonstrated its favorable properties via advanced Immunoinformatics analyses. This study may pave the path for combat against atherosclerosis.

Triangle of cytokine storm, central nervous system involvement, and viral infection in COVID-19: the role of sFasL and neuropilin-1.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is identified as the cause of coronavirus disease 2019 (COVID-19), and is often linked to extreme inflammatory responses by over activation of neutrophil extracellular traps (NETs), cytokine storm, and sepsis. These are robust causes for multi-organ damage. In particular, potential routes of SARS-CoV2 entry, such as angiotensin-converting enzyme 2 (ACE2), have been linked to central nervous system (CNS) involvement. CNS has been recognized as one of the most susceptible compartments to cytokine storm, which can be affected by neuropilin-1 (NRP-1). ACE2 is widely-recognized as a SARS-CoV2 entry pathway; However, NRP-1 has been recently introduced as a novel path of viral entry. Apoptosis of cells invaded by this virus involves Fas receptor-Fas ligand (FasL) signaling; moreover, Fas receptor may function as a controller of inflammation. Furthermore, NRP-1 may influence FasL and modulate cytokine profile. The neuroimmunological insult by SARS-CoV2 infection may be inhibited by therapeutic approaches targeting soluble Fas ligand (sFasL), cytokine storm elements, or related viral entry pathways. In the current review, we explain pivotal players behind the activation of cytokine storm that are associated with vast CNS injury. We also hypothesize that sFasL may affect neuroinflammatory processes and trigger the cytokine storm in COVID-19.

Early environmental enrichment prevents cognitive impairments and developing addictive behaviours in a mouse model of prenatal psychological and physical stress.

Environmental enrichment (EE) has shown remarkable effects in improving cognition and addictive behaviour. We tested whether EE could help recover from prenatal stress exposure. Mature Swiss Webster male and virgin female mice were placed together until vaginal plugs were detectable. Next, pregnant rodents were randomized into the control, physically and psychologically stressed groups. The application of stress was initiated on the 10th day of pregnancy and persisted for a week to induce stress in the mice. Open field and elevated plus-maze (EPM) tests were utilized as explorative and anxiety assays, respectively. A passive avoidance shuttle-box test was carried out to check anxiety-modulated behaviour. Morris water maze (MWM) test was undertaken to evaluate spatial learning and memory. Conditioned place preference (CPP) test was selected for evaluation of tendency to morphine consumption. Our results showed that prenatal stress elevated anxiety-like behaviour in the offspring which EE could significantly alleviate after weaning. We also found a higher preference for morphine use in the physical stress and psychological stress offspring group. However, no difference was observed among the genders. Application of EE for the stress group improved several parameters of the cognitive behaviour significantly. Although prenatal stress can lead to detrimental behavioural and cognitive outcomes, it can in part be relieved by early exposure to EE. However, some outcomes linked to prenatal stress exposure may not be diminished by EE therapy. In light of such irreversible effects, large-scale preventive actions promoting avoidance from stress during pregnancy should be advised.

Evaluating the effect of black myrobalan on cognitive, positive, and negative symptoms in patients with chronic schizophrenia: A randomized, double-blind, placebo-controlled trial.

Schizophrenia, as a chronic and disabling mental disorder, causes a wide range of symptoms, including cognitive impairments, positive, negative, and mood symptoms. There are no effective treatments for cognitive symptoms. Black myrobalan (Terminalia chebula Retz.), a medicinal plant of the Combretaceae family, exerts antioxidant, antiacetylcholinesterase, and anti-inflammatory effects. These effects can lessen the symptoms of schizophrenia. So, this study was conducted to evaluate black myrobalan's impact on cognitive impairments and negative/positive symptoms in patients with chronic schizophrenia. This was a randomized, double-blind, placebo-controlled clinical trial in which participants were divided into treatment and placebo groups. They received six 500 mg capsules of black myrobalan or placebo in two divided doses for 4 weeks. Patients' cognitive impairments, positive, negative, depression/anxiety, and excitement/activity symptoms were assessed using the Screen for Cognitive Impairments in Psychiatry (SCIP) and the relevant subscales of the Positive and Negative Syndrome Scale (PANSS) pretreatment and 4 weeks after treatment. Cognitive impairments (SCIP) (p value .004), negative symptoms (PANSS subscale) (p value .017), and excitement/activity (PANSS subscale) (p value .003) were significantly improved in the black myrobalan group compared with the control group after 4 weeks. No serious adverse effects were reported. Black myrobalan could improve cognitive impairments, negative and excitement/activity symptoms in chronic schizophrenic patients.

Addiction and the cerebellum with a focus on actions of opioid receptors.

Increasing evidence suggests that the cerebellum could play a role in the higher cognitive processes involved in addiction as the cerebellum contains anatomical and functional pathways to circuitry controlling motivation and saliency. In addition, the cerebellum exhibits a widespread presence of receptors, including opioid receptors which are known to play a prominent role in synaptic and circuit mechanisms of plasticity associated with drug use and development of addiction to opioids and other drugs of abuse. Further, the presence of perineural nets (PNNs) in the cerebellum which contain proteins known to alter synaptic plasticity could contribute to addiction. The role the cerebellum plays in processes of addiction is likely complex, and could depend on the particular drug of abuse, the pattern of use, and the stage of the user within the addiction cycle. In this review, we discuss functional and structural modifications shown to be produced in the cerebellum by opioids that exhibit dependency-inducing properties which provide support for the conclusion that the cerebellum plays a role in addiction.

Interferon therapy in patients with SARS, MERS, and COVID-19: A systematic review and meta-analysis of clinical studies.

Concern regarding coronavirus (CoV) outbreaks has stayed relevant to global health in the last decades. Emerging COVID-19 infection, caused by the novel SARS-CoV2, is now a pandemic, bringing a substantial burden to human health. Interferon (IFN), combined with other antivirals and various treatments, has been used to treat and prevent MERS-CoV, SARS-CoV, and SARS-CoV2 infections. We aimed to assess the clinical efficacy of IFN-based treatments and combinational therapy with antivirals, corticosteroids, traditional medicine, and other treatments. Major healthcare databases and grey literature were investigated. A three-stage screening was utilized, and included studies were checked against the protocol eligibility criteria. Risk of bias assessment and data extraction were performed, followed by narrative data synthesis. Fifty-five distinct studies of SARS-CoV2, MERS-CoV, and SARS-CoV were spotted. Our narrative synthesis showed a possible benefit in the use of IFN. A good quality cohort showed lower CRP levels in Arbidol (ARB) + IFN group vs. IFN only group. Another study reported a significantly shorter chest X-ray (CXR) resolution in IFN-Alfacon-1 + corticosteroid group compared with the corticosteroid only group in SARS-CoV patients. In a COVID-19 trial, total adverse drug events (ADEs) were much lower in the Favipiravir (FPV) + IFN-α group compared with the LPV/RTV arm (P = 0.001). Also, nausea in patients receiving FPV + IFN-α regimen was significantly lower (P = 0.03). Quantitative analysis of mortality did not show a conclusive effect for IFN/RBV treatment in six moderately heterogeneous MERS-CoV studies (log OR = -0.05, 95% CI: (-0.71,0.62), I2 = 44.71%). A meta-analysis of three COVID-19 studies did not show a conclusive nor meaningful relation between receiving IFN and COVID-19 severity (log OR = -0.44, 95% CI: (-1.13,0.25), I2 = 31.42%). A lack of high-quality cohorts and controlled trials was observed. Evidence suggests the potential efficacy of several combination IFN therapies such as lower ADEs, quicker resolution of CXR, or a decrease in inflammatory cytokines; Still, these options must possibly be further explored before being recommended in public guidelines. For all major CoVs, our results may indicate a lack of a definitive effect of IFN treatment on mortality. We recommend such therapeutics be administered with extreme caution until further investigation uncovers high-quality evidence in favor of IFN or combination therapy with IFN.

The involvement of the central nervous system in patients with COVID-19.

Coronaviruses disease (COVID-19) has caused major outbreaks. A novel variant, SARS-CoV-2, is responsible for COVID-19 pandemic. Clinical presentations and pathological mechanisms of COVID-19 are broad. The respiratory aspect of the disease has been extensively researched. Emerging studies point out the possibility of the central nervous system (CNS) involvement by COVID-19. Here, we discuss the current evidence for CNS involvement in COVID-19 and highlight that the high pathogenicity of SARS-CoV-2 might be due to its neuroinvasive potential.

The Relationship between Extrinsic and Intrinsic Religious Orientation with Perceived Stress and Cigarette Addiction among University Students.

BACKGROUND: Psychological stress is associated with unhealthy lifestyles, including smoking. Moreover, religious beliefs can play a significant role in relieving mental disorders such as anxiety and stress. Due to the frequent exposure of medical students to stressful situations, this study was conducted with the aim to investigate the relationship of internal and external religious orientation with perceived stress and nicotine dependence. METHODS: This correlational study was carried out on medical students of Kerman University of Medical Sciences, Kerman, Iran, in 2015. The sample size was determined to be 224 individuals using the Morgan table. The participants were selected using stratified random ýsampling. The data collection tools consisted of a demographic information form, the Religious Orientation Scale (ROS) (Allport and Ross), the Perceived Stress Scale (PSS-14), and the Fagerstrom Test for Nicotine Dependence (FTND). Data were analyzed using multiple regression analysis, analysis of variance (ANOVA), Pearson correlation coefficient, and t-test in SPSS software. FINDINGS: The findings of the study showed that internal religious orientation had a significant negative relationship with perceived stress and nicotine dependence; however, no significant relationship was observed between external religious orientation and these variables. CONCLUSION: Based on the results of the study, it can be concluded that the religious beliefs of individuals have a preventive role in perceived stress and nicotine dependence.

Successful management of acute necrotizing mediastinitis with trans-cervical drainage.

Acute necrotizing mediastinitis (ANM) is a lethal disease which without antibiotic therapy and surgical intervention can lead to about 40% mortality. With the development of imaging technology, spiral computed tomography (CT) scanning and shortening of the time of diagnosis and surgery, the prognosis of these patients is excellently improved. This study describes the clinical presentation, management and outcome of 4 patients (mean age: 35 years) with ANM. All patients were operated on by a trans-cervical approach, and only one patient was operated on by a trans-thoracic one. After surgery, patients were transferred to the intensive care unit and underwent daily washing and debridement with antibiotic treatments. Odontogenic infection (2 cases), pharyngeal perforation and cervical esophageal perforation were the causes of the ANM. Infection of cervical space (perivisceral spaces) and superior Mediastinum were found in all patients, and Infection below the carina was found in two. All patients were discharged with a good, general condition after an average of 24 days. Early diagnosis of ANM with clinical presentation and on-time CT scanning, early drainage and careful post operation care are very important in the management of patients with ANM and can improve the outcome of trans-cervical drainage to an acceptable technique.

Huge myxoid liposarcoma of the esophagus: a case report.

Although esophageal liposarcoma is an extremely rare tumor, liposarcoma is the most common soft tissue sarcoma in adults. Liposarcoma is currently classified into the types of well-differentiated, myxoid, round cell, pleomorphic and dedifferentiated liposarcoma. Up to now only a few cases of esophagus liposarcoma have been described in the world literature. We describe a myxoid type liposarcoma of the esophagus in a 68 year old man presented with hoarseness and intermittent dysphagea to solid food. He had a huge mass in his mouth which was mobile with gag reflex. A barium swallow, esophageal manometery and CT scan of the esophagus have not clearly revealed the mass. After endoscopic surgical resection of the tumor the histological examination revealed a myxoid liposarcoma. Both the presenting signs and symptoms and the histology type are rare for such tumor. This case demonstrate a rare differential diagnosis of intermittent dysphagia as early diagnosis is so important in those tumors and should kept in mind them, although they are quite rare.