Crosstalk Of Signaling Pathways Research Articles

Molecular Signaling Pathways and MicroRNAs in Bone Remodeling: A Narrative Review.

Bone remodeling is an intricate process executed throughout one's whole life via the cross-talk of several cellular events, progenitor cells and signaling pathways. It is an imperative mechanism for regaining bone loss, recovering damaged tissue and repairing fractures. To achieve this, molecular signaling pathways play a central role in regulating pathological and causal mechanisms in different diseases. Similarly, microRNAs (miRNAs) have shown promising results in disease management by mediating mRNA targeted gene expression and post-transcriptional gene function. However, the role and relevance of these miRNAs in signaling processes, which regulate the delicate balance between bone formation and bone resorption, are unclear. This review aims to summarize current knowledge of bone remodeling from two perspectives: firstly, we outline the modus operandi of five major molecular signaling pathways, i.e.,the receptor activator of nuclear factor kappa-B (RANK)-osteoprotegrin (OPG) and RANK ligand (RANK-OPG-RANKL), macrophage colony-stimulating factor (M-CSF), Wnt/β-catenin, Jagged/Notch and bone morphogenetic protein (BMP) pathways in regards to bone cell formation and function; and secondly, the miRNAs that participate in these pathways are introduced. Probing the miRNA-mediated regulation of these pathways may help in preparing the foundation for developing targeted strategies in bone remodeling, repair and regeneration.

Resveratrol nanoparticles induce apoptosis in oral cancer stem cells by disrupting the interaction between β-catenin and GLI-1 through p53-independent activation of p21.

Cancer stem cells (CSCs) are mainly responsible for tumorigenesis, chemoresistance, and cancer recurrence. CSCs growth and progression are regulated by multiple signaling cascades including Wnt/β-catenin and Hh/GLI-1, which acts independently or via crosstalk. Targeting the crosstalk of signaling pathways would be an effective approach to control the CSC population. Both Wnt/β-catenin and Hh/GLI-1 signaling cascades are known to be regulated by p53/p21-dependent mechanism. However, it is interesting to delineate whether p21 can induce apoptosis in a p53-independent manner. Therefore, utilizing various subtypes of oral CSCs (SCC9-PEMT p53+/+p21+/+, SCC9-PEMT p53-/-p21+/+, SCC9-PEMT p53+/+p21-/- and SCC9-PEMT p53-/-p21-/-), we have examined the distinct roles of p53 and p21 in Resveratrol nanoparticle (Res-Nano)-mediated apoptosis. It is interesting to see that, besides the p53/p21-mediated mechanism, Res-Nano exposure also significantly induced apoptosis in oral CSCs through a p53-independent activation of p21. Additionally, Res-Nano-induced p21-activation deregulated the β-catenin-GLI-1 complex and consequently reduced the TCF/LEF and GLI-1 reporter activities. In agreement with in vitro data, similar experimental results were obtained in in vivo mice xenograft model.

Influence of intersignaling crosstalk on the intracellular localization of YAP/TAZ in lung cells.

A cell is a dynamic system in which various processes occur simultaneously. In particular, intra- and intercellular signaling pathway crosstalk has a significant impact on a cell's life cycle, differentiation, proliferation, growth, regeneration, and, consequently, on the normal functioning of an entire organ. Hippo signaling and YAP/TAZ nucleocytoplasmic shuttling play a pivotal role in normal development, homeostasis, and tissue regeneration, particularly in lung cells. Intersignaling communication has a significant impact on the core components of the Hippo pathway and on YAP/TAZ localization. This review describes the crosstalk between Hippo signaling and key lung signaling pathways (WNT, SHH, TGFβ, Notch, Rho, and mTOR) using lung cells as an example and highlights the remaining unanswered questions.

Plasmacytoid dendritic cells are central regulators of the humoral ChAdOx1 nCoV-19 vaccine response in a human tonsil organoid model

Abstract Studying human vaccine responses is limited by the difficulty of access to secondary lymphoid tissues. To overcome this, we have optimized a human tonsil organoid model to investigate the processes that regulate the humoral responses to the ChAdOx1 nCoV-19 vaccine. Stimulation of tonsil cultures with ChAdOx1 nCoV-19 induced broad innate immune activation and cytokine secretion within 24 hours. This induced (global and antigen-specific) B cell activation and spike-specific antibody secretion over the following 14-day culture period. Stimulation with an irrelevant ChAdOx1 GFP vector did not induce spike-specific antibody secretion. Plasmacytoid dendritic cells (pDCs) showed the highest rate of transduction and activation. Critically, pDC-depletion decreased both innate and humoral responses. IFN-⍺ blockade phenocopied pDC depletion while supplementing IFN-⍺ to pDC-depleted cultures rescued humoral responses. IL-6 was also critical for optimal humoral responses, and its production was modulated in an IFN-⍺-dependent manner even in the absence of pDCs, suggesting cross-talk of multiple key signaling pathways. Overall, this model reveals a critical role for pDCs in inducing humoral responses to ChAdOx1 nCoV-19, primarily through IFN-⍺. IFN-⍺ appears to act directly and indirectly through IFN-induced IL-6 secretion to augment the humoral response. This model has the potential for studying other vaccine platforms.

Sulfate Availability and Hormonal Signaling in the Coordination of Plant Growth and Development.

Sulfur (S), one of the crucial macronutrients, plays a pivotal role in fundamental plant processes and the regulation of diverse metabolic pathways. Additionally, it has a major function in plant protection against adverse conditions by enhancing tolerance, often interacting with other molecules to counteract stresses. Despite its significance, a thorough comprehension of how plants regulate S nutrition and particularly the involvement of phytohormones in this process remains elusive. Phytohormone signaling pathways crosstalk to modulate growth and developmental programs in a multifactorial manner. Additionally, S availability regulates the growth and development of plants through molecular mechanisms intertwined with phytohormone signaling pathways. Conversely, many phytohormones influence or alter S metabolism within interconnected pathways. S metabolism is closely associated with phytohormones such as abscisic acid (ABA), auxin (AUX), brassinosteroids (BR), cytokinins (CK), ethylene (ET), gibberellic acid (GA), jasmonic acid (JA), salicylic acid (SA), and strigolactones (SL). This review provides a summary of the research concerning the impact of phytohormones on S metabolism and, conversely, how S availability affects hormonal signaling. Although numerous molecular details are yet to be fully understood, several core signaling components have been identified at the crossroads of S and major phytohormonal pathways.

Abstract 1844: Proteomic characterization of decitabine resistance in acute myeloid leukemia reveals signaling pathway crosstalk dampens the effectiveness of combination therapy

Abstract Acute myeloid leukemia (AML) is a deadly form of blood cancer primarily characterized by genetic abnormalities that guide treatment strategies. In recent years, several new therapies have emerged to target these genetic abnormalities such as gilteritinib or quizartinib, which target an internal tandem duplication (ITD) of the FLT3 gene. Additional drugs have been developed to target core cellular processes, such as venetoclax and the decitabine. Despite initial positive responses to these treatments, patients eventually relapse as they develop resistance to the individual drugs. One common approach to drug resistance is to add an additional drug to the treatment protocol. However, patients then develop further resistance to not just a single drug but multiple. As such, understanding the origins of both single and multi-drug resistance is crucial for improving treatment efficacy and clinical outcomes. Here, we present a collection of cell lines that have developed resistance to single, double, and triple drug combinations of gilteritinib, venetoclax, and decitabine. Through comprehensive global and phospho proteomics analyses under multiple conditions together with computational pathway interrogation, we unravel the underlying molecular mechanisms responsible for resistance. Leveraging our previous model of early and late drug resistance, we investigate the emergence of resistance to drug combinations involving gilteritinib alone, gilteritinib with venetoclax, gilteritinib with decitabine, and gilteritinib with venetoclax and decitabine. Through the characterization of molecular signatures for each drug combination, we identify molecular signals that are specific to combination treatments. Specifically, we find that the emergences of decitabine resistance alters the cellular pathways to effectively downregulate targets of venetoclax and gilteritinib, ultimately dampening the response to these drugs, regardless of co-administration. These findings provide a potential explanation for the limited success of combination treatments involving hypomethylating agents, as observed in recent clinical trials. Our results underscore the importance of monitoring proteome-level changes in single and combination drug treatments and shed light on the simple and intuitive reasons behind the lack of synergy often observed in combination therapies. In conclusion, we establish cell line models of resistance to various combinations of venetoclax, gilteritinib, and decitabine. By integrating global and phospo proteomic measurements, we gain a comprehensive understanding of the intricate molecular mechanisms underlying resistance. Citation Format: James C. Pino, Camilo Posso, Setareh Sharzehi, Sara Gosline, Chelsea Hutchinson-Bunch, Elie Traer, Paul D. Piehowski, Karin D. D. Rodland, Jeffrey W. Tyner, Tao Liu, Anupriya Agarwal. Proteomic characterization of decitabine resistance in acute myeloid leukemia reveals signaling pathway crosstalk dampens the effectiveness of combination therapy [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 1844.

Zein-Derived Peptides from Corn Promote the Proliferation of C2C12 Myoblasts via Crosstalk of mTORC1 and mTORC2 Signaling Pathways.

Dietary protein supplementation has emerged as a promising strategy in combating sarcopenia. Furthermore, searching for alternatives of animal proteins has been a hot topic. The present study aimed to investigate the effects of zein peptides on C2C12 myoblasts and explore their potential molecular mechanisms. The proliferative, cell cycle, and anti-apoptotic activities of zein peptides were evaluated. Peptidomics analysis and transcriptome sequencing were employed to explore the structure-activity relationship and underlying molecular mechanisms. The results indicated that zein peptides (0.05-0.2 mg/mL) exerted a significant proliferation-promoting impact on C2C12 cells, via increasing cell viability by 33.37 to 42.39%. Furthermore, zein peptides significantly increased S phase proportion and decreased the apoptosis rate from 34.08% (model group) to 28.96% in C2C12 cells. In addition, zein peptides exhibited a pronounced anti-apoptotic effect on C2C12 cells. Zein peptides are abundant in branch-chain amino acids, especially leucine. Transcriptomics analysis revealed that zein peptides can promote proliferation, accelerate cell cycle, and improve protein synthesis of muscle cells through mTORC1 and mTORC2 signaling pathways.

NopAA and NopD Signaling Association-Related Gene GmNAC27 Promotes Nodulation in Soybean (Glycine max).

Rhizobia secrete effectors that are essential for the effective establishment of their symbiotic interactions with leguminous host plants. However, the signaling pathways governing rhizobial type III effectors have yet to be sufficiently characterized. In the present study, the type III effectors, NopAA and NopD, which perhaps have signaling pathway crosstalk in the regulation of plant defense responses, have been studied together for the first time during nodulation. Initial qRT-PCR experiments were used to explore the impact of NopAA and NopD on marker genes associated with symbiosis and defense responses. The effects of these effectors on nodulation were then assessed by generating bacteria in which both NopAA and NopD were mutated. RNA-sequencing analyses of soybean roots were further utilized to assess signaling crosstalk between NopAA and NopD. NopAA mutant and NopD mutant were both found to repress GmPR1, GmPR2, and GmPR5 expression in these roots. The two mutants also significantly reduced nodules dry weight and the number of nodules and infection threads, although these changes were not significantly different from those observed following inoculation with double-mutant (HH103ΩNopAA&NopD). NopAA and NopD co-mutant inoculation was primarily found to impact the plant-pathogen interaction pathway. Common differentially expressed genes (DEGs) associated with both NopAA and NopD were enriched in the plant-pathogen interaction, plant hormone signal transduction, and MAPK signaling pathways, and no further changes in these common DEGs were noted in response to inoculation with HH103ΩNopAA&NopD. Glyma.13G279900 (GmNAC27) was ultimately identified as being significantly upregulated in the context of HH103ΩNopAA&NopD inoculation, serving as a positive regulator of nodulation. These results provide new insight into the synergistic impact that specific effectors can have on the establishment of symbiosis and the responses of host plant proteins.

Cytokine activity in Parkinson's disease.

The contribution of the immune system to the pathophysiology of neurodegenerative Parkinson's disease (PD) is increasingly being recognised, with alterations in the innate and adaptive arms of the immune system underlying central and peripheral inflammation in PD. As chief modulators of the immune response, cytokines have been intensely studied in the field of PD both in terms of trying to understand their contribution to disease pathogenesis, and if they may comprise much needed therapeutic targets for a disease with no current modifying therapy. This review summarises current knowledge on key cytokines implicated in PD (TNFα, IL-6, IL-1β, IL-10, IL-4 and IL-1RA) that can modulate both pro-inflammatory and anti-inflammatory effects. Cytokine activity in PD is clearly a complicated process mediated by substantial cross-talk of signalling pathways and the need to balance pro- and anti-inflammatory effects. However, understanding cytokine activity may hold promise for unlocking new insight into PD and how it may be halted.

CSIG-06. CROSSTALK BETWEEN ONCOGENIC SIGNALING PATHWAYS AS DRIVERS OF THERAPY RESISTANCE AGAINST SMALL MOLECULE INHIBITORS IN GLIOBLASTOMA

Abstract Patients with glioblastoma multiforme (GBM) have a median survival of 15 months. Despite an intensive treatment schedule with resection, radio- and chemotherapy, recurrence is inevitable. An important challenge to overcome GBM treatment resistance involves intratumoral heterogeneity, characterized by molecularly, phenotypically, and clinically distinctive GBM subtypes. Different small molecule inhibitors have been designed to inhibit signaling proteins in oncogenic driver pathways, including the EGFR, PDGFR, MET, CDK4, and PI3K/Akt pathway, in GBM. However, these small molecule inhibitors have been unsuccessful in improving patient outcome. Here, we investigate if crosstalk and redundancy in signaling pathways is responsible for single-agent resistance using patient-derived glioblastoma 2D stem cell cultures (pdGBM). Eight brain-penetrable and clinically approved small molecule inhibitors (SMI) were used to target key GBM driver genes. We measured cell viability in triplicate with a CellTiter-Glo assay. The half-maximal inhibitory concentration (IC50) for each inhibitor was defined for six molecularly distinct pdGBM 2D cell cultures. Although inhibition of downstream effector proteins reduced cell viability more effectively (IC50 70nM-1µM), compared to inhibiting upstream membrane-bound tyrosine kinase receptors (IC50 1-15µM), remaining cell proliferation was seen in all pdGBM using the different SMIs as single agent. To identify resistance mechanisms, we investigated changes in phosphokinase activity after SMI monotherapy in the different pdGBM 2D cell cultures. Based upon these results, we could identify combinations of SMIs targeting compensatory pathways that drive treatment resistance. In conclusion, this study presents a mechanistically driven selection of tumor tailored combination treatment to overcome resistance to SMI monotherapy in pdGBM. The efficacy of these novel SMI combinations will be challenged next, moving from pdGBM 2D stem cell cultures towards pdGBM organoids.

Trinity of inflammation, innate immune cells and cross-talk of signalling pathways in tumour microenvironment.

Unresolved inflammation is a pathological consequence of persistent inflammatory stimulus and perturbation in regulatory mechanisms. It increases the risk of tumour development and orchestrates all stages of tumorigenesis in selected organs. In certain cancers, inflammatory processes create the appropriate conditions for neoplastic transformation. While in other types, oncogenic changes pave the way for an inflammatory microenvironment that leads to tumour development. Of interest, hallmarks of tumour-promoting and cancer-associated inflammation are striking similar, sharing a complex network of stromal (fibroblasts and vascular cells) and inflammatory immune cells that collectively form the tumour microenvironment (TME). The cross-talks of signalling pathways initially developed to support homeostasis, change their role, and promote atypical proliferation, survival, angiogenesis, and subversion of adaptive immunity in TME. These transcriptional and regulatory pathways invariably contribute to cancer-promoting inflammation in chronic inflammatory disorders and foster "smouldering" inflammation in the microenvironment of various tumour types. Besides identifying common target sites of numerous cancer types, signalling programs and their cross-talks governing immune cells' plasticity and functional diversity can be used to develop new fate-mapping and lineage-tracing mechanisms. Here, we review the vital molecular mechanisms and pathways that establish the connection between inflammation and tumour development, progression, and metastasis. We also discussed the cross-talks between signalling pathways and devised strategies focusing on these interaction mechanisms to harness synthetic lethal drug combinations for targeted cancer therapy.

Transcriptome atlas of Striga germination: Implications for managing an intractable parasitic plant

Societal Impact StatementWitchweeds, parasitic plants of the genus Striga, are nicknamed “cereal killers” because of their devastating destruction of Africa's most staple cereals, including maize, sorghum, millets, and upland rice. The parasite relies on biomolecules emitted from the host roots to germinate and therefore initiate its infectious lifecycle. Some sorghum varieties have evolved to not produce effective germination stimulants, making them resistant to the parasite. Here, the genetic factors that underpin Striga germination were assessed, followed by a discussion of how such knowledge can be used to develop new Striga management strategies through the disruption of host–parasite communication exchange.Summary Seeds of the parasitic plant Striga are dormant. They only germinate in response to biomolecules emitted from the host's root exudate, strigolactones (SL). But it is now emerging that Striga germination is a much more complex process regulated by crosstalk of hormone signaling pathways. To further understand the genetic basis of the communication exchange between Striga and its host sorghum, we performed a comparative transcriptomic analysis. We sought to identify major transcriptomic changes that define the germination process in Striga and a set of genes that may contribute to the differences in germination rates. Results showed that germination proceeds immediately after SL perception and is marked by a wave of transcriptional reprogramming to allow for metabolic processes of energy mobilization. Cluster analysis using self‐organizing maps revealed a time‐phased and genotype‐differentiated response to germination stimulation. The variation in germination was also a function of hormonal crosstalk. The early germination stage was associated with significant repression of genes in the abscisic acid (ABA) biosynthesis pathway. Other hormones influenced germination as follows: (i) ABA and auxin repressed germination; (ii) brassinosteroid, ethylene, and jasmonic acid promoted germination; and (iii) cytokinin had a more prominent role post‐germination rather than during germination. Perception of SL sets the germination program leading to different rates of germination in sorghum, followed by a complex hormonal regulation network that acts to either repress or enhance germination. We discuss the implications of these findings and present new plausible Striga management strategies.

Abstract A002: A reciprocal signaling crosstalk between the AR and BCl2-AKT pathways induces castration resistance in castration sensitive prostate cancer

Abstract Introduction: A leading contributor to the significant mortality burden of prostate cancer (PC) is the resistance to androgen deprivation therapy (ADT). Although most PCs are initially sensitive to ADT, the duration of response is variable, and relapse invariably occurs in the transition to metastatic castration-resistant prostate cancer (mCRPC), the lethal form of the disease. Therefore, it is essential to discover and validate early resistance mechanisms that initially protect castration sensitive prostate cancer (CSPC) cells from ADT and to develop novel combination therapies that can block or delay the ADT-induced shift from CSPC to mCRPC. Overexpression of the hallmark antiapoptotic gene B-cell lymphoma 2 (BCL2) is a potential mechanism of resistance to ADT. Methods: To discover the molecular drivers of castration resistance, we analyzed the tumor transcriptomic profile of a cohort of localized PC patients (N=58) treated with neoadjuvant-intensive ADT (NCT00924469; Taplin et al, 2014, Sowalsky et al, 2018). Experimentally, we treated CSPC cells and genetically engineered mice (GEM) prostate tumors with ADT and analyzed the signaling pathways, which were enriched post-ADT treatment compared untreated samples. Results: We discovered ~10-fold increased mRNA expression of BCL2 (p<0.001) in ADT-treated localized PC patients compared to untreated (standard of care surgery) patients in NCT00924469 samples. Our experimental study showed that treatment with AR inhibitors strongly augments BCL2 expression in human CSPC cell lines and GEM PC model, indicating possible direct negative regulation of BCL2 by the AR-signaling pathway. Mechanistically, our preliminary data reveal a striking induction of cell metabolism pathways (fatty acid and xenobiotic metabolism), including activation of PI3K/AKT signaling in BCL2-overexpressing CSPC cells. We used siRNA-mediated BCL2 knockdown in LNCaP cells and showed that loss of BCL2 strongly suppressed ADT-induced AKT- phosphorylation. We also showed increased Bcl2 mRNA expression in PTEN-knockout mice-derived prostate organoids compared to the wild-type control. Furthermore, we observed that AKT kinase -inhibitor MK2206 strongly inhibits enzalutamide-induced BCL2 expression in LNCaP cells. Conclusion: Together our data indicate a non-canonical role of BCL2 in activating PI3K/AKT signaling in prostate cancer. For the first time, we demonstrate the crucial importance of AR-BCL2-AKT signaling pathway crosstalk in CSPC biology and reveal this complex signaling crosstalk may act as a key driver of CSPC transformation to lethal CRPC. Citation Format: Goutam Chakraborty, Rahim Hirani, Subhiksha Nandakumar, Nabila Zaman, Teja Muralidhar Kalidindi, Sai Harisha Rajanala, Gwo-Shu M. Lee, Konrad H. Stopsack, Naga Vara Kishore Pillarsetty, Lorelei A. Mucci, Daniel C. Danila, Philip W. Kantoff. A reciprocal signaling crosstalk between the AR and BCl2-AKT pathways induces castration resistance in castration sensitive prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A002.

Unraveling context-specific mechanisms governing calcium-YAP/TAZ distinct relationships through computational modeling.

Yes-associated protein (YAP) and its homolog TAZ are transducers of several biochemical and biomechanical signals, serving to integrate multiplexed inputs from the microenvironment into higher level cellular functions such as proliferation, differentiation, apoptosis, migration, and hemostasis. Emerging evidence suggests that calcium is a key second messenger that closely connects microenvironmental input signals and YAP/TAZ regulation. However, studies that directly modulate Ca2+ have reported contradictory YAP/TAZ responses: In some studies, a reduction in Ca2+ influx increases the activity of YAP/TAZ, while in others an increase in Ca2+ influx activates YAP/TAZ. Importantly, Ca2+ and YAP/TAZ exhibit distinct spatiotemporal dynamics, making it difficult to unravel their connections from a purely experimental approach. In this study, we developed a network model of Ca2+-mediated YAP/TAZ signaling to investigate how temporal dynamics and crosstalk of signaling pathways interacting with calcium can alter YAP/TAZ response. By including six signaling modules (e.g., GPCR, IP3- Ca2+, Kinases, RhoA, F-actin, and Hippo-YAP/TAZ) that interact with calcium, we investigated both transient and steady-state cell response to Angiotensin II, Thapsigargin, and ECM stiffness stimuli. The model predicts a context-dependent relationship between calcium signaling and YAP/TAZ activation primarily mediated by PKC, DAG, CaMKII, and F-actin. Model results illustrate the role of calcium dynamics and CaMKII bistable response in switching the direction of changes in Ca2+-induced YAP/TAZ activity. Frequency-dependent YAP/TAZ response revealed the competition between upstream regulators of LATS1/2, leading to the YAP/TAZ non-monotonic response to periodic GPCR stimulation. We also identified key roles of Ca2+ and CaMKII dynamics in shaping the nonlinear relationship between cell size and YAP/TAZ activity. The model predicts Ca2+-YAP/TAZ distinct relationships in different settings consistent with experiments. The model predictions provide new insights into the underlying mechanisms responsible for the controversial Ca2+-YAP/TAZ relationship observed in experiments.

Targeting crosstalk of signaling pathways in cancer stem cells: a promising approach for development of novel anti-cancer therapeutics

Wnt, Hedgehog (Hh), and Notch signaling pathways are the evolutionarily conserved signaling pathways that regulate the embryonic development and also play crucial role in maintaining stemness properties of cancer stem cells (CSCs) and inducing epithelial-to-mesenchymal transition (EMT), metastasis, and angiogenesis. It has been highly challenging to inhibit the CSCs growth and proliferation as these are capable of evading chemotherapeutic drugs and cause cancer recurrence through multiple signaling pathways. Therefore, novel therapeutic strategies to target the key players involved in the crosstalk of these signaling pathways need to be developed. In this review, we have identified the interacting molecules of Wnt, Hh, and Notch pathways responsible for enhancing the malignant properties of CSCs. Analyzing the functions of these crosstalk molecules will help us to find an approach toward the development of new anti-cancer drugs for inhibition of CSCs growth and progression. Long non-coding RNAs (LncRNAs) play a significant role in various cellular processes, like chromatin remodeling, epigenetic modifications, transcriptional, and post-transcriptional regulations. Here, we have highlighted the research findings suggesting the involvement of LncRNAs in maintenance of the stemness properties of CSCs through modulation of the above-mentioned signaling pathways. We have also discussed about the different therapeutic approaches targeting those key players responsible for mediating the crosstalk between the pathways. Overall, this review article will surely help the cancer biologists to design novel anti-CSCs agents that will open up a new horizon in the field of anti-cancer therapeutics.

Mechanisms underlying divergent relationships between Ca2+ and YAP/TAZ signalling.

Yes-associated protein (YAP) and its homologue TAZ are transducers of several biochemical and biomechanical signals, integrating multiplexed inputs from the microenvironment into higher level cellular functions such as proliferation, differentiation and migration. Emerging evidence suggests that Ca2+ is a key second messenger that connects microenvironmental input signals and YAP/TAZ regulation. However, studies that directly modulate Ca2+ have reported contradictory YAP/TAZ responses: in some studies, a reduction in Ca2+ influx increases the activity of YAP/TAZ, while in others, an increase in Ca2+ influx activates YAP/TAZ. Importantly, Ca2+ and YAP/TAZ exhibit distinct spatiotemporal dynamics, making it difficult to unravel their connections from a purely experimental approach. In this study, we developed a network model of Ca2+ -mediated YAP/TAZ signalling to investigate how temporal dynamics and crosstalk of signalling pathways interacting with Ca2+ can alter the YAP/TAZ response, as observed in experiments. By including six signalling modules (e.g. GPCR, IP3-Ca2+ , kinases, RhoA, F-actin and Hippo-YAP/TAZ) that interact with Ca2+ , we investigated both transient and steady-state cell response to angiotensin II and thapsigargin stimuli. The model predicts that stimuli, Ca2+ transients and frequency-dependent relationships between Ca2+ and YAP/TAZ are primarily mediated by cPKC, DAG, CaMKII and F-actin. Simulation results illustrate the role of Ca2+ dynamics and CaMKII bistable response in switching the direction of changes in Ca2+ -induced YAP/TAZ activity. A frequency-dependent YAP/TAZ response revealed the competition between upstream regulators of LATS1/2, leading to the YAP/TAZ non-monotonic response to periodic GPCR stimulation. This study provides new insights into underlying mechanisms responsible for the controversial Ca2+ -YAP/TAZ relationship observed in experiments. KEY POINTS: YAP/TAZ integrates biochemical and biomechanical inputs to regulate cellular functions, and Ca2+ acts as a key second messenger linking cellular inputs to YAP/TAZ. Studies have reported contradictory Ca2+ -YAP/TAZ relationships for different cell types and stimuli. A network model of Ca2+ -mediated YAP/TAZ signalling was developed to investigate the underlying mechanisms of divergent Ca2+ -YAP/TAZ relationships. The model predicts context-dependent Ca2+ transient, CaMKII bistable response and frequency-dependent activation of LATS1/2 upstream regulators as mechanisms governing the Ca2+ -YAP/TAZ relationship. This study provides new insights into the underlying mechanisms of the controversial Ca2+ -YAP/TAZ relationship to better understand the dynamics of cellular functions controlled by YAP/TAZ activity.

Calcium voltage-gated channel subunit alpha 1C and glial fibrillary acidic protein signaling pathways as a selective biomarker in predicting the efficacy of liposomal loaded co-enzyme Q in the autistic rat model.

Autism spectrum disorder (ASD) is an extreme neuropsychotic disturbance with both environmental and genetic origins. Sodium propionate (PPA) a metabolic bioproduct of gut microbiota is well-thought-out as a successful autism animal model. Nevertheless, Liposomal drug delivery system possess the advantagous of biocompatibility, targeting organs, ability to carry large drug payloads and skipping macrophages for this purpose the current study was carried out to investigate the hypothesis that Calcium Voltage-Gated channel subunit alpha 1C (CACNA1C) and glial fibrillary acidic protein (GFAP) signaling pathways crosstalk with the efficacy of Co-enzyme Q10 (Co-Q10) and liposomal loaded Co-enzyme Q10 (L Co-Q10) in PPA mediated autistic rat model. Autism was conducted by buffered PPA (500mg/Kg b.wt) daily for 5 consecutive days subsequently treatment via Co-Q10 in a dose of (10mg/kg b.wt) and L Co-Q10 (2mg/kg b.wt) for four weeks then the autistic model was followed for signs of autism at different time intervals of (one, two and four weeks). The control, PPA intoxicated, and treated groups were subjected to behavioral tests (Y-Maze and open field), antioxidant analysis, gene expression analysis, and histological examination at different time intervals of the study. The results revealed that Co-Q10 and L Co-Q10 significantly elevated antioxidative stress biomarkers, comprising superoxide dismutase (SOD), glutathione (GSH), and total antioxidant capacity (TAC). In addition, they significantly ameliorated the oxidative stress biomarker malondialdehyde (MDA). Meanwhile, they significantly downregulated GFAP and CACNA1C mRNA gene expressions, Co-Q10 and LCo-Q10 showed improvement in almost brain regions post PPA histopathological alterations, even better results were manifested via LCo-Q10 groups. These results showed the superiority of LCo-Q10 over Co-Q10 in competing autism. In conclusion: The administration of anti-inflammatory and antioxidant agents such as Co-Q10 and L Co-Q10 may represent a promising strategy to counteract pathological behaviors in ASD model via targeting organs, increasing retention time, and reducing side effects.

Targeting Crosstalk of Signaling Pathways among Muscles-Bone-Adipose Tissue: A Promising Therapeutic Approach for Sarcopenia.

The aging process is associated with the development of a wide range of degenerative disorders in mammals. These diseases are characterized by a progressive decline in function at multiple levels, including the molecular, cellular, tissue, and organismal. Furthermore, it is responsible for various healthcare costs in developing and developed countries. Sarcopenia is the deterioration in the quality and functionality of muscles, which is extremely concerning as it manages many functions in the human body. This article reviews the molecular crosstalk involved in sarcopenia and the specific roles of many mediator molecules in establishing cross-talk between muscles, bone, and fatty tissues, eventually leading to sarcopenia. Besides, the involvement of various etiological factors, such as neurology, endocrinology, lifestyle, etc., makes it exceedingly difficult for clinicians to develop a coherent hypothesis that may lead to the well-organized management system required to battle this debilitating disease. The several hallmarks contributing to the progression of the disease is a vital question that needs to be addressed to ensure an efficient treatment for sarcopenia patients. Also, the intricate molecular mechanism involved in developing this disease requires more studies. The direct relationship of cellular senescence with aging is one of the pivotal issues contributing to disease pathophysiology. Some patented treatment strategies have been discussed, including drugs undergoing clinical trials and emerging options like miRNA and protein-enclosed extracellular vesicles. A clear understanding of the secretome, including the signaling pathways involved between muscles, bone, and fatty tissues, is extremely beneficial for developing novel therapeutics for curing sarcopenia.

Analysis of metabolic and transcription levels provides insights into the interactions of plant hormones and crosstalk with MAPKs in the early signaling response of cherry tomato fruit induced by the yeast cell wall

Yeast cell walls (YCW) are promising bio-based elicitors for controlling post-harvest fruit decay. In this study, 1% YCW induction increased the resistance of cherry tomato fruits, reducing disease incidence by 66%. This study aimed to explore the interaction of hormones and crosstalk with MAPKs (mitogen-activated protein kinases) in the early response of resistance regulation in cherry tomato fruits treated with YCW and U0126. We analyzed the temporal changes in hormone content, the expression of critical genes involved in phytohormone biosynthesis, and signal transduction in cherry tomato fruits response to the induction. Results revealed that jasmonic acid (JA) and brassinosteroids (BR) significantly regulated early resistance response in fruit induced by 1% YCW. The salicylic acid (SA) pathway is inhibited by the activation of the JA pathway. JA and SA signaling pathway crosstalk with the MAPK3 pathway. BR plays an essential role in the regulation of fruit resistance. The BR pathway may function independently when JA/SA and MAPK3 pathways are inhibited.

Transgenic PDGF-BB sericin hydrogel potentiates bone regeneration of BMP9-stimulated mesenchymal stem cells through a crosstalk of the Smad-STAT pathways.

Silk as a natural biomaterial is considered as a promising bone substitute in tissue regeneration. Sericin and fibroin are the main components of silk and display unique features for their programmable mechanical properties, biocompatibility, biodegradability and morphological plasticity. It has been reported that sericin recombinant growth factors (GFs) can support cell proliferation and induce stem cell differentiation through cross-talk of signaling pathways during tissue regeneration. The transgenic technology allows the productions of bioactive heterologous GFs as fusion proteins with sericin, which are then fabricated into solid matrix or hydrogel format. Herein, using an injectable hydrogel derived from transgenic platelet-derived GF (PDGF)-BB silk sericin, we demonstrated that the PDGF-BB sericin hydrogel effectively augmented osteogenesis induced by bone morphogenetic protein (BMP9)-stimulated mesenchymal stem cells (MSCs) in vivo and in vitro, while inhibiting adipogenic differentiation. Further gene expression and protein-protein interactions studies demonstrated that BMP9 and PDGF-BB synergistically induced osteogenic differentiation through the cross-talk between Smad and Stat3 pathways in MSCs. Thus, our results provide a novel strategy to encapsulate osteogenic factors and osteoblastic progenitors in transgenic sericin-based hydrogel for robust bone tissue engineering.