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Apr 2024 DOI 10.14302/issn.2998-4211.jalr-24-4926
Bahadur Khan FaizaCorresponding author
This article has been retracted on 20 March 2025. VIEW THE RETRACTION NOTICE (https://doi.org/10.14302/issn.2998-4211.jalr-25-5855) The research is focused on neuroinflammation a normal physiological process which is known to be associated with neurodegenerative diseases could be the potential targeted therapy via the microglia cells, it starts with defining Alzheimer’s; a neurodegenerative disease which causes deposition of Aβ (amyloid beta) protein in the cerebral cortex as well as NFT (neurofibrillary tangles) in the hippocampus and basal ganglia. The paper then describes process of neuroinflammation, microglia’s role, apolipoprotein E4 gene in relation to Alzheimer’s, which leads to different stem cell research and how pruning microglia as well as targeting microglia receptors in the brain is being used in current research trials, we included multiple meta-analysis showing microglia receptors being targeted currently by emerging drugs like propofol, antibodies CSF1R inhibitor etc, which are currently under trial phase, the research ends with concluding potential diagnostic markers like sirt1 considered to be an anti-aging protein which can be used as therapeutic interventions and Lps effect on Sirt 1. A Microglia initiated target therapy in Neuroinflammation for Alzheimer’s Patients.
Jan 2024 DOI 10.14302/issn.2328-0182.japst-23-4771
Tariku Belay YilkalCorresponding author
Background Immunoglobulins are bio-receptors found embedded in the cell membrane with a biological role that detects the harmful molecules of a test compound. These bio-receptors interface between a biological system and its external environment that transduce information to the effector via intermediate messengers in which its response efficiency usually exhausts at high doses of exposure to external stimuli. The purpose of this review article is, therefore, to elaborate on the computational method for systemic biology which was designed to convert qualitative pharmacological data into the quantitative one that might help to determine the toxicity of a test compound. Methods First, acute toxicity studies using different levels of doses prepared from each test compound have been conducted on Balb c mice. Then, blood specimens from the tail and facial veins of each sampled Balb c mouse were collected 3 days before dosing as a reference test and 4 hr after dosing for comparison. The changes in the efficiency of immunoglobulins immune response (ΔIg) after dosing were determined using quantitative immunoassay and the body’s response against the dose as the toxic reaction rate (r) and the toxic severity (s) were finally determined using computational methods as r=d/t-ΔIg mg/sec and (s=r/w×100) %/sec respectively, where (w) represents the body weight of a study animal, (t) represents the period of time at which undesirable bio-physiological responses manifested on treated study animals and (ΔIg) represents the changes in the concentration of immunoglobulins in blood serum after dosing. Results The results of different studies revealed that the dose has never limited the toxic property of a test compound but the length of time at which the undesirable side effect was manifested on study animals. The period of time at which adverse effects manifested on treated Balb c mice was inversely related to the amount of dose administered in the oral route. The higher the dose of the administered test compound, the shorter the period of time at which the undesirable side effect was manifested on treated Balb c mice. This means that the adverse effect of test compounds was not because of the dose but rather due to its toxic reaction rate which ultimately determined the toxic severity in the natural process of treated Balb c mice. Balb c mice treated with a dose whose toxic reaction rate was ≤ 0 survived from death whereas Balb c mice treated with a dose that had a toxic reaction rate of > 0 died at different lengths of time after dosing depending on the toxic severity of a test compound. It could be a scientific fact to declare that a test compound is safe when the toxic reaction rate (r) and toxic severity (s) of a dose is ≤ 0 and toxic when it is > 0 in the natural processes of a study animal.
Jan 2024 DOI 10.14302/issn.2574-4496.jtc-23-4835
Hussein Saleh Hussein AbbasCorresponding author
The prevalence of thyroid cancer is rapidly increasing worldwide, majorly due to overdiagnosis and overtreatment methods of differentiated thyroid cancer. The emergent and potent preclinical models, high-throughput molecular techniques, and genetic expression microarrays have delivered deeper insights into understanding the molecular features in oncogenesis. Thus, molecular markers have become a promising tool in managing thyroid cancer for differentiating benign and malignant tumors, prognosis, recurrence, and determination of novel therapeutic targets. In differentiated thyroid cancer, molecular markers are majorly utilized for guiding the development of indeterminate thyroid nodules on fine needle aspiration (FNA) histologies. Dissimilar to this, in advanced thyroid cancer, molecular markers permit targeted treatment of a modified signaling cascade. Determining causal mutation of targeted kinase receptors in advanced thyroid cancer can depict a promising treatment strategy with mutation-targeted tyrosine kinase inhibitors to reduce progression and eradicate mutation effects when conventional methods fail to manage. This review will focus on the molecular landscape and discuss the impact of molecular markers on the prognosis, treatment, and surveillance of differentiated and anaplastic thyroid cancer.
Jun 2022 DOI 10.14302/issn.2328-0182.japst-22-4193
Tariku Belay YilkalCorresponding author
School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
The strategy for safe drug discovery and development has limited clinical success as compared to wasted time and resources annually. This is due to the fact that the results of multiphase preclinical trials are less likely to make an accurate early prediction on the safety of test compounds to progress into the clinic as a valuable therapeutic agent. A lot of time and resources has been wasted in the multistage processes of drug discovery and development that does not work at the end of the procedure every year. During pre-marketing stage, for instance, the number of unsuccessful clinical trials are greater than the successful one because of safety issues. A toxicity study at different stages of preclinical and clinical trials is a routine procedure to investigate the undesirable side effects of test compounds being manifested on the natural processes of living things. It deals with the effect and mechanism of toxicity of test compounds that triggers different biological responses on different organ systems. The biological responses that would be manifested as a result of interaction between the receptors and active molecules of a test compound could be desirable pharmacological effect or undesirable side effect or both responses are manifested simultaneously depending on the selectivity or specificity of the molecule of a test compound for its receptor subtype which makes safe drug discovery and development very challenging. The response efficiency of the body (the net outcome of the body’s biological reaction against the side effect) would determine the potency of a test compound to manifest undesirable pharmacologic effect. In other words, the amount of a drug required to cause a biological harm or injury depends on the magnitude of the body’s biological reaction in which the immune response plays a great pharmacological role by neutralizing and harmonizing xenobiotics with the biological molecules. The dose of a test compound at 100 mg/kg body weight, for instance, could be lethal to some of the study animals while it is still non-lethal to some other study animals depending on the response efficiency of the body. The immune system is well connected to each and every biological systems of the body which allows it to detect undesirable side effects being manifested through immunoglobulins signalling and activation mechanisms. This complex communication network helps to localize the diverse side effects of a test compound being manifested on different organ systems into the immune system which makes a toxicity study relatively simple to monitor. The cellular immune system becomes active following the molecule-receptor interaction and start producing antibodies which is also known as immunoglobulins to protect bodily harm and destruction. Under normal biological circumstances, the amount of immunoglobulins produced by the cellular immune system following exposure to a test compound is proportional to the number of harmful molecules interacted with its receptor subtype. Thus, with the reference to the changes in the immune response against the administered dose, it would be able to deal with the diverse undesirable side effects of a test compound being manifested on treated study animals using computational systemic biology.
Sep 2019 DOI 10.14302/issn.2470-0436.jos-19-2829
Abo Taleb EmanCorresponding author
Regional hospital for vitreo retina and eye care Sana'a Yemen.
Purpose To study outcome and spectral domain optical coherence tomography (SD-OCT) macular findings in patients who underwent surgery for spared macula giant retinal tear (GRT) retinal detachment. Methods a retrospective study of 12 patients with spared macula giant retinal tear (GRT) retinal detachment who underwent vitrectomy (N=7), vitrectomy with an encircling scleral buckle (n=4) and scleral buckle (n=1) with at least 3 months follow up after silicon oil removal (SOR) . Post-SOR macular SD-OCT scans were studied in all eyes. Results Final reattachment achieved in all eyes with single primary surgery. Post-SOR SD-OCT macular finding was photoreceptors layer disruption in 6 eyes, epiretinal membrane (ERM) in 4 eyes, Macular hole in 1 eye and choroidal neovascularisation in 1 eye. Significant correlation found between final Best-Corrected Visual Acuity (BCVA) and macular pathology on SD-OCT p value (0.048). Conclusion SD-OCT plays a high role in diagnosis of macular alterations that can be associated with poor functional outcome in anatomically successful GRT surgery with spared macula pre-operatively.
Apr 2019 DOI 10.14302/issn.2377-2549.jndc-19-2736
Łukasiewicz SylwiaCorresponding author
Antibody phage display has become a useful technique for discovering and optimizing target-specific monoclonal antibodies suitable for many applications, including therapeutic ligands, which may act as direct pharmacological compounds or may be used as targeting ligands for controlled drug delivery. Recently, the D2-5-HT1A heteromer, which is formed by the dopamine D2 and serotonin 5-HT1A receptors has attracted attention as a potential target of antipsychotic drugs. Therefore, the aim of the study was to identify scFv monoclonal antibodies that are able to specifically recognize epitopes formed within the heteromer structure. Because both receptors are membrane proteins, it is important to conduct bio-panning experiments in the most natural conditions, in which the presented antigens (D2-5-HT1A heteromers) are in their native form and possibly in their best-preserved spatial structure. It has been shown here that phage display methodology can be successfully used in the preparation of monoclonal antibodies against dimers of membrane proteins. To separate phages specifically binding the D2-5-HT1A heteromer, the selection process using CHO+ cells with overexpression of both receptors was conducted. Phages that were bound to receptor monomers or other CHO-K1 cell surface proteins were eliminated as a result of negative selection by using CHO- cells expressing separate receptor monomers.
Aug 2018 DOI 10.14302/issn.2639-1716.jn-18-2208
J. Mizejewski GeraldCorresponding author
Wadsworth Center, New York State Department of Health, PO Box 509, Empire State Plaza, Albany, NY 12201-0509
Breast cancer (BC) is the leading cause of cancer-related deaths in young to middle-aged women worldwide. Moreover, the survival rate in BC-patients is only 20% when associated with metastatic disease. The high mortality rate observed in BC women with metastatic disease has precipitated a major challenge revealing an unmet need to develop new therapeutic strategies in treating metastatic cancer. One such approach has involved utilization of chemokines and their receptors as therapeutic targets for cancer metastasis. It has been established that a definitive correlation exists between overexpressed CXCR4 malignant cell receptors and cancer cell growth, invasion, and migration. It is also widely accepted that the CXCR4 receptor, complexed to its CXCL12 ligand, plays a major role in establishing migratory pathway gradients for cancer cells migrating to distant tissues/organ sites. It would follow that chemokine decoy ligands, such as peptide antagonists and inhibitors, could serve to induce receptor blockade and impede subsequent intracellular signaling. Such ligands, synthetic and natural, reportedly contribute to reducing cancer cell growth, invasion, adherence, and migration. The present commentary describes several existing synthetic CXCR4 receptor-ligand peptide antagonists and presents a strategy to develop naturally-occurring human protein-derived peptide candidates.
May 2018
Yousef FarahCorresponding author
Candidate in pharmaceutical sciences, Faculty of Pharmacy, Damascus University.
Sulfonamide group is a magic group introduced as the main core for different bio-activities in drug industry. According to its substitutes, literature divides sulfonamide derivatives to antibacterial sulfonamides and non-anti-bacterial sulfonamides. As Data was collected from different sources such as Drug Bank.com and Pubchem.com databases and then was analyzed, we found that these compounds are different in their pharmacokinetics and pharmacodynamics; in addition to their sulfa cross allergy property. We presented these differences from these compounds changes in their chemical structure, in a way to build a solid base that can be depended on for developing new drugs from these compounds that interact with different receptors.
Mar 2018 DOI 10.14302/issn.2575-1212.jvhc-18-2013
A Halawa AmalCorresponding author
Department of Forensic Medicine and Toxicology, Faulty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
Lipopolysaccharide (LPS) is a component of the outer membrane of gram negative bacteria. LPS challenging allows switching transcription of proinflammatory cytokines on via over stimulation of Toll-like receptors (TLRs) signaling pathway with subsequent pathogenic inflammatory response. We investigated the possible reproductive toxicity of LPS in male Wister albino rats. Oxidative stress markers, antioxidant status and caspase-3 activity were analyzed in testicular tissues of rats exposed to either saline or LPS (4 mg/kg BW, ip; 0.18 of the LD50). The samples were collected at 6 h and 72 h after injection of LPS. A significant reduction in testicular reduced glutathione (GSH), glutathione-S-transferase (GST) and superoxide dismutase (SOD) was observed at 72 h compared to control group. Total antioxidant capacity was decreased at 6 h with additional significant reduction at 72 h. Catalase activity was reduced significantly at both 6 and 72 h. Malondialdehyde (MDA) was increased (P ≤ 0.05) in LPS injected rats without variation between 6 and 72 h. A significant increase in nitric oxide (NO) was observed at 72 h after injection. A time-dependent increase in LPS-treated groups was observed in the concentration of caspase-3.Histopathological analysis revealed degenerative changes and necrosis of seminiferous tubules after 6 h with further accumulation of eosinophilic edematous transudate in its lumen after 72 h. In conclusion, by increasing time of exposure, LPS induced lipid peroxidation, oxidative stress, reduced testicular antioxidant capacity and encouraged testicular apoptosis which could be possible mechanisms for impairment of testicular function.
Mar 2018
Rizzello LorisCorresponding author
Department of Chemistry, University College London (UCL), 20 Gordon Street, WC1H 0AJ - London (UK)
The crusade against cancer has a new army: immunotherapy. The rational design is very simple, but brilliant at the same time. Extract the patients T-cells, reprogram them in vitro for the expression of highly specific receptors against cancer, perfuse them back to the patient. As a result, T-cells are now instructed to selectively kill circulating tumor cells, while avoiding potential side effects. This ‘Fairy Tale’ however does not lack of drawbacks and limitations. First, malignant progression can be accompanied by profound immune suppression, which counteracts the immune system-mediated tumor elimination. Second, the immune cells modification does not match high standards in terms of safety for humans. Here, nanotech can fill these gaps, and help immunotherapy to be safer and more effective.
Feb 2018 DOI 10.14302/issn.2372-6601.jhor-18-1938
Mostafa Ali ElsayedCorresponding author
Clinical Oncology Department, Faculty of Medicine, Sohag University
Neuropilins are transmembrane glycoproteins that act as receptors for vascular endothelial growth factors (VEGF) and are involved in the process of tumor angiogenesis. Its importance in hematological malignancies such as acute leukemia (AL) remains to be elucidated. The aim of this study was to evaluate the significance of neuropilin-1 expression in acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) patients by flowcytometry and the difference between both groups of acute leukemia. Bone marrow aspirates of 52 patients with acute leukemia, 29 patients with de novo AML and 23 ALL patients were examined in this study. 15 subjects with non-hematological malignancy serving as the control group were also included. Neuropilin-1 expression by flow cytometry showed a highly significant increase in de novo AML and ALL patients with a mean of 37.9 ± 20.92% and 32.33±19.8%, respectively, compared to control group’s mean of 11.51 ± 3.04% (p= 0.001, 0.006). There were no statistically significanct difference between ALL and AML patients (p= 0.76). Neuropilin-1 surface expression by flowcytometry showed a significant positive correlation with total leukocyte count, bone marrow blast percentage, CD45 and CD14 and negative correlation with hemoglobin level, RBCs count in AML patients. In ALL patients, positive significant correlations were found with bone marrow blast percentage and negative correlation with hemoglobin level, RBCs count. Neuropilin-1expression was detected significantly in acute leukemias and it is related to the disease severity.
Feb 2018 DOI 10.14302/issn.2377-2549.jndc-18-1933
Bharanidharan S.Corresponding author
Department of Physics, Bharath Institute of Higher Education and Research, Bharath University, Chennai-600 073, India
The organic molecule (E)-1-(4-bromobenzylidene)thiourea (BBTU) have been synthesized and characterized using FT-IR and FT-Raman spectral studies. The quantum chemical calculations of BBTU have been studied using DFT/B3LYP/6-31G(d,p) level of theory. The stable conformer is identified by the potential energy surface scan. The complete vibrational assignments were performed on the basis of PED analysis with the help of SQM method. NBO analysis was carried out to explore the various conjucative/hyperconjucative interactions within the molecule and their second order stabilization energy. The NLO activity of BBTU is calculated and compared with the standard Urea molecule. The energies of the FMOs are used for the determination of global reactivity descriptors. The electrophilic and nucleophilic charge sites were identified by the molecular electrostatic potential mapped surface. The molecular docking of BBTU is carried out with the receptors of 3U2D and 1JIJ to screen the bacterial activity.
Aug 2017 DOI 10.14302/issn.2576-2818.jfb-14-553
Bernardini LCorresponding author
Lunicare Medical Center-SISMER Satellite, Sarzana, Italy
All independent experimental data on epithelial and glandular cells lines of human endometrium support the evidence for a rapid production of eicosanoids from the LH/hCG receptors when exposed to the hCG hormone. Prostaglandins rapidly act on the surrounding endometrial stromal cells throughout the adenylyl cyclase enzyme leading to very large amounts of cAMP and angiogenic factors (VEGF) production. The cAMP is the most important intracellular second messenger and along with progesterone accomplishes the full process of decidualization and acquisition of receptivity after estrogenic priming of the endometrium. The status of uterine receptivity lasts few days only and timing for successful embryo-signal transduction system activation by the endometrium is probably short. In absence of in vivo embryonic signals it is impossible to predict, on individual bases, how the intensity of all the complex interlinked molecular changes of decidualization might ever be in case of exposure to native hCG. In other terms, amount of prostaglandins and cAMP produced in response to variably glycosylated hCG are all, in vivo, not measurable variables and should be viewed as a “wave” of biochemical chain reactions. Embryonic hCG is secreted in form of multiple isomers having an unpredictable variable level of glycosylation and control of this variable remains elusive. During cycles of ovarian stimulation many drugs (FSH, LH, HCG) interact with different G-protein coupled receptors (GPCRs) making it possible to alter the prostaglandins-mediated decidualization process ready to be elicited only by hCG of pregnancy. Since the molecules (cAMP and progesterone) controlling endometrial stromal cells differentiation into decidual cells are critical for successful implantation and placenta formation, the evidence of fast eicosanoids production associated with endometrial LH/hCG receptors exposure to hCG and the potential by human endometrium to produce, in response, very large amounts of cAMP has biological and clinical relevance.
Jun 2016 DOI 10.14302/issn.2574-4526.jddd-16-1101
A. M. Herbella FernandoCorresponding author
Department of Surgery, Escola Paulista de Medicina, Federal University of Sao Paulo, São Paulo, Brazil
Background/Aims: Esophageal motor abnormalities are frequently found in patients with gastroesophageal reflux disease. The effect of bile in esophageal dysmotility is probably secondary to mucosal signaling to the muscular layer and not a transmural process. This study aims to identify the mucosa-muscular signaling path by receptors blockage in an experimental study. Methods: Fifteenguinea pig esophagi were isolated and ex-vivo esophageal contractility was assessed with force transducers. The esophagi were incubated in 100 µM ursodeoxycholic acid for 1 hour and 5 sequential contractions induced by 40 mM KCl spaced by 5 minutes were measured. After 30 minutes, esophagi specimens were incubated in 3 different smooth-muscle contraction antagonists: atropine (1µM) in 5, suramin (1µM) in 5 and genistein (1µM) in 5. The same protocol for contractions was repeated. Values are expressed as mean ± standard deviation and encompass the mean of five stimuli. Experimental procedures were approved by the University Institutional Review Board. Results: Contraction amplitudes after bile incubation but before antagonist incubation were 1.6±0.6 g, 1.2±0.8 g, and 1.2±0.4 g for atropine, suramin and genistein, respectively. Mean contraction amplitudes after antagonists instillation were 1.2±0.6 g, 1.4±0.5 g, 0.9±0.2 g, respectively. There was no different in contraction amplitude before and after instillation of atropine (p=0.188), suramin (p=0.488) or genistein (p=0.079). Conclusion: Our results show that blockage of cholinergic (atropine), purinergic (suramin) or tyrosine kinase (genistein) paths do not change esophageal dysmotility induced by bile. Other molecular path may play the role in this scenario.
Mar 2016 DOI 10.14302/issn.2470-0436.jos-15-739
P. Sarthy VijayCorresponding author
Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL 606111.
Ciliary neurotrophic factor (CNTF) is a well-tested, neuroprotective agent that has been shown to retard photoreceptor degeneration in several animal models of retinitis pigmentosa. The molecular mechanisms underlying CNTF-mediated neuroprotection are currently not understood. CNTF could act directly on photoreceptors or it could act indirectly by stimulating Müller glial cells to produce photoreceptor neuroprotective agents. To better characterize CNTF action on Müller cells, we have studied signaling pathways activated by CNTF using an established retinal Müller cell line, rMC-1. RNA was isolated from CNTF-treated cultures, and suppressor of signal transducer and activator of transcription (SOCS3) and Glial fibrillary acidic protein (GFAP) transcript levels were assessed by quantitative real-time PCR. Immunoblotting was used to examine activation ofmitogen activated protein kinase (ERK1/2/MAPK) and phosphoinositide 3-kinase (PI3-K)/Aktpathways in response to CNTF. Additionally, the level of5' AMP-activated protein kinase (AMPK), an enzyme that plays a key role in cellular energy homeostasis levels, was determined by immunoblotting. CNTF treatment resulted strong upregulation of SOCS3 and GFAP transcripts that were blocked by expression of a dominant-negative STAT3 mutant. CNTF treatment also resulted in transient activation of ERK1/2/MAPK but not PI3K/Akt signaling pathway. There was no change in activation of AMPK. We conclude that CNTF treatment leads to stimulation of JAK-STAT and MAPK signaling pathways but not the PI3K/AKT pathway, associated with cell death, in Müller cells.
Feb 2016 DOI 10.14302/issn.2326-0793.jpgr-15-889
E. Buroker NormanCorresponding author
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA
Purpose The endothetal Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) gene which encodes hypoxia-inducible-factor-2 alpha (HIF2a) is a transcription factor that is involved in the response to hypoxia. EPAS1 has been found to have four (rs56721780, rs6756667, rs7589621, rs1868092) simple nucleotide polymorphisms (SNPs) associated with human disease.These SNPs were computationally examined with respect to changes in potential transcriptional factor binding sites (TFBS) and these changes were discussed in relation to disease and alterations in high altitude adaptation in humans. Methods The JASPAR CORE and ConSite databases were instrumental in identifying the TFBS. The Vector NTI Advance 11.5 computer program was employed in locating all theTFBS in theEPAS1 gene from 1.6 kb upstream of the transcriptional start site to 539 bps past the 3’UTR. The JASPAR CORE database was also involved in computing each nucleotide occurrence (%) within the TFBS. Results The EPAS1 SNPs in the promoter, intron two and the 3’UTR regions have previously been found to be significantly associated with disease and different levels of high-altitude hypoxia among native Tibetans. The SNP alleles were found to alter the DNA landscape for potential transcriptional factors (TFs) to attach resulting in changes in TFBS and thereby, alter which transcriptional factors potentially regulate the EPAS1 genesuch as for the glucocorticoid and mineralocorticoid nuclear receptor binding sites created by the rs7589621 rSNP EPAS1-G allele. These receptors regulate carbohydrate, protein and fat metabolism. Also the minor rs7589621 rSNP EPAS1-A creates a punitive TFBS for the FOXC TF which is an important regulator of cell viability and resistance to oxidative stress. These EPAS1 SNPs should be considered as regulatory (r) SNPs. Conclusion The alleles of each rSNP were found to generate unique TFBS resulting in potential changes in TF EPAS1 regulation. The punitive changes in TFBS created by the four rSNPs could very well influence the significant cline in allele frequencies seen in Tibetans with increasing altitude or the haplotype association with high altitude polycythemia in male Han Chinese. These regulatory changes were discussed with respect to changes in human health that result in disease and sickness.