Current Signal Transduction Therapy - Volume 18, Issue 2, 2023

Bilirubin is a yellow tetrapyrrole molecule found in the gastrointestinal system, and it is produced when hemoglobin (Hb) is degraded. For treating various liver disorders like jaundice, serum bilirubin in the body is a testing marker. Jaundice develops when the serum bilirubin level is more significant than 2.0 to 2.5 mg/dl. Examining different forms of bilirubin, i.e., conjugated (direct) bilirubin, unconjugated (indirect) bilirubin, and total bilirubin, helps the physician identify the cause and metabolic disorder of jaundice. Inconsistent bilirubin production and removal results in lasting neurologic consequences (kernicterus). In this paper, we have presented a brief introduction to jaundice, the physiological mechanism of bilirubin, its types and causes, clinical approaches toward patients having jaundice, i.e., the conventional method being practiced in clinical laboratories, and various non-invasive systems in the point-of-care settings along with their advantages and disadvantages. Information on bilirubin production and elimination with tracking of bilirubin levels may help to guide the proper clinical management of jaundice. The primary focus is on the progression of established methodologies and techniques to newer ones capable of measuring bilirubin in biological materials.

Background: Probiotics exhibit significant activity in the immune system by activating multiple immune mechanisms. Resveratrol is a non-flavonoid polyphenol. It has various pharmacological effects, including anti-oxidative, anti-inflammatory, anti-proliferative, and anti-angiogenesis effects. Objectives: The present study investigates the potential immunomodulatory and antitumor activity of the combination treatment of probiotics and resveratrol in sensitive and cisplatin-resistant breast cancer. Methods: In the in vivo study, tumor-bearing mice received one of the following treatments: 2.5*10⁸CFU/ml probiotics, 50 mg/kg resveratrol, the combination of probiotics and resveratrol, vehicle, or cisplatin. Balb/C mice were inoculated with sensitive EMT6/P and cisplatin resistance EMT6/CPR cancer cell lines, and in vivo antitumor activity was evaluated. Results: The antiproliferative activity of the probiotics, resveratrol, and their combination treatments was assessed using an MTT assay to evaluate lymphocyte proliferation activity. LDH colorimetric assay was conducted to measure the effectiveness of the treatments on the activity of natural killer cells. Nitro blue tetrazolium assay and neutral red method were used to evaluate macrophage function. Conclusion: The combination treatment showed an enhanced effect in splenic lymphocyte proliferation, macrophage function, phagocytosis, and pinocytosis in both cell lines. A significant reduction in tumor size and weight in EMT6/P and EMT6/CPR-bearing mice occurred. Hence, the combination treatment of probiotics and resveratrol was found to have a valuable activity against sensitive and cisplatin-resistant breast cancer cells and might act as a stimulator of the immune system. Therefore, the combination of probiotics and resveratrol deserves further analysis to be used in cancer prevention and treatment.

According to the latest data, the cancer prevalence fraction has surged to the highest number. This is why cancer has become a prominent disease that must be seen as a serious issue. Inhibitory action and ideas become prominent and necessary because of the rising death incidence daily. The simplifying idea of inhibition of cancer is targeting the complex that forms between the tyrosine kinase and ATP, which ultimately provides a clear way. Tyrosine kinase is a proteinaceous enzyme responsible for various cellular events like cell development, growth, and division. But these functions are performed by the activated tyrosine kinase, and the activation occurs by phosphorylation using ATP. The transfer of the phosphate group from ATP to tyrosine is known as phosphorylation. The basic idea is to enhance the competitive inhibition of the ATP-Tyrosine complex is a promising target for treating cancer. Various molecules have a substantial effect on the above-said target. This review summarizes molecules currently in any drug development or clinical trial with the same effect. This review covers most inhibitory molecules from different categories, which either directly or indirectly inhibit the Tyrosin kinase-ATP complex by incorporating.

Introduction: Janus kinase 2 (JAK2) is an intracellular signaling protein. JAK2 p. V617F is a common variant in normal karyotype myeloproliferative neoplasms (MPN). Highresolution melting (HRM) analysis is one of the essential methods for detecting the JAK2 p.V617F variant. In this study, we have investigated the effect of DNA concentration on detecting the JAK2 p.V617F variant using the HRM method. Methods: Genomic DNA was extracted from human blood and diluted ten times in distilled water from 1 to 0.03; afterward, HRM was conducted for each dilution (triplicate). Using SPSS v.20.0 software, the mean Tm of each dilution was calculated and compared. Results: The HRM results revealed the JAK2 wild type and variant to have Tms of 81/64°C and 80/76°C, respectively. At the endpoint of the pre-amplification, the dilutions had different emissions. The statistical analysis revealed no statistically significant differences in Tm between samples with varying DNA concentrations (P value > 0.05). Conclusion: There have been no significant differences obtained in the analysis of JAK2 p.V617F point variant in different DNA dilutions, implying that the HRM analysis has no relation to DNA concentration.

Background: Large datasets are logically common yet frequently difficult to interpret. Principal Component Analysis (PCA) is a technique to reduce the dimensionality of a dataset. Objective: The main objective of this work is to use principal component analysis to interpret and classify phonocardiogram signals. Methods: Finding new factors aids in the reduction of important components of an eigenvalue/ eigenvector problem, thus enabling the new factors to be represented by the current dataset and making PCA a flexible data analysis tool. PCA is adaptable to a variety of systems created to update different data types and technology advancements. Results: Signals acquired from a patient, i.e., bio-signals, are used to investigate the patient's strength. One such bio-signal of central significance is the phonocardiogram (PCG), which addresses the working of the heart. Any change in the PCG signal is a characteristic proportion of heart failure, an arrhythmia condition. Conclusion: Long-term observation is difficult due to the many complexities, such as the lack of human competence and the high chance of misdiagnosis.

Introduction: RET (Rearranged during transcription) kinase is one of the key targets for anticancer drug development. Understanding the real mechanism of pharmacological action is aided by the protein-ligand interaction. The purpose of this study is to find the most effective RET inhibitors. Methods: Firstly, through a literature survey, we understood that tetrazole is useful nuclei to provide anticancer activity. Hence, a molecule was drawn containing tetrazole ring using Chemdraw 16.0. This drawn compound was used to determine further ligands employing Zincpharmer. Then, the 3D energy minimized structure of proposed ligands and positive control (selpercatinib and pralsetinib) were drawn using Chem3D. Further, docking was performed for all the ligands with phosphorylated RET kinase (PDB ID - 2IVU) using trial version of Molegro virtual docker 7.0. Results: Determined ligands were docked with the help of Molegro virtual Docker (MVD) 7.0 employing RET kinase (2ivu) as protein. Conclusion: Top 10 compounds were selected and their drug-like properties along with their oral bioavailability were also determined. ZINC12180698, ZINC12180696, ZINC09616526, ZINC12180701, ZINC09616182, ZINC09616145, ZINC17052231, ZINC17052262, ZINC12180700, and ZINC0961 6518 were among the top ten compounds that showed the strongest affinity for the target for RETmediated cancer in this study.

Background: Deltamethrin is a class II synthetic pyrethroid pesticide extensively used to control pests and vectors in the agriculture sector and health management programme. Due to excessive applications of this pesticide in the environment, it is harming many organisms other than the target organisms. Higher organisms like human beings are also affected by this pesticide because it instigates the impairment of the central nervous system and also distresses the immune system of vertebrates. Methods: In the current research study, MHC I and MHC II molecules of human origin have been targeted to evaluate the interaction with deltamethrin molecules by the AutoDock tool to establish the immunomodulatory effect. MHC I receptor molecule is presented on every nucleated cell, and MHC II receptors are located specifically on cell surfaces of antigen-presenting cells. These receptors play a role in cell-mediated and humoral immune responses. The binding affinity of deltamethrin with MHC receptors can affect the immune response, specifically the acquired immunity of an individual. Results: Findings of the current research study support that deltamethrin causes the suppression of the immune system by interaction with MHC I and MHC II molecules and may cause the organisms to be more prone towards antigen and disease development. Conclusion: The autoDock tool can be utilized to analyse other pesticides’ effects on the immune system and in the drug development process to minimize the toxic effects due to several types of pesticides.

Background: Bladder cancer is the 9th most prevalent malignancy worldwide. Fibroblast Growth Factor Receptor 3b (FGFR3b), involved in cell proliferation, differentiation, and migration, is a mutations hotspot for bladder cancer with the most prevalent aberration being S249C. Objective: Impact of S249C of FGFR3b on bladder tumorigenesis via immediate downstream adapter proteins, Fibroblast Growth Factor Receptor Substrate (FRS2 and FRS3) is analyzed computationally. Methods: Wildtype FGFR3b monomer was modeled using I-TASSER and Phyre2. Whereas, S249C mutation was introduced via DynaMut. Wildtype FGFR3b homodimer and mutant heterodimer were structured and docked with downstream proteins using HADDOCK. PDBSum was used to study the amino acid residues involved in intermolecular and intramolecular interactions. Results: Parameters of molecular flexibility and interatomic interactions predicted S249C heterodimer mutation of FGFR3b to be stable. Furthermore, docking with FRS2 protein revealed greater stability and higher binding affinity for S249C heterodimer mutant compared to wildtype homodimer. However, FRS3 docking showed a negligible decline in binding affinity for the S249C mutation but based on Van der Waal’s energy and insights into the interacting residues, it was revealed that these interactions might be stronger and for longer duration in comparison to the wildtype homodimer. Conclusion: S249C heterodimer mutation of FGFR3b is predicted to be stable with a tumorigenic potential where FRS2 and FRS3 might be among the key players of altered downstream signaling. Further investigations are required for a detailed picture.