Multifaceted Biological Processes Research Articles

OsSCYL2 is Involved in Regulating ABA Signaling-Mediated Seed Germination in Rice.

Seed germination represents a multifaceted biological process influenced by various intrinsic and extrinsic factors. In the present study, our investigation unveiled the regulatory role of OsSCYL2, a gene identified as a facilitator of seed germination in rice. Notably, the germination kinetics of OsSCYL2-overexpressing seeds surpassed those of their wild-type counterparts, indicating the potency of OsSCYL2 in enhancing this developmental process. Moreover, qRT-PCR results showed that OsSCYL2 was consistently expressed throughout the germination process in rice. Exogenous application of ABA on seeds and seedlings underscored the sensitivity of OsSCYL2 to ABA during both seed germination initiation and post-germination growth phases. Transcriptomic profiling following OsSCYL2 overexpression revealed profound alterations in metabolic pathways, MAPK signaling cascades, and phytohormone-mediated signal transduction pathways, with 15 genes related to the ABA pathways exhibiting significant expression changes. Complementary in vivo and in vitro assays unveiled the physical interaction between OsSCYL2 and TOR, thereby implicating OsSCYL2 in the negative modulation of ABA-responsive genes and its consequential impact on seed germination dynamics. This study elucidated novel insights into the function of OsSCYL2 in regulating the germination process of rice seeds through the modulation of ABA signaling pathways, thereby enhancing the understanding of the functional significance of the SCYL protein family in plant physiological processes.

Abstract 4638: Integrated proteogenomic characterization of longitudinal glioblastoma

Abstract Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor, with no curative treatment options and median patient survival time of almost one year. Despite multi-modal therapy including surgery, irradiation and chemotherapy, all patients experience tumor progression and recurrence. Our group proposed and validated the first single cell guided functional classification of primary GBM in four tumor-intrinsic cell states which informed clinical outcome and delivered therapeutic options. However, recurrent GBM remains therapeutically unresolved due in part to the diffusely invasive nature and in part to marked cellular heterogeneity of the tumor.The evolutionary trajectory of glioblastoma after therapy is a multifaceted biological process that extends beyond discrete genetic alterations alone. Here, we profiled by multi-omics platforms the largest dataset of matched primary and recurrent GBM including 123 longitudinal glioblastoma pairs, temporally separated by standard-of-care treatment. Genomics, proteomics, and phosphoproteomics all independently captured the loss of proliferative-progenitor characteristics and a significant upregulation of specialized neuronal and synaptic signaling programs in recurrent GBM. Proteomic and phosphoproteomic analyses revealed that the molecular transition from proliferative to neuronal state at recurrence is marked by coherent post-translational activation of the WNT/PCP signaling pathway and the BRAF protein kinase. Multi-omic analysis of Patient-Derived Xenograft (PDX) models mimicked the patterns of evolutionary trajectory, consisting of marked activation of neuronal signaling programs in recurrent patients. Inhibition of the BRAF kinase with small molecule inhibitors impaired both neuronal transition and migration capability of recurrent glioblastoma cells, which are the phenotypic hallmarks of glioblastoma progression after therapy. Accordingly, combinatorial treatment of temozolomide with BRAF inhibitor, vemurafenib, significantly prolonged the survival of mouse PDX models. This work provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance and highlights new therapeutic opportunities to effectively counter them in the clinic. Citation Format: Simona Migliozzi, Kyung-Hee Kim, Harim Koo, Jun-Hee Hong, Seung Min Park, Hyung Joon Kwon, Luciano Garofano, Young Taek Oh, Fulvio D'Angelo, Chan Il Kim, Anna-Luisa Di Stefano, Franck Bielle, Jinlong Yin, Marc Sanson, Do-Hyun Nam, Jason K. Sa, Anna Lasorella, Jong Bae Park, Antonio Iavarone. Integrated proteogenomic characterization of longitudinal glioblastoma [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 4638.

CAFs vs. TECs: when blood feuds fuel cancer progression, dissemination and therapeutic resistance.

Neoplastic progression involves complex interactions between cancer cells and the surrounding stromal milieu, fostering microenvironments that crucially drive tumor progression and dissemination. Of these stromal constituents, cancer-associated fibroblasts (CAFs) emerge as predominant inhabitants within the tumor microenvironment (TME), actively shaping multiple facets of tumorigenesis, including cancer cell proliferation, invasiveness, and immune evasion. Notably, CAFs also orchestrate the production of pro-angiogenic factors, fueling neovascularization to sustain the metabolic demands of proliferating cancer cells. Moreover, CAFs may also directly or indirectly affect endothelial cell behavior and vascular architecture, which may impact in tumor progression and responses to anti-cancer interventions. Conversely, tumor endothelial cells (TECs) exhibit a corrupted state that has been shown to affect cancer cell growth and inflammation. Both CAFs and TECs are emerging as pivotal regulators of the TME, engaging in multifaceted biological processes that significantly impact cancer progression, dissemination, and therapeutic responses. Yet, the intricate interplay between these stromal components and the orchestrated functions of each cell type remains incompletely elucidated. In this review, we summarize the current understanding of the dynamic interrelationships between CAFs and TECs, discussing the challenges and prospects for leveraging their interactions towards therapeutic advancements in cancer.

Integrated proteogenomic characterization of glioblastoma evolution

The evolutionary trajectory of glioblastoma (GBM) is a multifaceted biological process that extends beyond genetic alterations alone. Here, we perform an integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs and identify a highly proliferative cellular state at diagnosis and replacement by activation of neuronal transition and synaptogenic pathways in recurrent tumors. Proteomic and phosphoproteomic analyses reveal that the molecular transition to neuronal state at recurrence is marked by post-translational activation of the wingless-related integration site (WNT)/ planar cell polarity (PCP) signaling pathway and BRAF protein kinase. Consistently, multi-omic analysis of patient-derived xenograft (PDX) models mirror similar patterns of evolutionary trajectory. Inhibition of B-raf proto-oncogene (BRAF) kinase impairs both neuronal transition and migration capability of recurrent tumor cells, phenotypic hallmarks of post-therapy progression. Combinatorial treatment of temozolomide (TMZ) with BRAF inhibitor, vemurafenib, significantly extends the survival of PDX models. This study provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance, highlighting promising therapeutic strategies for clinical intervention.

Accelerating wound healing: Unveiling synergistic effects of P25/SWCNT/Ag and P25/rGO/Ag nanocomposites within PRP-gelatin scaffold, highlighting the synergistic antimicrobial activity.

Wound healing is a multifaceted biological process requiring innovative strategies to enhance efficiency and counter infections. In this groundbreaking study, we investigate the regenerative potential of platelet-rich plasma (PRP) integrated into a gelatin (GLT) scaffold along with nanocomposites of titanium dioxide (TiO2) (P25)/single-walled carbon nanotubes (SWCNTs)/Ag and P25/reduced graphene oxide (rGO)/Ag. Incorporating these advanced materials into the PRP/GLT delivery system aims to optimize the controlled release of growth factors (GFs) and leverage the exceptional properties of nanomaterials for enhanced tissue repair and wound healing outcomes. Antioxidant activity assessment using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity reveals the superior performance of P25/SWCNTs/Ag compared to P25/rGO/Ag. Their synergistic effects are evaluated in conjunction with antibacterial and antifungal antibiotics. Furthermore, the wound healing potential of P25/SWCNTs/Ag and P25/rGO/Ag, combined with PRP/GLT, is examined. Notably, both nanocomposites exhibit promising synergistic effects with gentamicin and fluconazole against pathogenic strains. Significantly, the inclusion of non-activated PRP substantially augments the wound healing efficacy of P25/SWCNTs/Ag on days 3 (p<0.01) and 15 (p<0.05). These findings pave the way for advanced wound dressing and therapeutic interventions, capitalizing on the synergistic effects of PRP and nanomaterials, thus ultimately benefiting patients and advancing regenerative medicine.

CNSC-08. PROTEOGENOMIC ANALYSIS OF LONGITUDINAL TRAJECTORY OF GLIOBLASTOMA EVOLUTION

Abstract The evolutionary trajectory of glioblastoma after therapy is a multifaceted biological process that extends beyond discrete genetic alterations alone. Here, we performed a proteogenomic analysis of 123 longitudinal glioblastoma pairs, temporally separated by standard-of-care treatment. Integrative analyses identified a prevalence of a highly proliferative cellular state at diagnosis and its replacement by recurrent tumors sharing activation of neuronal differentiation and synaptogenicpathways. Proteomic and phosphoproteomic analyses revealed that the molecular transition from the proliferative to the neuronal state at recurrence is marked by coherent post-translational activation of the WNT/PCP signaling pathway and the BRAF protein kinase. Multi-omic analysis of the Patient-Derived Xenograft (PDX) model demonstrated similar patterns of evolutionary trajectory, marked by activation of neuronal signaling programs that were consistently observed in longitudinal patients. Inhibition of the BRAF kinase with small molecule inhibitors impaired both neuronal differentiation and migration capability of recurrent glioblastoma cells, which are the phenotypic hallmarks of glioblastoma progression after therapy. This work provides comprehensive insights into the biological mechanisms of glioblastoma evolution and treatment resistance and highlights new therapeutic opportunities to effectively counter them in the clinic.

Identification of selective 5-LOX and FLAP inhibitors as novel anti-inflammatory agents by ligand-based virtual screening

Inflammation is a multifaceted biological process in which the conversion of arachidonic acid to eicosanoids, including prostaglandins and leukotrienes (LTs), plays a crucial role. 5-Lipoxygenase (5-LOX) is a key enzyme in cellular LT biosynthesis, and it is supported by the accessory protein 5-lipoxygenase-activating protein (FLAP). Pharmacological interventions to modulate LTs aim at either decreasing their biosynthesis or at mitigating their biological effects. Therefore, inhibiting 5-LOX or FLAP represents a useful strategy to reduce inflammation. Herein we present the identification and pharmacological evaluation of novel inhibitors targeting 5-LOX or FLAP. By means of a ligand-based virtual screening approach, we selected 38 compounds for in vitro assays. Among them, ALR-38 exhibits direct 5-LOX inhibition, while ALR-6 and ALR-27 showed potential as FLAP inhibitors. These latter not only reduced LT production but also promoted the generation of specialized pro-resolving mediators in specific human macrophage phenotypes. Interestingly, the identified compounds turned out to be selective for their respective targets, as none of them displayed activity towards microsomal prostaglandin E2 synthase-1 and soluble epoxide hydrolase, which are other proteins involved in eicosanoid biosynthesis. Thus, these compounds are endowed with potential therapeutic utility in mitigating inflammatory responses and might offer a venue for tackling inflammation-based disorders.

Curcumin-Loaded Nanofibrous Matrix Accelerates Fibroblast Cell Proliferation and Enhances Wound Healing via GSK3-β Inhibition

Wound healing is a multifaceted biological process influenced by both intrinsic and extrinsic factors. The ability of Wnt signaling to activate cell proliferation appears to serve a central role in wound healing. Therefore, the direct activation of Wnt or inhibition of the Wnt antagonist could be an ideal approach for the stimulation of wound healing. This study aimed to investigate the underlying mechanism of small molecule-loaded nanofibrous matrix in inducing wound healing. Herein, a naturally derived small molecule, curcumin, was used to inhibit the GSK3-β, which is considered a negative regulator of the Wnt/β-catenin signaling pathway. The docking results demonstrated that curcumin makes a complex with GSK3-β at seven specific sites, thereby inhibiting its activity. Moreover, the stabilization of β-catenin appeared to be increased with the treatment of curcumin. Next, curcumin was incorporated in poly ε-caprolactone nanofibrous matrices for controlled–sustained drug release to induce cell function. Curcumin-loaded nanofibrous matrix not only enhanced fibroblast cell proliferation, but also induced the expression of the fibroblast growth factor (FGF) in vitro. Moreover, the in vivo results showed that these nanofibrous mats significantly induced wound closure in 12 mm critical-sized defect. Collectively, these results suggest that the developed nanofibrous matrix promotes impaired wound healing by modulating cell proliferation and enhancing FGF expression that promotes wound closure.

Emerging biology of noncoding RNAs in malaria parasites.

In eukaryotic organisms, noncoding RNAs (ncRNAs) have been implicated as important regulators of multifaceted biological processes, including transcriptional, posttranscriptional, and epigenetic regulation of gene expression. In recent years, it is becoming clear that protozoan parasites encode diverse ncRNA transcripts; however, little is known about their cellular functions. Recent advances in high-throughput “omic” studies identified many novel long ncRNAs (lncRNAs) in apicomplexan parasites, some of which undergo splicing, polyadenylation, and encode small proteins. To date, only a few of them are characterized, leaving a big gap in our understanding regarding their origin, mode of action, and functions in parasite biology. In this review, we focus on lncRNAs of the human malaria parasite Plasmodium falciparum and highlight their cellular functions and possible mechanisms of action.

Cordyceps militaris as a Bio Functional Food Source: Pharmacological Potential, Anti-Inflammatory Actions and Related Molecular Mechanisms.

Cordyceps militaris (C. militaris) is a medicinal mushroom possessing a variety of biofunctionalities. It has several biologically important components such as polysaccharides and others. The diverse pharmacological potential of C. militaris has generated interest in reviewing the current scientific literature, with a particular focus on prevention and associated molecular mechanisms in inflammatory diseases. Due to rising global demand, research on C. militaris has continued to increase in recent years. C. militaris has shown the potential for inhibiting inflammation-related events, both in in vivo and in vitro experiments. Inflammation is a multifaceted biological process that contributes to the development and severity of diseases, including cancer, colitis, and allergies. These functions make C. militaris a suitable functional food for inhibiting inflammatory responses such as the regulation of proinflammatory cytokines. Therefore, on the basis of existing information, the current study provides insights towards the understanding of anti-inflammatory activity-related mechanisms. This article presents a foundation for clinical use, and analyzes the roadmap for future studies concerning the medical use of C. militaris and its constituents in the next generation of anti-inflammatory drugs.

Alzheimer Disease Pathogenesis: The Role of Autoimmunity.

In addition to deposits of amyloid β (Aβ) plaques and neurofibrillary tangles, growing evidence demonstrates that complex and multifaceted biological processes can arise during Alzheimer disease (AD) pathogenesis. The recent failures of clinical trials based on the amyloid hypothesis and the presence of Aβ plaques in cognitively healthy elderly persons without AD point toward a need to explore novel pathobiological mechanisms of AD. In the search for alternative AD mechanisms, numerous genome-wide association studies and mechanistic discoveries suggest a potential immunologic component of the disease. However, new experimental tools are needed to uncover these immunogenic components. The current methods, such as ELISAs or protein microarrays, have limitations of low throughput and/or sensitivity and specificity. In this article, we briefly discuss evidence of potential autoimmune contributions to AD pathobiology, describe the current methods for identifying autoantibodies in patient fluids, and outline our own efforts to develop new techniques for novel autoantibody biomarker discovery. Uncovering the putative autoimmune components of AD may be crucial in paving the way to new concepts for pathogenesis, diagnosis, and therapy. In addition to deposits of amyloid β plaques and neurofibrillary tangles, growing evidence demonstrates that complex and multifaceted biological processes can arise during Alzheimer disease (AD) pathogenesis. Numerous research directions, including genome-wide association, clinical correlation, and mechanistic studies, have pointed to a potential autoimmunologic contribution to AD pathology. We present research suggesting the association between autoimmunity and AD and demonstrate the need for new laboratory techniques to further characterize potential brain antigen-specific autoantibodies. Uncovering the putative autoimmune components of AD may be crucial in paving the way to new concepts for pathogenesis, diagnosis, and therapy.

Extracting Insights From Temporal Data by Integrating Dynamic Modeling and Machine Learning.

Biological processes are dynamic. As a result, temporal analyses are necessary to fully understand the complex interactions that occurs within these systems. One example of a multifaceted biological process is restitution: the initial step in complex wound repair. Restitution is a dynamic process that depends on an elegant orchestration between damaged cells and their intact neighbors. Such orchestration enables the quick repair of the damaged area, which is essential to preserve epithelial integrity and prevent further injury. High quality dynamic data of the cellular and molecular events that make up the gastric restitution process has been documented. However, comprehensive dynamic models that connect all relevant molecular interactions to cellular behaviors are challenging to construct and experimentally validate. In order to efficiently provide feedback to ongoing experimental work, we have integrated dynamical modeling and machine learning to efficiently extract data-driven insights without incorporating detailed mechanisms. Dynamical models convert time course data into a set of static features, which are then subjected to machine learning analysis. The integrated analysis provides data-driven insights into how repair might be regulated in individual gastric organoids. We have provided a “proof of concept” of how such an analysis pipeline can be used to analyze any temporal dataset and provide timely data-driven insights.

Crafting Polymeric and Peptidic Hydrogels for Improved Wound Healing.

Wound healing is a multifaceted biological process involving the replacement of damaged tissues and cellular structures, restoring the skin barrier's function, and maintaining internal homeostasis. Over the past two decades, numerous approaches are undertaken to improve the quality and healing rate of complex acute and chronic wounds, including synthetic and natural polymeric scaffolds, skin grafts, and supramolecular hydrogels. In this context, this review assesses the advantages and drawbacks of various types of supramolecular hydrogels including both polymeric and peptide-based hydrogels for wound healing applications. The molecular design features of natural and synthetic polymers are examined, as well as therapeutic-based and drug-free peptide hydrogels, and the strategies for each system are analyzed to integrate key elements such as biocompatibility, bioactivity, stimuli-responsiveness, site specificity, biodegradability, and clearance.

Genome-wide identification and expression analysis of genes associated with peach (Prunus persica) fruit ripening

Fruit ripening is determined by the coordinated action of multi-faceted biological processes. However, little is known about the molecular mechanism of fruit ripening in peach. To explore the genes involved into fruit ripening, in this study, transcriptome sequencing was conducted in the peach fruits at the stone hardening, the second rapid growth, and ripening stages. By comparing the expression levels of whole genes between the ripening (LYE) and developing fruits (LYD and LYC), 1 615 and 1 938 genes were up- and down-regulated in the ripening fruits. In these differential expressed genes, the PG, PL8, and XTH33 genes related to cell wall degradation were up-regulated in ripening fruits, in contrast, two GDSL genes against the xyloglucan oligosaccharides were down regulated. The CABs, photosystem I/II, and OEE genes involved in photosynthesis were detected having the lowest expression levels in the ripening fruits. The genes associated with ethylene response, biosynthesis, and auxin-responsive were remarkably increased in expression levels in ripening fruits. The stress related genes UP3, EDR2L, PR1, PR4 and programmed cell death gene ACD11 also displayed an up-regulation trends during fruit ripening. Few ripening-related transcription factors, such as NAC, MADS-box, and MYB, were also detected from the differential expressed genes. Moreover, expression patterns of the selected genes were tested by real-time quantitative PCR (qRT-PCR), and the qRT-PCR results were consistent with transcriptome data. This study provides important candidate genes for exploring the complex metabolic process involved in ripening.

BAG3 promotes proliferation of ovarian cancer cells via post-transcriptional regulation of Skp2 expression

Bcl-2 associated athanogene 3 (BAG3) contains a modular structure, through which BAG3 interacts with a wide range of proteins, thereby affording its capacity to regulate multifaceted biological processes. BAG3 is often highly expressed and functions as a pro-survival factor in many cancers. However, the oncogenic potential of BAG3 remains not fully understood. The cell cycle regulator, S-phase kinase associated protein 2 (Skp2) is increased in various cancers and plays an important role in tumorigenesis. The current study demonstrated that BAG3 promoted proliferation of ovarian cancer cells via upregulation of Skp2. BAG3 stabilized Skp2 mRNA via its 3′-untranslated region (UTR). The current study demonstrated that BAG3 interacted with Skp2 mRNA. In addition, miR-21-5p suppressed Skp2 expression, which was compromised by forced BAG3 expression. These results indicated that at least some oncogenic functions of BAG3 were mediated through posttranscriptional regulation of Skp2 via antagonizing suppressive action of miR-21-5p in ovarian cancer cells.

Ruptured abdominal aortic aneurysm-epidemiology, predisposing factors, and biology.

Abdominal aortic aneurysm is a common degenerative vascular disorder associated with sudden death due to aortic rupture. This review describes epidemiology, predisposing factors, and biology of ruptured abdominal aortic aneurysms (rAAAs). Based on a selective literature search in Medline (PubMed), original publications, meta-analyses, systematic reviews, and Cochrane reviews were evaluated for rAAA. The hospital admission rate for rAAA is decreasing and is now in the range of approximately 10 per 100,000 population in men. Smoking contributes to about 50% of population risk for rupture or surgically treated AAA. AAA rupture is a multifaceted biological process involving biochemical, cellular, and proteolytic influences, in addition to biomechanical factors. AAA rupture occurs when the stress (force per unit area) on the aneurysm wall exceeds wall strength. Proteolytic activities of matrix metalloproteinases have been implicated in aneurysm wall weakening and rupture. Aneurysm diameter is the most prominent predisposing factor for aneurysm growth and rupture. Wall stress, aneurysm shape and geometry, intraluminal thrombus, wall thickness, calcification, and metabolic activity influence the rupture risk. The best conservative option to avoid AAA rupture consists in smoking cessation and control of hypertension. Many biological factors influence rupture risk.

Pharmacokinetics of Dietary Isoflavones

Dietary isoflavones are reported to have significant influences on human health. The beneficial effects reported include reduced risk of cancers, decreased menopausal symptoms, reduced osteoporosis etc. Most of these benefits have been deduced from epidemiological studies involving soy bean as the source of dietary isoflavones, since soy bean is an important food crop in several parts of the world. Over the last 30 years, considerable progress has been made in understanding the fate of dietary isoflavones in humans. Now we understand that the pharmacokinetics of dietary isoflavones is a complex phenomenon and involving multifaceted biological processes. The role of gut micro flora in deciding the bioavailability of isoflavones is quite significant. This review examines various pharmacokinetic aspects of dietary isoflavones and factors influencing the systemic bioavailability of isoflavones. This review also attempts to identify important factors which may contribute to the inter-person differences in the effects of isoflavones.

How Environmental Agents Influence the Aging Process

Abstract － Aging is a multifaceted biological process that affects all organs and organ systems of the body. This review provides an up-to-date analysis of this highly exciting, rapidly changing field of science. The aging process is largely under genetic control but is highly responsive to diverse environmental influences. The genes that control aging are those that are involved with cell maintenance, cell damage and repair. The environmental factors that accelerate aging are those that influence either damage of cellular macro-molecules, or interfere with their repair. Prominent among these are chronic inflammation, chronic infection, some metallic chemicals, ultraviolet light, and others that heighten oxidative stress. Other environment factors slow the aging process. Included among these agents are resveratrol and vitamin D. In addition, dietary restriction and exercise have been found to extend human lifespan. The various mechanisms whereby all these agents exert their influence on aging include epigenetic modification, chromatin maintenance, protection of telomeres, and anti-oxidant defense, among others. The complex process of aging remains under continued, intense investigation. Keywords: Aging, Environment, Oxidative stress, Inflammation, Heavy metals, Resveratrol, Calorie restriction

Starting and propagating apoptotic signals in UVB irradiated keratinocytes

The ultraviolet (UV) B portion of the UV light has been recognized as the most prominent risk factor for the development of skin cancer, the most common malignancy in the Caucasian population. At the cellular level, UVB signal transduction regulates replicative arrest and DNA repair, gene expression and, when damage is beyond repair, apoptotic cell death, which is induced to protect the host against the accumulation of potentially mutagenic keratinocytes. An increasing body of evidence indicates that the UVB response in skin is a complex and multifaceted biological process. The UVB signal transduction originates at multiple intracellular sites, and the cross talk between dedicated molecular mediators acting within a complex signal network, determines whether the UVB damaged cell will survive, proliferate or die. However, very little is known about the original targets or direct chromophores that put in motion the UVB response in its main target: the keratinocyte. In this review we discuss the recent identification of signalling pathways linking apical UVB mediated damaging events with the induction of apoptosis. Understanding the molecular mechanisms that underlie the process of apoptotic cell death in UVB exposed keratinocytes, is of outmost importance to reveal how defects in apoptotic pathways can contribute to skin cancer.