A comprehensive insight into potential roles of Nigella sativa on diseases by targeting AMP-activated protein kinase: a review

ObjectivesNigella sativa (NS) is a known medicinal herb with numerous therapeutic effects such as antidiabetic, anti-proliferative, anti-inflammatory, and anti-cancer activities. It has been indicated that NS can regulate cellular metabolism by adjusting transduction signaling pathways. Adenosine monophosphate-activated protein kinase (AMPK) is one of the main physiological processes, such as energy hemostasis, cellular metabolism, and autophagy regulators. Herb-derived medicines have always been considered as one of the main AMPK activators, and surprisingly recent data has demonstrated that it can be a target for NS and its derivatives.Evidence acquisitionThe literature search was conducted in PubMed, SCOPUS, Embase, ProQuest, and Google Scholar electronic resources. Published articles up to September 2020 were considered, and those of which investigated Nigella sativa effects on the AMPK pathway after meeting the inclusion criteria were included.ResultsThe search was performed on several online databases such as PubMed, Scopus, Embase, ProQuest, and Google Scholar from inception until January 2020. Among the initial search, 245 studies were found. After removing duplicated data and meeting the inclusion criteria, only 14 studies were selected. They included the effects of NS and its bioactive compounds as anti-hyperglycemic (n = 5), on liver function (n = 4), cancers (n = 3), and on Neuroinflammation and Atherosclerosis (n = 2). Most of the included studies are animals or in-vitro investigations.ConclusionIn this review, we discuss the latest findings on the molecular mechanism of NS effecting the AMPK signaling pathway. We also focus on the therapeutic effects of NS, including the prevention and treatment of metabolic and pro-inflammatory disease by targeting the AMPK pathway.Graphical abstract     

Investigating the temporal dynamics of electroencephalogram (EEG) microstates using recurrent neural networks

Electroencephalogram (EEG) microstates that represent quasi‐stable, global neuronal activity are considered as the building blocks of brain dynamics. Therefore, the analysis of microstate sequences is a promising approach to understand fast brain dynamics that underlie various mental processes. Recent studies suggest that EEG microstate sequences are non‐Markovian and nonstationary, highlighting the importance of the sequential flow of information between different brain states. These findings inspired us to model these sequences using Recurrent Neural Networks (RNNs) consisting of long‐short‐term‐memory (LSTM) units to capture the complex temporal dependencies. Using an LSTM‐based auto encoder framework and different encoding schemes, we modeled the microstate sequences at multiple time scales (200–2,000 ms) aiming to capture stably recurring microstate patterns within and across subjects. We show that RNNs can learn underlying microstate patterns with high accuracy and that the microstate trajectories are subject invariant at shorter time scales (≤400 ms) and reproducible across sessions. Significant drop in the reconstruction accuracy was observed for longer sequence lengths of 2,000 ms. These findings indirectly corroborate earlier studies which indicated that EEG microstate sequences exhibit long‐range dependencies with finite memory content. Furthermore, we find that the latent representations learned by the RNNs are sensitive to external stimulation such as stress while the conventional univariate microstate measures (e.g., occurrence, mean duration, etc.) fail to capture such changes in brain dynamics. While RNNs cannot be configured to identify the specific discriminating patterns, they have the potential for learning the underlying temporal dynamics and are sensitive to sequence aberrations characterized by changes in metal processes. Empowered with the macroscopic understanding of the temporal dynamics that extends beyond short‐term interactions, RNNs offer a reliable alternative for exploring system level brain dynamics using EEG microstate sequences.     

O6-Methyguanine-DNA Methyl Transferase (MGMT) Promoter Methylation in Serum DNA of Iranian Patients with Colorectal Cancer

Introduction: Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide but current molecular targetedtherapy is not providing major success in CRC treatment, so early detection by non-invasive methods continues tobe vital. Aberrant methylation of CpG islands in promoter regions is associated with inactivation of various tumorsuppressor genes. O6-methyguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes mutagenicand cytotoxic adducts from O6-guanine in DNA. Aberrant hypermethylation of the MGMT promoter has beenassociated with lack of mRNA expression, with concomitant loss of protein content and enzyme activity. AIM: Ouraim was to determine whether MGMT promoter methylation might be detectable in circulating free DNA in the serumof CRC patients and normal individuals using a methylation specific (MSP) polymerase chain reaction (PCR) method.Methods: A total of 70 subjects were enrolled in the study. Of these, 30 patients who were diagnosed previously asuntreated colon adenocarcinoma by a gastroenterologist and the other 40 were nearly age-matched individuals who hada normal colonoscopic evaluation (except for hemorrhoids or fissures) and normal pathologic reports. After bisulphitemodification of DNA, serum samples were examined for MGMT promoter methylation using MSP. Results: Ninetypercent of CRC patients had MGMT promoter hypermethylation as compared to no methylation in normal subjects’serum. Most of the cancers were stage П and moderately differentiated adenocarcinomas; nearly 60% were found inthe left colon. No statistically significant correlation was found between the promoter methylation status and genderand age. Discussion and Conclusions: MGMT hypermethylation can be detected in free circulating DNA in serum ofCRC patients and can be used “as a clinical biomarker” for early diagnosis and prognostic assessment of the disease.Our data confirm previous studies indicating utility for free circulating DNA as a serum biomarker for early detection,diagnosis and monitoring of CRC patients.     

Pathogenic Acanthamoeba spp secrete a mannose-induced cytolytic protein that correlates with the ability to cause disease

The pathogenesis of Acanthamoeba keratitis begins when Acanthamoeba trophozoites bind specifically to mannosylated glycoproteins upregulated on the surfaces of traumatized corneal epithelial cells. When Acanthamoeba castellanii trophozoites are grown in methyl-alpha-D-mannopyranoside, they are induced to secrete a novel 133-kDa protein that is cytolytic to corneal epithelial cells. Clinical isolates of Acanthamoeba spp., and not the soil isolates, were proficient at producing a mannose-induced protein (MIP-133) and generating disease in Chinese hamsters. The purified protein was efficient at killing corneal epithelial cells, the first mechanistic barrier, by inducing apoptosis in a caspase 3-dependent pathway. Subsequent steps in pathogenesis require the amoebae to penetrate and degrade collagen. Only the clinical isolates tested were efficient at migrating through a collagenous matrix in vitro, presumably by MIP-133 degradation of both human type I and human type IV collagen. A chicken anti-MIP-133 antiserum effectively bound to the protein and blocked collagenolytic activity, migration, and cytopathic effects (CPE) against corneal cells in vitro. Chinese hamsters orally immunized with MIP-133 displayed a >30% reduction in disease. Immunoglobulin A isolated from immunized animals bound MIP-133 and blocked CPE on corneal cells in vitro. Animals induced to generate severe chronic infections displayed significant reductions in disease symptoms upon oral immunization postinfection. These data suggest that MIP-133 production might be necessary to initiate corneal disease and that it may play an important role in the subsequent steps of the pathogenic cascade of Acanthamoeba keratitis. Furthermore, as antibodies produced both prior to and after infection reduced clinical symptoms of disease, the protein may represent an important immunotherapeutic target for Acanthamoeba keratitis.     

Suppressive properties of human CD4+CD25+ regulatory T cells are dependent on CTLA-4 expression

It has been demonstrated that T cells with regulatory properties are present within the peripheral blood CD4(+)CD25(+) T cell compartment. Here, we describe an original method to purify human CD4(+)CD25(+)CD152(+) T lymphocytes as living cells by forcing the exportation of CTLA-4 molecules stored in intracellular vesicules at the cell surface. By doing so, we demonstrate that CD4(+)CD25(+) T cells contain a smaller and more homogeneous population enriched in cells with in vitro regulatory activity. Moreover, we show that this enrichment in regulatory T cells is associated with an increased expression of Foxp3 and that CD4(+)CD25(+)CD152(+) T lymphocytes display a much stronger suppressive activity in controlling in vitro proliferation of alloantigen-specific T cells than CD4(+)CD25(+)CD152(-) T lymphocytes purified in parallel. Lastly, by purifying such cells expressing CTLA-4, we demonstrate that indeed CTLA-4 is involved in CD4(+)CD25(+)CD152(+) T cell regulatory activity, while suppressive cytokines are not.     

Online Spectroscopic Monitoring of Drug Release Kinetics from Nanostructured Dual-Stimuli-Responsive Conducting Polymer

Purpose

The potential of electrochemical/temperature dual stimuli-responsive conducting polymer to be used as general drug delivery systems. It allows on-demand release of incorporated drug is kinetically investigated in real time.

Methods

Online spectroscopic monitoring was used to investigate the electrochemically/thermally controlled release behavior of a model drug (naproxen) from drug-doped polypyrrole (DDPPy) film. Avrami’s equation has been used to study the kinetics and further analyzing has been carried out using the Arrhenius and the Eyring equations. Furthermore, drug release behavior, with two other electrochemical techniques was investigated.

Results

It was observed both temperature and electrical stimuli increase the rate of release while electrical potential has a greater effect as revealed in the values of release rate constant (from 0.0068 to 0.018 min^?1 at 37°C). It was also shown that a linear relationship exists between the applied electrical potentials and release activation parameters.

Conclusion

The electronic properties of the conducting polymer has an important role in release kinetics, there might be a single mechanism with the same limiting step. In addition, it was demonstrated the rate of drug release from DDPPy dramatically depends on the amounts as well as modes of applying potential which provides enhanced control of drug-release kinetics which can be accelerated or even sustained.

     

Repeated administration of nicotine attenuates the development of morphine tolerance and dependence in mice

Clinical use of morphine in pain management is a controversial issue. Both nicotine and morphine are widely abused. So, investigating the interaction between nicotinic and opioid receptors is of great interest to both basic mechanistic and clinical view. We investigated the influence of repeated administration of nicotine on the development of morphine tolerance and dependence. Adult male albino mice were rendered dependent on morphine by subcutaneous (s.c.) injections three times daily for 3 days. Repeated intraperitoneal (i.p.) injection of nicotine (0.001-2 mg/kg) or saline (1 ml/kg) was performed 15 min prior to each morphine injection. Maximal possible effect (MPE%) of morphine (50 mg/kg; s.c.) was used on the fourth day as an index for the development of tolerance. Likewise, to assess the occurrence of dependence in drug-treated mice, naloxone (5 mg/kg; i.p.) was injected 2 h after the last dose of morphine. Repeated nicotine administration significantly attenuated the development of tolerance in a dose-dependent manner whereas it significantly decreased withdrawal jumping behavior in a biphasic profile (V-shape) manner. Furthermore, the central nicotinic receptor antagonist mecamylamine (0.01-0.1 mg/kg; i.p.) neither the peripheral nicotinic receptor antagonist hexamethonium (0.01 and 0.1 mg/kg; i.p.) nor the muscarinic receptor antagonist atropine (2.5-10 mg/kg; i.p.), dose-dependently antagonized both the inhibition of withdrawal jumping as well as increase in MPE% which was produced by repeated nicotine administration (0.1 mg/kg; i.p.). On the other hand, 3 days of solely nicotine treatment resulted in significant jumping behavior precipitated by naloxone after single morphine injection on the test day. The data suggests that the inhibitory effect of nicotine on the morphine tolerance and dependence is mediated by central nicotinic receptors and there is a cross-dependence between nicotine and morphine.     

Cultural competence dimensions and outcomes: a systematic review of the literature

It has been widely suggested that cultural competence is an individual's core requirement for working effectively with culturally diverse people. However, there is no consensus regarding the definition or the components of this concept and there is a dearth of empirical proof indicating the benefits of cultural competence. Therefore, a systematic review was conducted to identify the most common cultural competence dimensions proposed in recent publications and to identify whether sufficient evidence exists regarding the efficacy of cultural competence in the healthcare context. A total of 1204 citations were identified through an electronic search of databases, of which 18 publications included cultural competence frameworks, and 13 studies contained empirical data on cultural competence outcomes. The overarching themes of the review were centred around the challenges faced by the healthcare sector in many countries due to growing cultural diversity, but lack of cultural competence, leading to predicaments that arise during intercultural interactions between patients and clinicians. This review will benefit researchers exploring cultural competence as one of the research variables impacting research outcomes.     

CAR T cells for brain tumors: Lessons learned and road ahead

Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.