Biochemical Signaling Pathways Research Articles

Targeting Oligodendrocyte Dynamics and Remyelination: Emerging Therapies and Personalized Approaches in Multiple Sclerosis Management.

Multiple sclerosis [MS] is a progressive autoimmune condition that primarily affects young people and is characterized by demyelination and neurodegeneration of the central nervous system [CNS]. This in-depth review explores the complex involvement of oligodendrocytes, the primary myelin- producing cells in the CNS, in the pathophysiology of MS. It discusses the biochemical processes and signalling pathways required for oligodendrocytes to function and remain alive, as well as how they might fail and cause demyelination to occur. We investigate developing therapeutic options that target remyelination, a fundamental component of MS treatment. Remyelination approaches promote the survival and differentiation of oligodendrocyte precursor cells [OPCs], restoring myelin sheaths. This improves nerve fibre function and may prevent MS from worsening. We examine crucial parameters influencing remyelination success, such as OPC density, ageing, and signalling pathway regulation [e.g., Retinoid X receptor, LINGO-1, Notch]. The review also examines existing neuroprotective and antiinflammatory medications being studied to see if they can assist oligodendrocytes in surviving and reducing the severity of MS symptoms. The review focuses on medicines that target the myelin metabolism in oligodendrocytes. Altering oligodendrocyte metabolism has been linked to reversing demyelination and improving MS patient outcomes through various mechanisms. We also explore potential breakthroughs, including innovative antisense technologies, deep brain stimulation, and the impact of gut health and exercise on MS development. The article discusses the possibility of personalized medicine in MS therapy, emphasizing the importance of specific medicines based on individual molecular profiles. The study emphasizes the need for reliable biomarkers and improved imaging tools for monitoring disease progression and therapy response. Finally, this review focuses on the importance of oligodendrocytes in MS and the potential for remyelination therapy. It also underlines the importance of continued research to develop more effective treatment regimens, taking into account the complexities of MS pathology and the different factors that influence disease progression and treatment.

Mechanosensitive Piezo1 channels promote neurogenic bladder fibrosis via regulating TGF-β1/smad and Hippo/YAP1 pathways

Bladder fibrosis is the final common pathway of neurogenic bladder (NB), and its underlying mechanisms are not fully understood. The current study aims to evaluate the involvement of Piezo1, a mechanosensitive channel, in bladder fibrosis. A full-thickness bladder specimen was taken during ileocystoplasty or ureteral reimplantation from the surgical cut's edge. By chopping off the bilateral lumbar 6 (L6) and sacral 1 (S1) spinal nerves, NB rat models were produced. Utilizing both pharmacological inhibition and Piezo1 deletion, the function of Piezo1 in the TGF-β1-induced fibrosis model of SV-HUC-1 cells was delineated. RNA-seq, immunofluorescence, immunohistochemistry (IHC), and Western blotting were used to evaluate the degrees of fibrosis and biochemical signaling pathways. Piezo1 protein expression was noticeably elevated in the human NB bladder. The abundance of Piezo1 protein in bladder of NB rats was significantly increased. RNA-seq analysis revealed that the ECM-receptor interaction signaling pathway and collagen-containing ECM were increased in spinal cord injury (SCI)-induced bladder fibrosis. Moreover, the bladder of the NB rat model showed activation of YAP1 and TGF-β1/Smad. In SV-HUC-1 cells, siRNA suppression of Piezo1 led to profibrotic responses and activation of the TGF-β1/Smad pathway. However, Yoda1, a Piezo1-specific agonist, significantly reduced these effects. TGF-β1 increased Piezo1 activation and profibrotic responses in SV-HUC-1 cells. In the TGF-β1-induced fibrosis model of SV-HUC-1 cells, the TGF-β1/Smad pathway was activated, whereas the Hippo/YAP1 signal pathway was blocked. Inhibition of Piezo1 further prevented this process. Piezo1 is involved in the progression of NB bladder fibrosis and profibrotic alterations in SV-HUC-1 cells, likely through regulating the TGF-β1/Smad and Hippo/YAP1 pathways.

Dynamical forces drive organ morphology changes during embryonic development.

Organs and tissues must change shape in precise ways during embryonic development to execute their functions. Multiple mechanisms including biochemical signaling pathways and biophysical forces help drive these morphology changes, but it has been difficult to tease apart their contributions, especially from tissue-scale dynamic forces that are typically ignored. We use a combination of mathematical models and in vivo experiments to study a simple organ in the zebrafish embryo called Kupffer's vesicle. Modeling indicates that dynamic forces generated by tissue movements in the embryo produce shape changes in Kupffer's vesicle that are observed during development. Laser ablations in the zebrafish embryo that alter these forces result in altered organ shapes matching model predictions. These results demonstrate that dynamic forces sculpt organ shape during embryo development.

Cynomorium songaricum: UHPLC/ESI-LTQ-Orbitrap-MS analysis and mechanistic study on insulin sensitivity of a flavonoid-enriched fraction

BackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by elevated blood glucose levels, posing a significant global health concern due to its increasing prevalence. Insulin resistance (IR) plays a major role in the development of T2DM and is often linked to factors such as obesity, physical inactivity, and a sedentary lifestyle. Recently, there has been growing interest in exploring the potential of natural products for improving insulin sensitivity and glucose metabolism. Among these, Cynomorium songaricum Rupr., an edible parasitic plant, has shown promising antidiabetic effects. However, research on its beneficial effects on IR is still nascent. Therefore, this study aims to investigate the application of a Cynomorium songaricum flavonoid-enriched fraction (CSF) in the treatment of IR in T2DM, along with elucidating the chemical and biochemical mechanisms involved. MethodFirst, UHPLC/ESI-LTQ-Orbitrap-MS was utilized to perform a chemical profiling of CSF. Subsequently, glycogen synthesis, gluconeogenesis and glucose consumption assays were conducted on HepG2 cells with a high glucose high insulin-induced IR model to illustrate the favorable impacts of CSF on IR. Then, an innovative network pharmacology analysis was executed to predict the potential chemical components and hub genes contributing to CSF's protective effect against IR. To further elucidate molecular interactions, molecular docking studies were performed, focusing on the binding interactions between active constituents of CSF and crucial targets. Additionally, an RNA-sequencing assay was employed to uncover the underlying biochemical signaling pathway responsible for CSF's beneficial effects. To validate these findings, western blot and qPCR assays were employed to verify the pathways related to IR and the potential signaling cascades leading to the amelioration of IR. ResultsThe UHPLC/ESI-LTQ-Orbitrap-MS analysis successfully identified a total of thirty-six flavonoids derived from CSF. Moreover, CSF was shown to significantly improve glycogen synthesis and glucose consumption as well as inhibit gluconeogenesis in HepG2 cells of IR. An innovative network pharmacology analysis unveiled key hub genes—AKT1 and PI3K—integral to metabolic syndrome-related signaling pathways, which contributed to the favorable impact of CSF against IR. Noteworthy active ingredients including quercetin, ellagic acid and naringenin were identified as potential contributors to these effects. The results of western blot and qPCR assays provided compelling evidence that CSF improved insulin sensitivity by modulating the PI3K-Akt signaling pathway. Subsequent RNA-sequencing analysis, in tandem with western blot assays, delved deeper into the potential mechanisms underlying CSF's advantageous effects against IR, potentially associated with the enhancement of endoplasmic reticulum (ER) proteostasis. ConclusionCSF exhibited a remarkable ability to enhance insulin sensitivity in the IR model of HepG2 cells. This was evident through enhancements in glycogen synthesis and glucose consumption, along with its inhibitory impact on gluconeogenesis. Furthermore, CSF demonstrated an improvement in the insulin-mediated PI3K-Akt signaling pathway. The potential active constituents were identified as quercetin, ellagic acid and naringenin. The underlying biochemical mechanisms responsible for CSF's beneficial effects against IR were closely linked to its capacity to mitigate ER stress, thereby offering a comprehensive understanding of its protective action.

Functional properties of dietary quercetin in cardiovascular health and disease

AbstractThe increasing incidence of cardiovascular diseases has resulted in an escalating need for natural dietary supplements with cardioprotective properties. This review provides a thorough analysis of laboratory and clinical studies conducted on dietary quercetin, a widely available flavonoid, and its influence on the management of cardiovascular health and disease. The references cited in this review were obtained from reputable databases, including SciFinder, Web of Science, and ClinicalTrials.gov, with a specific focus on the period spanning from 1999 to 2023 pertaining to this subject matter. Notably, a bibliometric approach was used to analyze the bibliometric attribute trends of the research on quercetin associated with vascular health for the first time. Numerous investigations conducted on animal and human subjects at different phases of cardiac illness have consistently shown that the administration of quercetin substances improves cardiac function, suggesting the potential efficacy of quercetin in the management of heart disease. Evidently, the consumption of quercetin through dietary sources holds promise in conferring significant cardiovascular benefits through physiological mechanisms and biochemical signaling pathways, thus positioning it as a promising dietary contender for the prevention of cardiovascular disorders. Renewable food resources, including lovage leaves, elderberry, and radish leaves, which are abundant in quercetin, exhibit significant potential for the development and production of novel healthcare products with the objective of preventing cardiovascular disorders. This review is anticipated to provide valuable insights for the advancement of cardioprotective functional foods in the foreseeable future.

MCell4 with BioNetGen: A Monte Carlo simulator of rule-based reaction-diffusion systems with Python interface.

Biochemical signaling pathways in living cells are often highly organized into spatially segregated volumes, membranes, scaffolds, subcellular compartments, and organelles comprising small numbers of interacting molecules. At this level of granularity stochastic behavior dominates, well-mixed continuum approximations based on concentrations break down and a particle-based approach is more accurate and more efficient. We describe and validate a new version of the open-source MCell simulation program (MCell4), which supports generalized 3D Monte Carlo modeling of diffusion and chemical reaction of discrete molecules and macromolecular complexes in solution, on surfaces representing membranes, and combinations thereof. The main improvements in MCell4 compared to the previous versions, MCell3 and MCell3-R, include a Python interface and native BioNetGen reaction language (BNGL) support. MCell4's Python interface opens up completely new possibilities for interfacing with external simulators to allow creation of sophisticated event-driven multiscale/multiphysics simulations. The native BNGL support, implemented through a new open-source library libBNG (also introduced in this paper), provides the capability to run a given BNGL model spatially resolved in MCell4 and, with appropriate simplifying assumptions, also in the BioNetGen simulation environment, greatly accelerating and simplifying model validation and comparison.

Potential Common Mechanisms of Cytotoxicity Induced by Organophosphorus Pesticides via NLRP3 Inflammasome Activation.

The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1β, IL-18), in which the order of cytotoxicity was dichlorvos>dipterex>dibrom>paraoxon>fenthion>dimethoate, based on the IC50 values of 274, 410, 551, 585, 2,158, and 1,527,566μM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1β, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate>paraoxon>dichlorvos>dibrom>(fenthion and dipterex) based on K D values of 89.8, 325, 1,460, and 2,690μM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning.

Abstract 5641: Transcriptional regulation by nuclear deformation

Abstract Establishment and maintenance of cell identities requires transcriptional rewiring and modulation of three-dimensional genome organization. The nucleus is subject to constant mechanical forces, both intrinsic from the cytoskeleton and extrinsic, such as compression, confinement, and stretch. Recently, work from us and others implicate mechanical force, through activating biochemical signaling pathways as well as direct nuclear deformation, in remodeling nuclear architecture, chromatin state and global gene expression patterns. Thus, we hypothesize that mechanical force plays an important role in coordinating and thresholding transcriptional responses. Here, we challenge this hypothesis by quantifying the effect of nuclear deformation on transcription in real time at single cell resolution quasi genome wide. Further, recent work elucidated that the MYC oncogene exerts global effects on transcriptional output by altering the binding dynamics of transcription factors involved in the activation and productive elongation of RNA Polymerase II. This contrasts with mechanical stress which reduces global levels of RNA Polymerase II. Here we interrogate how transcriptional output is tuned for specific genetic programs/loci by mechanical force using MYC as a paradigm. Citation Format: Andrew Cook, Rebecca Stephens, Nadezda Fursova, Carson C. Chow, Dan Larson, Yekaterina Miroshnikova. Transcriptional regulation by nuclear deformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5641.

Transcriptomic analysis to identify genes associated with hypothalamus vulnerability in aging mice with cognitive decline

The normal aging process is accompanied by cognitive decline, and previous studies have indicated the crucial role of the hypothalamus in regulating both aging and cognition. However, the precise molecular mechanism underlying this relationship remains unclear. Therefore, this present study aimed to identify potential predictors of cognitive decline associated with aging specifically within the hypothalamus. To achieve this, we employed Morris water maze (MWM) testing to assess learning and memory differences between young and aged mice. Additionally, transcriptome sequencing was conducted on the hypothalamus of young and aged mice to identify potential genes. Subsequently, GO and KEGG analyses were performed to investigate the functions of differentially expressed genes (DEGs) and their associated biological pathways. Finally, the results obtained from sequencing analysis were further validated using qRT-PCR. Notably, MWM testing revealed a significant decrease in spatial learning and memory ability among aged mice. According to KEGG analysis, the DEGs primarily encompassed various biochemical signaling pathways related to immune system (e.g., C3; C4b; Ccl2; Ccl7; Cebpb; Clec7a; Col3a1; Cxcl10; Cxcl2; Fosb; Fosl1; Gbp5; H2-Ab1; Hspa1a; Hspa1b; Icam1; Il1b; Itga5; Itgax; Lilrb4a; Plaur; Ptprc; Serpine1; Tnfrsf10b; Tnfsf10), neurodegenerative disease (e.g., Atp2a1; Creb5; Fzd10; Hspa1a; Hspa1b; Il1b; Kcnj10; Nxf3; Slc6a3; Tubb6; Uba1y; Wnt9b), nervous system function (e.g., Chrna4; Chrna6; Creb5; Slc6a3),and aging (e.g., Creb5; Hspa1a; Hspa1b) among others. These identified genes may serve as potential predictors for cognitive function in elderly individuals and will provide a crucial foundation for further exploration into the underlying molecular mechanisms.

Mechanotransduction and epigenetic modulations of chromatin: Role of mechanical signals in gene regulation.

Mechanical forces may be generated within a cell due to tissue stiffness, cytoskeletal reorganization, and the changes (even subtle) in the cell's physical surroundings. These changes of forces impose a mechanical tension within the intracellular protein network (both cytosolic and nuclear). Mechanical tension could be released by a series of protein-protein interactions often facilitated by membrane lipids, lectins and sugar molecules and thus generate a type of signal to drive cellular processes, including cell differentiation, polarity, growth, adhesion, movement, and survival. Recent experimental data have accentuated the molecular mechanism of this mechanical signal transduction pathway, dubbed mechanotransduction. Mechanosensitive proteins in the cell's plasma membrane discern the physical forces and channel the information to the cell interior. Cells respond to the message by altering their cytoskeletal arrangement and directly transmitting the signal to the nucleus through the connection of the cytoskeleton and nucleoskeleton before the information despatched to the nucleus by biochemical signaling pathways. Nuclear transmission of the force leads to the activation of chromatin modifiers and modulation of the epigenetic landscape, inducing chromatin reorganizationand gene expression regulation; by the time chemical messengers (transcription factors) arrive into the nucleus. While significant research has been done on the role of mechanotransduction in tumor development and cancer progression/metastasis, the mechanistic basis of force-activated carcinogenesis is still enigmatic. Here, in this review, we have discussed the various cues and molecular connections to better comprehend the cellular mechanotransduction pathway, and we also explored the detailed role of some of the multiple players (proteins and macromolecular complexes) involved in mechanotransduction. Thus, we have described an avenue: how mechanical stress directs the epigenetic modifiers to modulate the epigenome of the cells and how aberrant stress leads to the cancer phenotype.

Synthesis and quantification of short-chain fatty acid esters of hydroxy fatty acids in rat intestinal contents and fecal samples by LC-MS/MS

Short-chain fatty acid esters of hydroxy fatty acids (SFAHFAs) are a new class of endogenous lipids belonging to the fatty acid esters of the hydroxy fatty acid family. We previously uncovered their chemical structure and discussed their potential biological significance. We anticipate an increased need for SFAHFA measurements as markers of metabolic and inflammatory health. In this study, we synthesized sixty isomeric SFAHFAs by combining 12 hydroxy fatty acids (C16–C24) and five short-chain fatty acids (C2–C6) including a labelled internal standard. SFAHFA enrichment was achieved by solid-phase extraction and established a sensitive method for their quantitation by targeted LC-MS/MS. The method was applied to profile SFAHFAs in intestinal contents and fecal samples collected from rats fed a high-fat diet (HFD). The results demonstrated a significant decrease in SFAHFAs in the intestinal contents of the HFD group compared with the control group. The fecal time course (0–8 weeks) profile of SFAHFAs showed significant downregulation of acetic and propanoic acid esters in just 2 weeks after HFD administration. This study offers the first synthesis and quantitation method for SFAHFAs, demonstrating their potential use in elucidating SFAHFA sources, their role in various diseases, and potential biochemical signalling pathways.

The Roles of the Hippo-YAP signalling pathway in Cartilage and Osteoarthritis.

Osteoarthritis (OA) is an age-related disease, characterized by cartilage degeneration. The pathogenesis of OA is complicated and the current therapeutic approaches for OA are limited. Cartilage, an integral part of the skeletal system composed of chondrocytes, is essential for skeletal development, tissue patterning, and maintaining the normal activity of joints. The development, homeostasis and degeneration of cartilage are tightly associated with OA. Over the past decade, accumulating evidence indicates that Hippo/YAP is a vital biochemical signalling pathway that strictly governs tissue development and homeostasis. The joint tissues, especially for cartilage, are sensitive to changes of Hippo/YAP signalling. In this review, we summarize the role of Hippo/YAP signalling in cartilage and discuss its involvement in OA progression from points of cartilage degradation, subchondral bone remodeling, and synovial alteration. We also highlight the potential therapeutic implications of Hippo/YAP signalling and further discuss current limitations and controversy on Hippo/YAP-based application for OA treatment.

Regulation and Expression of Phytohormones for Root Architectural Trait Development in Rice: A Review

The root system architecture (RSA) in monocotyledonous plants like rice is consists of primary roots, lateral roots, seminal/crown roots, and root hairs. The soil nutrients also influence many physiological processes via various root parameters like root length, root diameter and root angle for growth and development. The variation in root system architecture in rice is influenced by the intrinsic factors (phytohormones, transcription factors) and extrinsic factors (light, temperature and moisture) and their collective effect. The phytohormones such as; auxin, cytokinin, abscisic acid and ethylene, and their mutual effects play vital role for root architectural trait development. Many genes/QTLs were identified in rice which are strong role player for root development. But the biochemical signaling pathways are not completely understood. The modern molecular tools like genome editing, sequencing and multi-omics (transcriptomics and proteomics) approaches and multi-disciplinary system biology studies can provide a better solution for this issue. To improve the sustainable food grain production under extreme environment, it is important to understand the physiological and biochemical mechanism of root development. Moreover, it is imperative to establish a resilient root system in rice cultivation in order to mitigate the overuse of chemical fertilizers, enhance nutrient efficiency, and improve climate resilience of the plant.

Anti-inflammatory activities of flavonoid derivates.

Flavonoids are a group of phytochemicals found abundantly in various plants. Scientific evidence has revealed that flavonoids display potential biological activities, including their ability to alleviate inflammation. This activity is closely related to their action in blocking the inflammatory cascade and inhibiting the production of pro-inflammatory factors. However, as flavonoids typically have poor bioavailability and pharmacokinetic profile, it is quite challenging to establish these compounds as a drug. Nevertheless, progressive advancements in drug delivery systems, particularly in nanotechnology, have shown promising approaches to overcome such challenges. This narrative review provides an overview of scientific knowledge about the mechanism of action of flavonoids in the mitigation of inflammatory reaction prior to delivering a comprehensive discussion about the opportunity of the nanotechnology-based delivery system in the preparation of the flavonoid-based drug. Various studies conducted in silico, in vitro, in vivo, and clinical trials have deciphered that the anti-inflammatory activities of flavonoids are closely linked to their ability to modulate various biochemical mediators, enzymes, and signalling pathways involved in the inflammatory processes. This compound could be encapsulated in nanotechnology platforms to increase the solubility, bioavailability, and pharmacological activity of flavonoids as well as reduce the toxic effects of these compounds. In Summary, we conclude that flavonoids and their derivates have given promising results in their development as new anti-inflammatory drug candidates, especially if they formulate in nanoparticles.

Transducing compressive forces into cellular outputs in cancer and beyond.

In living organisms, cells sense mechanical forces (shearing, tensile, and compressive) and respond to those physical cues through a process called mechanotransduction. This process includes the simultaneous activation of biochemical signaling pathways. Recent studies mostly on human cells revealed that compressive forces selectively modulate a wide range of cell behavior, both in compressed and in neighboring less compressed cells. Besides participating in tissue homeostasis such as bone healing, compression is also involved in pathologies, including intervertebral disc degeneration or solid cancers. In this review, we will summarize the current scattered knowledge of compression-induced cell signaling pathways and their subsequent cellular outputs, both in physiological and pathological conditions, such as solid cancers.

Hepatic transcriptomic analysis reveals that Hif1α/ldha signal is involved in the regulation of hypoxia stress in black rockfish Sebastes schlegelii

Hypoxia has become a common problem for aquatic organisms due to the interaction of global climate change and human activity. Black rockfish inhabits rocky reefs in waters of Japan, Korea and China, whereas the limited hypoxia tolerance leads to mass mortality and great economic loss. In this study, high-throughput RNA-seq for transcriptomic analysis was used to investigate the hepatic response in black rockfish under hypoxia (critical oxygen tension, Pcrit; loss of equilibrium, LOE) and reoxygenation (recover normal dissolved oxygen 24 h, R24) to explore the mechanisms underlying hypoxia tolerance and adaptation. A total of 573,040,410 clean reads and 299 differentially expressed genes (DEGs) in total were obtained during hypoxia and reoxygenation. GO annotation and Kyoto Encyclopedia of Genes and Genomes analysis demonstrated that the DEGs are mainly enriched in the biochemical metabolic pathways and HIF-1 signaling pathways. Transcriptomic analysis also identified 18 DEGs associated with HIF-1 signaling pathway (hif1α, tf, epo, hmox, gult1, mknk2, ldha, pfkfb3, hkdc, aldoa) and biological process (hif2α, apoeb, bcl6, mr1, errfi1, slc38a4, igfbp1a, ap4m1) as further validated by quantitative real-time PCR. Moreover, hif1α was positively or negatively correlated with glucose (ldha, pfkfb3, hkdc, aldoa) and lipid (apoeb) metabolism-related genes. The mRNA level of hif1α was significantly up-regulated under acute hypoxia stress and obtained the higher values than hif2α. Meanwhile, hif1α recognized the hypoxia response element located in the promoter of ldha and directly bound to the promoter to transactivate ldha expression. These results indicated that black rockfish may mainly utilize glycolysis to maintain homeostasis, and hif1α facilities hypoxia tolerance by modulating ldha expression.

Insights to Gossypium defense response against Verticillium dahliae: the Cotton Cancer.

The soil-borne pathogen Verticillium dahliae, also referred as "The Cotton Cancer," is responsible for causing Verticillium wilt in cotton crops, a destructive disease with a global impact. To infect cotton plants, the pathogen employs multiple virulence mechanisms such as releasing enzymes that degrade cell walls, activating genes that contribute to virulence, and using protein effectors. Conversely, cotton plants have developed numerous defense mechanisms to combat the impact of V. dahliae. These include strengthening the cell wall by producing lignin and depositing callose, discharging reactive oxygen species, and amassing hormones related to defense. Despite the efforts to develop resistant cultivars, there is still no permanent solution to Verticillium wilt due to a limited understanding of the underlying molecular mechanisms that drive both resistance and pathogenesis is currently prevalent. To address this challenge, cutting-edge technologies such as clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9 (Cas9), host-induced gene silencing (HIGS), and gene delivery via nano-carriers could be employed as effective alternatives to control the disease. This article intends to present an overview of V. dahliae virulence mechanisms and discuss the different cotton defense mechanisms against Verticillium wilt, including morphophysiological and biochemical responses and signaling pathways including jasmonic acid (JA), salicylic acid (SA), ethylene (ET), and strigolactones (SLs). Additionally, the article highlights the significance of microRNAs (miRNAs), circular RNAs (circRNAs), and long non-coding RNAs (lncRNAs) in gene expression regulation, as well as the different methods employed to identify and functionally validate genes to achieve resistance against this disease. Gaining a more profound understanding of these mechanisms could potentially result in the creation of more efficient strategies for combating Verticillium wilt in cotton crops.

Analysis of EMT induction in a non-invasive breast cancer cell line by mesenchymal stem cell supernatant: Study of 2D and 3D microfluidic based aggregate formation and migration ability, and cytoskeleton remodeling.

The process of Epithelial-to-mesenchymal transition (EMT) as a phenotypic invasive shift and the factors affecting it, are under extensive research. Application of supernatants of human adipose-derived mesenchymal stem cells (hADMSCs) on non-invasive cancer cells is a well known method of in vitro induction of EMT like process. While previous researches have focused on the effects of hADMSCs supernatant on the biochemical signaling pathways of the cells through expression of different proteins and genes, we investigated pro-carcinogic alterations of physico-mechanical cues in terms of changes in cell motility and aggregated formation in 3D microenvironments, and cytoskeletal actin-myosin content and fiber arrangement. MCF-7 cancer cells were treated by the supernatant from 48hour-starved hADMSCs, and their vimentin/E-cadherin expressions were evaluated. The invasive potential of treated and non-treated cells was measured and compared through aggregate formation and migration capability. Furthermore, alterations in cell and nucleus morphologies were studied, and F-actin and myosin-II alterations in terms of content and arrangement were investigated. Results indicated that application of hADMSCs supernatant enhanced vimentin expression as the biomarker of EMT, and induced pro-carcinogenic effects on non-invasive cancer cells through increased invasive potential by higher cell motility and reduced aggregate formation, rearrangement of actin structure and generation of more stress fibers, together with increased myosin II that lead to enhanced cell motility and traction force. Our results indicated that in vitro induction of EMT through mesenchymal supernatant influenced biophysical features of cancer cells through cytoskeletal remodeling that emphasizes the interconnection of chemical and physical signaling pathways during cancer progress and invasion. Results give a better insight to EMT as a biological process and the synergy between biochemical and biophysical parameters that contribute to this process, and eventually assist in improving cancer treatment strategies.

Role of Vav1, a hematopoietic signal transduction molecule, as an adaptor protein in health and disease

The growth and differentiation of normal cells are controlled by protein-tyrosine kinases, which serve as receptors for a wide variety of external signals. Small protein modules called Src homology 2 (SH2) and SH3 domains mediate protein-protein interactions in signaling pathways that are triggered by protein tyrosine kinases. The SH2 domain, a protein module of around 100 amino acids, is present in tyrosine kinase targets within the cell. SH2 domains are recruited to activated and autophosphorylated growth factor receptors by directly recognizing tyrosine phosphorylation sites. Growth factor receptors and other phosphoproteins have short phosphotyrosine (pTyr)-containing sequences that are bound by SH2 domains. The SH3 domain, a distinct element of approximately 50 residues that recognizes proline-rich and hydrophobic-amino-acid-containing regions, is frequently found in SH2-containing proteins. Tyrosine kinases can be coupled to downstream targets with SH3-binding sites by proteins with SH2 and SH3 domains acting as adaptors. These intricate and precise biochemical signaling pathways result in the regulation of gene expression, cytoskeletal architecture, and cell metabolism. The role of SH2/SH3 proteins in T cell signaling will be discussed. A special focus will be on the role of the hematopoietic signal transducer with SH2/SH3 domains, Vav1, in health and cancer.

Interleukins (Cytokines) as Biomarkers in Colorectal Cancer: Progression, Detection, and Monitoring.

Cancer is the primary cause of death in economically developed countries and the second leading cause in developing countries. Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Risk factors for CRC include obesity, a diet low in fruits and vegetables, physical inactivity, and smoking. CRC has a poor prognosis, and there is a critical need for new diagnostic and prognostic biomarkers to reduce related deaths. Recently, studies have focused more on molecular testing to guide targeted treatments for CRC patients. The most crucial feature of activated immune cells is the production and release of growth factors and cytokines that modulate the inflammatory conditions in tumor tissues. The cytokine network is valuable for the prognosis and pathogenesis of colorectal cancer as they can aid in the cost-effective and non-invasive detection of cancer. A large number of interleukins (IL) released by the immune system at various stages of CRC can act as "biomarkers". They play diverse functions in colorectal cancer, and include IL-4, IL-6, IL-8, IL-11, IL-17A, IL-22, IL-23, IL-33, TNF, TGF-β, and vascular endothelial growth factor (VEGF), which are pro-tumorigenic genes. However, there are an inadequate number of studies in this area considering its correlation with cytokine profiles that are clinically useful in diagnosing cancer. A better understanding of cytokine levels to establish diagnostic pathways entails an understanding of cytokine interactions and the regulation of their various biochemical signaling pathways in healthy individuals. This review provides a comprehensive summary of some interleukins as immunological biomarkers of CRC.