Brain-Derived Neurotrophic Factor - The Protective Agent Against Neurological Disorders.

The burden of neurological illnesses on global health is significant. Our perception of the molecular and biological mechanisms underlying intellectual processing and behavior has significantly advanced over the last few decades, laying the groundwork for potential therapies for various neurodegenerative diseases. A growing body of literature reveals that most neurodegenerative diseases could be due to the gradual failure of neurons in the brain's neocortex, hippocampus, and various subcortical areas. Research on various experimental models has uncovered several gene components to understand the pathogenesis of neurodegenerative disorders. One among them is the brain-derived neurotrophic factor (BDNF), which performs several vital functions, enhancing synaptic plasticity and assisting in the emergence of long-term thoughts. The pathophysiology of some neurodegenerative diseases, including Alzheimer's, Parkinson's, Schizophrenia, and Huntington's, has been linked to BDNF. According to numerous research, high levels of BDNF are connected to a lower risk of developing a neurodegenerative disease. As a result, we want to concentrate on BDNF in this article and outline its protective role against neurological disorders.

Aqueous Nyctanthes arbortristis and doxorubicin conjugated gold nanoparticles synergistically induced mTOR-dependent autophagy-mediated ferritinophagy in paclitaxel-resistant breast cancer stem cells.

Aim: Nyctanthes arbortristis Linn is a potential anti-diabetic drug that reduces glucose levels by delaying carbohydrate digestion. The tumor microenvironment is characterized by elevated glucose levels that activate various genes, such as mTOR. mTOR plays a critical role in maintaining the hypoxic environment and inhibiting autophagy. Although natural compounds pose fewer side effects, their hydrophobic nature makes these compounds not suitable as therapeutics. Hence, we conjugated aqueous NAT into gold nanoparticles (AuNP) in the current study and evaluated the ability of the chosen drugs to induce cell death in breast cancer cells resistant to Paclitaxel. Materials and methods: Particle size analyzer, UV-Vis spectrophotometer, FTIR, and XRD were used in the present study to characterize NAT and Doxorubicin encapsulated AuNPs. To check the cytotoxic effect of AuNP-NAT and AuNP-doxorubicin on PacR/MCF-7 stem cells MTT assay was performed. RT-PCR was performed to check the altered expression of ferritinophagy-related genes. The proliferation and migration potential of the cells before and after treatment with the desired drug combinations was evaluated by clonogenic and scratch assays, respectively. Flow cytometry analysis was done to quantify apoptotic bodies and cell cycle arrest. Cellular ROS was determined using DCD-FA staining. Results and conclusion: NAT and doxorubicin loaded into AuNP showed enhanced stability and induced ferritinophagy in PacR/MCF-7 stem cells. The obtained results suggest that AuNP-NAT, combined with a low AuNP-Doxorubicin nanoconjugate dose, might be an effective anti-neoplastic drug targeting the necroptosis-autophagy axis, thereby reducing the adverse side-effects induced by the conventional chemotherapeutic drugs.

Polyherbal formulation conjugated to gold nanoparticles induced ferroptosis in drug-resistant breast cancer stem cells through ferritin degradation.

Aim: Due to their minimal side effects, the anti-cancer properties of the polyherbal formulation are being investigated. However, due to their low absorption potential, the administration of polyherbal formulations is restricted. Loading the polyherbal formulation into gold nanoparticles enhances the bioavailability of the polyherbal formulation (PHF) accompanied by reducing the concentration of doxorubicin (dox). Ferroptosis is one of the novel pathways that specifically target cancer stem cells due to high ferritin levels. Hence, in the present study, we conjugated polyherbal formulation with gold nanoparticles and studied its effect on inducing ferroptosis in drug-resistant breast cancer cell lines. Materials and methods: PHF and dox conjugated to gold nanoparticles were characterized using FTIR, UV-Vis spectrophotometer, DLS, particle size analyzer, and XRD. The drug entrapment and efficiency studies were performed to assess the biodegradable potential of the synthesized gold nanoparticles. Paclitaxel-resistant breast cancer stem cells were generated, and an MTT assay was performed to evaluate the cytotoxicity potential of AuNP-PHF and AuNP-dox. Scratch assay and clonogenic assay were performed to assess the migration and proliferation of the cells after treatment with chosen drug combinations. The ability of PHF and dox conjugated to gold nanoparticles to induce ferritinophagy was evaluated by RT-PCR. Finally, image analysis was performed to check apoptosis and cellular ROS using inverted fluorescent microscope. The ability to induce cell cycle arrest was assessed by cell cycle analysis using flow cytometer. Results and conclusion: PHF and dox conjugated to gold nanoparticles showed high stability and showed to induce ferritin degradation in drug resistant breast cancer stem cells through ferritin degradation. AuNP-PHF in combination with low dose of AuNP-Dox nanoconjugate could be used as an effective cancer therapeutic agent, by targeting the autophagy necroptosis axis.

Clinically Deployable Bioelectronic Sensing Platform for Ultrasensitive Detection of Transferrin in Serum Sample.

Varying levels of transferrin (Tf) have been associated with different disease conditions and are known to play a crucial role in various malignancies. Regular monitoring of the variations in Tf levels can be useful for managing related diseases, especially for the prognosis of certain cancers. We fabricated an immunosensor based on graphene oxide (GO) nanosheets to indirectly detect Tf levels in cancer patients. The GO nanosheets were deposited onto an indium tin oxide (ITO)-coated glass substrate and annealed at 120 °C to obtain reduced GO (rGO) films, followed by the immobilization of an antibody, anti-Tf. The materials and sensor probe used were systematically characterized by UV-Visible spectroscopy (UV-Vis), X-ray diffraction (XRD), atomic force microscopy (AFM), and Fourier transform infrared spectroscopy (FTIR). Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and differential pulse voltammetry (DPV) were also used for the stepwise sensor probe characterizations and Tf detection in serum samples, respectively. The anti-Tf/rGO/ITO immunosensor DPV output demonstrated an excellent Tf detection capability in the linear range of 0.1 mg mL-1 to 12 mg mL-1 compared to the enzyme-linked immunosorbent assay (ELISA) detection range, with a limit of detection (LOD) of 0.010 ± 0.007 mg mL-1. Furthermore, the results of the fabricated immunosensor were compared with those of the ELISA and autobioanalyzer techniques, showing an outstanding match with < 5% error and demonstrating the immunosensor's clinical potential.

A Review on Psychrophilic ß-D-Galactosidases and Their Potential Applications.

The majority of the Earth's ecosystem is frigid and frozen, which permits a vast range of microbial life forms to thrive by triggering physiological responses that allow them to survive in cold and frozen settings. The apparent biotechnology value of these cold-adapted enzymes has been targeted. Enzymes' market size was around USD 6.3 billion in 2017 and will witness growth at around 6.8% CAGR up to 2024 owing to shifting consumer preferences towards packaged and processed foods due to the rising awareness pertaining to food safety and security reported by Global Market Insights (Report ID-GMI 743). Various firms are looking for innovative psychrophilic enzymes in order to construct more effective biochemical pathways with shorter reaction times, use less energy, and are ecologically acceptable. D-Galactosidase catalyzes the hydrolysis of the glycosidic oxygen link between the terminal non-reducing D-galactoside unit and the glycoside molecule. At refrigerated temperature, the stable structure of psychrophile enzymes adjusts for the reduced kinetic energy. It may be beneficial in a wide variety of activities such as pasteurization of food, conversion of biomass, biological role of biomolecules, ambient biosensors, and phytoremediation. Recently, psychrophile enzymes are also used in claning the contact lens. ß-D-Galactosidases have been identified and extracted from yeasts, fungi, bacteria, and plants. Conventional (hydrolyzing activity) and nonconventional (non-hydrolytic activity) applications are available for these enzymes due to its transgalactosylation activity which produce high value-added oligosaccharides. This review content will offer new perspectives on cold-active ß-galactosidases, their source, structure, stability, and application.

Cell-cell communications: new insights into targeting efficacy of phytochemical adjuvants on tight junctions and pathophysiology of various malignancies.

Cancer is a cellular impairment disorder characterized by the loss of cell cycle regulation leading to aberrant cell proliferation. Cell-cell communication plays a crucial role in cell signaling which is highly disrupted in various malignancies. Tight junctions (TJs) are major proteins that regulate the proper communication, and the dysregulation of TJ proteins makes these tumor cells more aggressive, leading to tumor invasion and metastasis. Hence targeting TJs might be a novel insight towards addressing these highly invasive, metastatic tumors. Due to the prohibitive costs of treatments, side effects, and development of resistance, herbal medications comprising bioactive ingredients have become more popular for various human ailments. Unfortunately, the importance of natural compounds has significantly reduced due to the development of modern synthetic techniques to formulate drugs. However, the pharmaceutical industry that adopts chemistry-based drug development in combination with high throughput synthesis have not resulted in the expected drug productivity. Hence, the focus was shifted back to natural compounds in search of novel drugs with advanced technology to isolate the biologically active compound from the natural ones. The current review delivers the importance of TJ regulation, promoting it through phytochemicals to target malignant tumor cells.

Analyzing the drivers of cancer relapse: hypocalcemia and iron absorption in hormone-dependent female cancers.

BACKGROUND: Alterations in the levels of nutrients like calcium, ferritin, and electrolytes play a pivotal role in human physiology and might serve as biomarkers. Ferritin, an iron storage protein is important in various metabolic reactions of both cancer and cancer stem cells (CSCs) and is found to regulate 'stemness' leading to cancer relapse. Interestingly, ferritin levels are found to be regulated by calcium uptake. Several studies have shown that high levels of calcium inhibit absorption of iron, thereby reducing ferritin levels. In the present study, we evaluated and correlated the serum ferritin and calcium levels in pre- and post-treated hormone-dependent female cancers and deciphered their role in tumor recurrence and relapse. MATERIALS AND METHODS: The present retrospective study was approved by the Institutional Ethical Committees (IEC) of GIMSR (No. GIMSR/Admn./Ethics/approval/IEC-3/2021), and Omega cancer hospitals (Reg No: ECR/1486/Inst/AP/2020). Serum from 197 clinical samples diagnosed with breast, cervical, and ovarian cancers (99 pre-and 98 post-treatment) and 10 blood samples were analyzed for ferritin and calcium using auto bioanalyzer and sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: Ferritin levels were elevated in both pre- and post-treatment hormone-dependent female cancer patients while calcium levels showed gradual decrease. The mean ferritin value for pre-treatment was 0.0409 mg/dL while it was 0.0428 mg/dL for post-treatment hormone-dependent female cancer. CONCLUSION: Our results suggest that hypocalcaemia in post-treatment cancer patients leads to ferritin accumulation which might make these patients more prone to tumor recurrence and relapse.

Role of Lipoproteins in the Pathophysiology of Breast Cancer.

Breast cancer is one of the most common malignancies in women and the leading cause of cancer mortality. Hypercholesterolemia and obesity are potential risk factors for the incidence of breast cancer, and their detection can enhance cancer prevention. In this paper, we discuss the current state of investigations on the importance of lipoproteins, such as low denisity lipoproteins (LDL) and high density lipoproteins (HDL), and cholesterol transporters in the progression of breast cancer, and the therapeutic strategies to reduce breast cancer mortality. Although some research has been unsuccessful at uncovering links between the roles of lipoproteins and breast cancer risk, major scientific trials have found a straight link between LDL levels and incidence of breast cancer, and an inverse link was found between HDL and breast cancer development. Cholesterol and its transporters were shown to have significant importance in the development of breast cancer in studies on breast cancer cell lines and experimental mice models. Instead of cholesterol, 27-hydroxycholesterol, which is a cholesterol metabolite, is thought to promote propagation and metastasis of estrogen receptor-positive breast cancer cell lines. Alteration of lipoproteins via oxidation and HDL glycation are thought to activate many pathways associated with inflammation, thereby promoting cellular proliferation and migration, leading to metastasis while suppressing apoptosis. Medications that lower cholesterol levels and apolipoprotein A-I mimics have appeared to be possible therapeutic agents for preventing excessive cholesterol's role in promoting the development of breast cancer.

Role of Intracellular Iron in Switching Apoptosis to Ferroptosis to Target Therapy-Resistant Cancer Stem Cells.

Iron is a crucial element required for the proper functioning of the body. For instance, hemoglobin is the vital component in the blood that delivers oxygen to various parts of the body. The heme protein present in hemoglobin comprises iron in the form of a ferrous state which regulates oxygen delivery. Excess iron in the body is stored as ferritin and would be utilized under iron-deficient conditions. Surprisingly, cancer cells as well as cancer stem cells have elevated ferritin levels suggesting that iron plays a vital role in protecting these cells. However, apart from the cytoprotective role iron also has the potential to induce cell death via ferroptosis which is a non-apoptotic cell death dependent on iron reserves. Apoptosis a caspase-dependent cell death mechanism is effective on cancer cells however little is known about its impact on cancer stem cell death. This paper focuses on the molecular characteristics of apoptosis and ferroptosis and the importance of switching to ferroptosis to target cancer stem cells death thereby preventing cancer relapse. To the best of our knowledge, this is the first review to demonstrate the importance of intracellular iron in regulating the switching of tumor cells and therapy resistant CSCs from apoptosis to ferroptosis.

Role of dietary iron revisited: in metabolism, ferroptosis and pathophysiology of cancer.

Iron is the most abundant metal in the human body. No independent life forms on earth can survive without iron. However, excess iron is closely associated with carcinogenesis by increasing oxidative stress via its catalytic activity to generate hydroxyl radicals. Therefore, it is speculated that iron might play a dual role in cells, by both stimulating cell growth and causing cell death. Dietary iron is absorbed by the intestinal enterocytes in the form of ferrous ion which forms cLIP. Excess iron stored in the form of Ferritin serves as a reservoir under iron depletion conditions. Ferroptosis, is an iron-dependent non-mutational form of cell death process and is suppressed by iron-binding compounds such as deferoxamine. Blocking transferrin-mediated iron import or recycling of iron-containing storage proteins (i.e., ferritin) also attenuates ferroptosis, consistent with the iron-dependent nature of this process. Unsurprisingly, ferroptosis also plays a role in the development of cancer and maybe a beneficial strategy for anticancer treatment. Different lines of evidence suggest that ferroptosis plays a crucial role in the suppression of tumorigenesis. In this review, we have discussed the pros and cons of iron accumulation, utilization and, its role in cell proliferation, ferroptosis and pathophysiology of cancer.

Study of single nucleotide polymorphisms of tumour necrosis factors and HSP genes in nasopharyngeal carcinoma in North East India.

Nasopharyngeal carcinoma (NPC) is an epithelial tumour with a distinctive racial and geographical distribution. High incidence of NPC has been reported from China, Southeast Asia, and northeast (NE) region of India. The immune mechanism plays incredibly role in pathogenesis of NPC. Tumour necrosis factors (TNFs) and heat shock protein 70 (HSP 70) constitute significant components of innate as well as adaptive host immunity. Multi-analytical approaches including logistic regression (LR), classification and regression tree (CART) and multifactor dimensionality reduction (MDR) were applied in 120 NPC cases and 100 controls to explore high order interactions among TNF-α (-308 G>A), TNF ß (+252 A>G), HSP 70-1 (+190 G>C), HSP 70-hom (+2437 T>C) genes and environmental risk factors. TNF ß was identified as the primary etiological factor by all three analytical approaches. Individual analysis of results showed protective effect of TNF ß GG genotype (adjusted odds ratio (OR2) = 0.27, 95 % CI = 0.125-0.611, P = 0.001), HSP 70 (+2437) CC genotype (OR2 = 0.17, 95 % CI = 0.0430.69, P = 0.013), while AG genotype of TNF ß was found significantly associated with risk of NPC (OR2 = 1.97, 95 % CI = 1.019-3.83, P = 0.04). Analysis of environmental factors demonstrated association of alcohol consumption, living in mud houses and use of firewood for cooking as major risk factors for NPC. Individual haplotype association analysis showed significant risk associated with GTGA haplotype (OR = 68.61, 95 % CI = 2.47-190.37, P = 0.013) while a protective effect with CCAA and GCGA haplotypes (OR = 0.19, 95 % CI = 0.05-0.75, P = 0.019; OR = 0.01 95 % CI = 0.05-0.30, P = 0.007). The multi-analytical approaches applied in this study helped in identification of distinct gene-gene and gene-environment interactions significant in risk assessment of NPC.

Establishment and characterization of two primary breast cancer cell lines from young Indian breast cancer patients: mutation analysis.

Two novel triple negative breast cancer cell lines, NIPBC-1 and NIPBC-2 were successfully established from primary tumors of two young breast cancer patients aged 39 and 38 years respectively, diagnosed as infiltrating duct carcinoma of breast. Characterization of these cell lines showed luminal origin with expression of epithelial specific antigen and cytokeratin 18 and presence of microfilaments and secretary vesicles, microvilli, tight junctions and desmosomes on ultra-structural analysis. Both the cell lines showed anchorage independent growth and invasion of matrigel coated membranes. Karyotype analysis showed aneuploidy, deletions and multiple rearrangements in chromosomes 7, 9, X and 11 and isochromosomes 17q in both the cell lines. P53 mutational analysis revealed no mutation in the coding region in both the cell lines; however NIPBC-2 cell line showed presence of heterozygous C/G polymorphism, g.417 C > G (NM_000546.5) resulting in Arg/Pro allele at codon 72 of exon 4. Screening for mutations in BRCA1&2 genes revealed presence of three heterozygous polymorphisms in exon 11 of BRCA1 and 2 polymorphisms in exons 11, and14 of BRCA2 gene in both the cell lines. Both the cell lines showed presence of CD 44+/24-breast cancer stem cells and capability of producing mammosphere on culture. The two triple negative breast cancer cell lines established from early onset breast tumors can serve as novel invitro models to study mechanisms underlying breast tumorigenesis in younger age group patients and also identification of new therapeutic modalities targeting cancer stem cells.

Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells--an in vitro and in silico study.

Targeting breast cancer stem cells (BCSCs) offers a promising strategy for breast cancer treatment. We examined the plant alkaloid ellipticine for its efficacy to inhibit the expression of aldehyde dehydrogenase 1 class A1 (ALDH1A1)-positive BCSCs by in vitro and in silico methods. At 3 mM concentration, ellipticine decreased the expression of ALDH1A1-positive BCSCs by 62% (p = 0.073) in the MCF7 cell line and by 53% (p = 0.024) in the SUM159 cell line compared to vehicle-treated cultures. Ellipticine significantly reduced the formation of mammospheres, whereas paclitaxel enhanced mammosphere formation in both the treated cell lines. Interestingly, when treated with a combination of ellipticine and paclitaxel, the percentage of ALDH1A1-positive BCSCs dropped by several fold in vitro. A homology model of Homo sapiens ALDH1A1 was built using the crystal structure of NAD-bound sheep liver class I aldehyde dehydrogenase [PDB ID: 1BXS] as a template. Molecular simulation and docking studies revealed that the amino acids Asn-117 and Asn-121, Glu-249, Cys-302, and Gln-350, present in the active site of human ALDH1A1, played a vital role in interacting with the drug. The present study suggests that ellipticine reduces the proliferation and self-renewal ability of ALDH1A1-positive BCSCs and can be used in combination with a cytotoxic drug like paclitaxel for potential targeting of BCSCs.

Molecular docking and dynamics simulations of A.niger RNase from Aspergillus niger ATCC26550: for potential prevention of human cancer.

The aim of the present research was to study the anticancer effects of Aspergillus niger (A.niger) RNase. We found that RNase (A.niger RNase) significantly and dose dependently inhibited invasiveness of breast cancer cell line MDA MB 231 by 55 % (P<0.01) at 1 µM concentration. At a concentration of 2 µM, the anti invasive effect of the enzyme increased to 90 % (P<0.002). Keeping the aim to determine molecular level interactions (molecular simulations and protein docking) of human actin with A.niger RNase we extended our work in-vitro to in-silico studies. To gain better relaxation and accurate arrangement of atoms, refinement was done on the human actin and A.niger RNase by energy minimization (EM) and molecular dynamics (MD) simulations using 43A(2) force field of Gromacs96 implemented in the Gromacs 4.0.5 package, finally the interaction energies were calculated by protein-protein docking using the HEX. These in vitro and in-silico structural studies prove the effective inhibition of actin activity by A.niger RNase in neoplastic cells and thereby provide new insights for the development of novel anti cancer drugs.