Interlinked Pathways Research Articles

Teatime: epigallocatechin gallate targets fibroblast-epithelial cell crosstalk to combat lung fibrosis.

Epigallocatechin gallate (EGCG) is a polyphenol plant metabolite abundant in tea that has demonstrated antifibrotic properties in the lung. In this issue of the JCI, Cohen, Brumwell, and colleagues interrogated the mechanistic action of EGCG by investigating lung biopsies of patients with mild interstitial lung disease (ILD) who had undergone EGCG treatment. EGCG targeted the WNT inhibitor SFRP2, which was enriched in fibrotic fibroblasts and acted as a TGF-β target, with paracrine effects leading to pathologic basal metaplasia of alveolar epithelial type 2 cells. This study emphasizes the epithelial-mesenchymal trophic unit as a central signaling hub in lung fibrosis. Understanding and simultaneous targeting of interlinked signaling pathways, such as TGF-β and WNT, paves the road for future treatment options for pulmonary fibrosis.

Simultaneous measurement of 17 endogenous steroid hormones in human serum by liquid chromatography-tandem mass spectrometry without derivatization

Mass spectrometric-based steroidomics is a valuable analytical approach that gives a comprehensive understanding of the interlinked steroid biosynthetic pathways. Here, we describe a rapid and versatile liquid chromatography-tandem mass spectrometry (LC-MS/MS) method designed to accurately quantify endogenous steroids in human serum. Sample preparation involved liquid-liquid extraction with methyl tert-butyl ether (MTBE) from 180 µL serum. The targeted steroids for quantification included androgens: dehydroepiandrosterone (DHEA), androstenedione (A4), testosterone (T), dihydrotestosterone (DHT), 11-oxyandrogens: 11β-hydroxy-androstenedione (11OHA4), 11-keto-androstenedione (11KA4), 11β-hydroxy-testosterone (11OHT), 11-keto-testosterone (11KT), progestogens: 17α-hydroxy-progesterone (17OHP4), progesterone (P4), 11β-hydroxy-progesterone (11OHP4), 11-keto-progesterone (11KP4), mineralocorticoids: aldosterone, corticosterone, and glucocorticoids: 11-deoxycortisol, cortisol, and cortisone. The lower limits of quantification (LLOQ) were 0.05 ng/mL for A4, T, 11KA4, P4, and cortisone, 0.1 ng/mL for DHT, 11OHA4, 11OHT, 11KT, 17OHP4, 11OHP4, 11KP4, corticosterone, aldosterone, 11-deoxycortisol, and cortisol, and 0.5 ng/mL for DHEA. Accuracy, precision, reproducibility, and recovery fell within acceptable limits for bioanalytical method validation. Using serum samples from 29 premenopausal women in different menstrual phases, we demonstrated the clinical utility of our method, which showed sufficient sensitivity to reliably quantify all targeted steroids at levels typically found in circulation, except for 11OHP4 and 11KP4.

Role of oxidative stress in the concurrent development of osteoporosis and tendinopathy: Emerging challenges and prospects for treatment modalities.

Both osteoporosis and tendinopathy are widely prevalent disorders, encountered in diverse medical contexts. Whilst each condition has distinct pathophysiological characteristics, they share several risk factors and underlying causes. Notably, oxidative stress emerges as a crucial intersecting factor, playing a pivotal role in the onset and progression of both diseases. This imbalance arises from a dysregulation in generating and neutralising reactive oxygen species (ROS), leading to an abnormal oxidative environment. Elevated levels of ROS can induce multiple cellular disruptions, such as cytotoxicity, apoptosis activation and reduced cell function, contributing to tissue deterioration and weakening the structural integrity of bones and tendons. Antioxidants are substances that can prevent or slow down the oxidation process, including Vitamin C, melatonin, resveratrol, anthocyanins and so on, demonstrating potential in treating these overlapping disorders. This comprehensive review aims to elucidate the complex role of oxidative stress within the interlinked pathways of these comorbid conditions. By integrating contemporary research and empirical findings, our objective is to outline new conceptual models and innovative treatment strategies for effectively managing these prevalent diseases. This review underscores the importance of further in-depth research to validate the efficacy of antioxidants and traditional Chinese medicine in treatment plans, as well as to explore targeted interventions focused on oxidative stress as promising areas for future medical advancements.

Two tales of Kushtau Hill movement: ethnic environmental mobilisation and perceived costs of neopatrimonialism

In recent years the number of environmental protests in Russian regions has been on the rise, despite the shrinking political opportunity structure. In the Bashkortostan republic, the Bashkir Soda Company's (BSC) decision to develop the Kushtau Hill for soda ash provoked an environmental campaign to save the mountain. The Kushtau Hill movement succeeded, despite the highly repressive response from regional government and its tight patrimonial link to the BSC - two conditions identified in the literature as unfavorable to protesters. How is environmental discontent successfully mobilised under a repressive government and embedded extractive practices? Drawing on semi-structured interviews with activists, I trace two interlinked pathways to successful mobilisation. The first one testifies to the role played by national organisations in sustaining environmental collective action. Under a shrinking opportunity structure for formal ENGOs, the Bashkir national organisation “Bashkort” provided the emerging movement with its experience of informal organisation. Its leadership successfully linked ethnic grievances to environmental mobilisation byclaiming the Bashkirs' special relation to the mountain. However, ethnic and neighbour ties did not prevent a repressive response from the regional government due to a limited scale of the mobilisation. The second story deals with framing processes that expand the scope of potential supporters beyond particularistic ties. Protesters highlighted the perceived costs of neopatrimonialism to justify their demands. This framing put the republic head as a scapegoat who secured interests of the federal centre and BSC, compromising the residents' ecological well-being. Therefore, Kushtau Hill activists attracted new members, not putting themselves into danger of being perceived as extremists that targeted a regime-dimension.

At the Limits of Willing: Anticipatory Attunements and Mooded Backgrounds

ABSTRACT This article proceeds along three interlinked pathways of thinking about the ‘will.’ First, a phenomenological analysis of willing is explored that pays special attention to what Edmund Husserl termed the background of willing – namely, the always already present existential conditions within which particular experiences of willing unfold. Second, further reflection upon the background of willing is advanced to consider how experiences of willing relate to other ongoing forms of worldly attunement, such as those that are evidenced in moods. Third, three distinct examples of despair as a mooded background of willing are analysed. These examples range from Bourdieu’s description of postwar unemployment to Bukowski’s reflections on his early working life to an exploration of despair and the limits of willing on the island of Yap, Federated States of Micronesia.

Complex chemical reaction networks for future information processing.

Tackling the increasing energy demand of our society is one of the key challenges today. With the rise of artificial intelligence, information and communication technologies started to substantially contribute to this alarming trend and therefore necessitate more sustainable approaches for the future. Brain-inspired computing paradigms represent a radically new and potentially more energy-efficient approach for computing that may complement or even replace CMOS in the long term. In this perspective, we elaborate on the concepts and properties of complex chemical reaction networks (CRNs) that may serve as information-processing units based on chemical reactions. The computational capabilities of simpler, oscillatory chemical reactions have already been demonstrated in scenarios ranging from the emulation of Boolean gates to image-processing tasks. CRNs offer higher complexity and larger non-linearity, potentially at lower energy consumption. Key challenges for the successful development of CRN-based computers are associated with their specific physical implementations, operability, and readout modalities. CRNs are sensible to various reaction triggers, and provide multiple and interlinked reaction pathways and a diverse compound space. This bears a high potential to build radically new hardware and software concepts for energy-efficient computing based on neuromorphic architectures-with computing capabilities in real-world applications yet to be demonstrated.

Immunoregulation: the interplay between metabolism and redox homeostasis.

Regulatory T cells are fundamental for the induction and maintenance of immune homeostasis, with their dysfunction resulting in uncontrolled immune responses and tissue destruction predisposing to autoimmunity, transplant rejection and several inflammatory and metabolic disorders. Recent discoveries have demonstrated that metabolic processes and mitochondrial function are critical for the appropriate functioning of these cells in health, with their metabolic adaptation, influenced by microenvironmental factors, seen in several pathological processes. Upon activation regulatory T cells rearrange their oxidation-reduction (redox) system, which in turn supports their metabolic reprogramming, adding a layer of complexity to our understanding of cellular metabolism. Here we review the literature surrounding redox homeostasis and metabolism of regulatory T cells to highlight new mechanistic insights of these interlinked pathways in immune regulation.

Adipose-Derived Stem Cells to Treat Ischemic Diseases: The Case of Peripheral Artery Disease

Critical limb ischemia incidence and prevalence have increased over the years. However, there are no successful treatments to improve quality of life and to reduce the risk of cardiovascular and limb events in these patients. Advanced regenerative therapies have focused their interest on the generation of new blood vessels to repair tissue damage through the use of stem cells. One of the most promising sources of stem cells with high potential in cell-based therapy is adipose-derived stem cells (ASCs). ASCs are adult mesenchymal stem cells that are relatively abundant and ubiquitous and are characterized by a multilineage capacity and low immunogenicity. The proangiogenic benefits of ASCs may be ascribed to: (a) paracrine secretion of proangiogenic molecules that may stimulate angiogenesis; (b) secretion of microvesicles/exosomes that are also considered as a novel therapeutic prospect for treating ischemic diseases; and (c) their differentiation capability toward endothelial cells (ECs). Although we know the proangiogenic effects of ASCs, the therapeutic efficacy of ASCs after transplantation in peripheral artery diseases patients is still relatively low. In this review, we evidence the potential therapeutic use of ASCs in ischemic regenerative medicine. We also highlight the main challenges in the differentiation of these cells into functional ECs. However, significant efforts are still needed to ascertain relevant transcription factors, intracellular signaling and interlinking pathways in endothelial differentiation.

An Adaptive Framework for Regenerative Agriculture based on Environmental Management

Introduction The scope of implementing innovative research findings aimed at sustainable development goals seems to be inherently limited by economic and social acceptance, despite their technical efficacy. There exists a huge demand for coordinated efforts to mitigate the negative impacts of the so-called ‘development’ activities that are tampering with the very existence of humanity, natural resources, and the environment. Agriculture, though historically the first and foremost occupation of humans, has always been intrigued by nature at the cost of natural calamities and uncertainties in ensuring the availability and timely distribution of essential resources. In the modern context of water-energy-food paradigms, the agriculture sector can play a pivotal role in bolstering the state economy in multifaceted ways by assuming the adaptability of recent scientific advancements to the core functional attributes of sustainability. In this scenario, the concept of regenerative agriculture can be better understood as a holistic, self-adaptive, and integrated approach towards not only bringing about a revolutionary breakthrough in agricultural productivity but also providing a retroactive and reconstructive strategy for minimizing the inevitable consequences of destructive developments. An organized, synthesized approach in this direction would certainly culminate in fabricating close-connected, supportive interlinking pathways for related fields of science and technology to make them more beneficial towards the responsible productivity expected from the agriculture sector [1].The prospects of environmental research have established a close interlink with the agriculture sector, mainly through the attributes of material, energy, and living species. It is envisaged that the environment is a bigger space with multiple spheres of activity, while agriculture comprises a smaller sect with limited but well-defined interactions with the environment [2]. Even though it is generally accepted that most of these interactions (such as soil quality and crop growth, water requirement and crop selection, raining pattern and cropping seasons, etc.) are mutually directed, one could perceive them as if initially driven by agricultural activities. However, there are some other interactions where environmental attributes are driving agricultural activities and outputs [3-5]. Most of these interactions are, nonetheless, subtle and complex, and little is known about their individual lead roles. Hence, it is important to identify the specific attributes of some of the well-known interactions and look for the key drivers towards addressing the original problem of agriculture and sustainability.A dynamic interaction between agriculture and environment is observed to be well-reinstated through the simultaneous existence and exchanges of the energy, materials and activities (Figure 1). It is, however, expected that a compensating step is essential to redirect (or push forward) such exchanges without creating adverse environmental impacts as well as agricultural losses.List of About the Conference, Conference Model, Publication of the Proceedings, Proceedings Editors, Technical Advisory Committee are available in this Pdf.

Transcriptomic profile of GLCs of PCOS women highlights metabolic dysregulation as a plausible contributor to PCOS pathophysiology

Polycystic ovary syndrome (PCOS) is a complex heterogeneous disorder with reproductive and metabolic consequences whose aetiology is still elusive. To understand the cellular mechanisms that potentially govern follicular defect in women with PCOS, we performed transcriptomic profiles of granulosa-lutein cells (GLCs) by RNA-Seq analysis. We found differential expression of 876 genes in GLCs between PCOS and controls that belonged to various processes such as cell cycle, extracellular matrix organization, angiogenesis, oxidative stress, metabolism, etc. that support folliculogenesis, oocyte development, and maturation. The cross-talk between oocyte and GLCs is a fundamental cornerstone in determining oocyte quality and highly interlinked pathways of metabolism and redox homeostasis may influence this. We found several genes involved in the metabolism of carbohydrates, nucleotides, cholesterol, and lipids were dysregulated, which may impair the supply of metabolites to the growing oocyte, affecting oocyte development and competence. Additionally, high metabolic activity during folliculogenesis may augment oxidative damage to cells and macromolecules if not counter-balanced. We observed dysregulation of redox homeostasis and AGE-RAGE signalling in the follicular environment. Among the validated genes, prokineticin-1 and growth differentiation factor-15 were found to be negatively regulated, while, S100, calcium-binding protein A9 and angiomotin-like-2 were positively regulated in GLCs of women with PCOS. Comparing our data with previously published relevant transcriptomic studies showed metabolic, cytokine-cytokine receptor interaction, IL-17, and chemokine signalling pathways were most commonly affected in PCOS. Overall, this data can provide insights into mechanisms contributing to PCOS pathophysiology and can be explored as potential indicators for oocyte/embryo quality in IVF settings.

What makes a health system good? From cost-effectiveness analysis to ethical improvement in health systems.

Fair allocation of scarce healthcare resources has been much studied within philosophy and bioethics, but analysis has focused on a narrow range of cases. The Covid-19 pandemic provided significant new challenges, making powerfully visible the extent to which health systems can be fragile, and how scarcities within crucial elements of interlinked care pathways can lead to cascading failures. Health system resilience, while previously a key topic in global health, can now be seen to be a vital concern in high-income countries too. Unfortunately, mainstream philosophical approaches to the ethics of rationing and prioritisation provide little guidance for these new problems of scarcity. Indeed, the cascading failures were arguably exacerbated by earlier attempts to make health systems leaner and more efficient. This paper argues that health systems should move from simple and atomistic approaches to measuring effectiveness to approaches that are holistic both in focusing on performance at the level of the health system as a whole, and also in incorporating a wider range of ethical concerns in thinking about what makes a health system good.

Climate change, mobility and violent conflict: a typology of interlinked pathways

Despite increased attention toward the links between climate, human mobility and conflict, the pathways through which resulting human insecurity may lead to violence are poorly understood. Although there is no inherent link between climate-related mobility and conflict, a coherent understanding of the triple nexus is needed to address the impact of intersecting crises on millions of lives and livelihoods. To achieve this, an in-depth literature review is employed to identify and explore four pathways that connect climate, human mobility and violent conflict: conflict as a result of climate-related disaster displacement, conflict as a result of scarcity-related mobility, conflict as a result of abundance-related migration, and conflict as a result of pre-existing tensions and migratory patterns interacting with climate change and/or variability. Finally, recommendations are made to guide research, policies and programming aiming to sever the link between climate-related mobility and conflict, where it may exist.Published open access under a CC BY licence. https://creativecommons.org/licences/by/4.0/

P104 Exploring the transcriptomic miRNA signatures of Egyptian Inflammatory Bowel Disease patients

Abstract Background Inflammatory Bowel Disease (IBD) is a chronic autoimmune gastrointestinal disease, sub-classified into Crohn’s disease (CD) and ulcerative colitis (UC). The two subclasses are characterized by a relapsing-remitting course with an increasingly high incidence and prevalence worldwide. Molecular mechanisms guarding the pathogenesis of these diseases remain, to the present day, ambiguous to researchers. MicroRNAs are 22 nucleotides long small noncoding RNAs that have been recently described as essential participants in immune cell development and the immune response to pathogens. During the past decade, genetic and epigenetic studies in IBD have been labeled as essential; since endoscopic assessment and biopsies provide limited data concerning early disease activity, factors for relapse, and response to treatment. To the best of our knowledge, IBD research has never addressed miRNA profiles in Egyptian CD and UC patients as compared to unaffected controls. Methods Therefore, this study aims to profile miRNAs in Egyptian patients suffering from UC and CD, using RNA-seq of total RNA extracted from colonoscopically obtained tissue pinch biopsies. Results The sequencing results showed that 30 miRNAs were uniquely expressed in tissue biopsies obtained from the CD patients, as compared to only 14 uniquely expressed in UC patients. Further web-based functional enrichment analysis showed that the miRNAs- in both disease groups- are mainly involved in six interlinked molecular pathways; including the JAK/STAT, WNT, PI3K/AKT, FOXO, MAPK, and NF-κB signaling pathways. One of the most interesting findings of the current study is the fact that the downregulation of the miR-204-5p in UC patients (log2 FC= 5.05)-as compared to CD patients- may be caused by the sponging effect of the MALAT1 long non-coding RNA (lncRNA); affecting related signaling pathways such as the Wnt/β-catenin signaling. This suggests an essential interplay between miRNAs and lncRNAs in shaping the molecular pathogenesis of UC vs. CD. Conclusion The results of the current study revealed explicit-previously undetermined- differences in the miRNA profiles of patients suffering from UC and CD. Such results are expected to impact the understanding of the difference in the molecular pathogenesis of IBD subtypes affecting patients’ response to treatment.

Cellular Senescence and Ageing.

Cellular senescence has become a subject of great interest within the ageing research field over the last 60years, from the first observation in vitro by Leonard Hayflick and Paul Moorhead in 1961, to novel findings of phenotypic sub-types and senescence-like phenotype in post-mitotic cells. It has essential roles in wound healing, tumour suppression and the very first stages of human development, while causing widespread damage and dysfunction with age leading to a raft of age-related diseases. This chapter discusses these roles and their interlinking pathways, and how the observed accumulation of senescent cells with age has initiated a whole new field of ageing research, covering pathologies in the heart, liver, kidneys, muscles, brain and bone. This chapter will also examine how senescent cell accumulation presents in these different tissues, along with their roles in disease development. Finally, there is much focus on developing treatments for senescent cell accumulation in advanced age as a method of alleviating age-related disease. We will discuss here the various senolytic and senostatic treatment approaches and their successes and limitations, and the innovative new strategies being developed to address the differing effects of cellular senescence in ageing and disease.

The bromelain and rutoside advantage in systemic enzyme therapy: pharmacological basis of combination with trypsin

Inflammation involves various interlinked pathways and processes. In its uncontrolled form, inflammation results in variety of diseased sates. Current therapy for inflammatory diseases is limited to steroidal and non-steroidal anti-inflammatory drugs (NSAIDs). But these are associated with safety concerns and have a deleterious effect on wound healing. Proteolytic enzymes, also called proteases, which are naturally occurring substances derived from animal or plant sources, are believed to be effective and safer alternatives to the conventional medications. Combined with the bioflavonoid rutoside, the proteases trypsin and bromelain have been extensively investigated as alternatives to conventional therapies for pain and swelling associated with diverse conditions. Their individual mechanisms of action and the advantages of combining bromelain and rutoside with trypsin has been discussed. The combination not only covers a wider range of processes involved in inflammation, but they also complement each other’s actions and provide a more well-rounded control of the inflammatory processes.

Dysfunctional regulation of pivotal and key inflammatory pathways in infertile Indian women with genital tuberculosis.

Diagnosis of female genital tuberculosis (FGTB) remains elusive due to the paucibacillary nature of the disease. We evaluated if analysis of inflammatory pathways of endometrial tissue could establish a better diagnosis of FGTB. One hundred and four infertile women suspected of having GTB or having been treated for GTB in the past, underwent endometrial biopsies for diagnosis and Gene Inflammatory Pathways analysis at our center between 2018-2020. Diagnosis of FGTB was based on acid-fast bacilli culture, immunocytochemistry, nested-polymerase chain reaction, histopathological examination, TB GeneXpert, or combinations thereof. Gene expression profiles were also analyzed. Based on diagnostic tests of 104 women, 44 (42%) were considered TB-positive, 35 (34%) TB-negative, and 25 (24%) TB-negative after TB treatment in the past. Inflammatory pathways were significantly upregulated in TB-positive women versus TB-negative (41%vs. 6%; p =.0005), and in women who were TB-negative after TB treatment in the past versus TB-negative (never treated for TB in the past) (38%vs. 6%; p =.0037). Two-hundred seventy-one genes were upregulated, and 61 genes were downregulated in TB-positive women versus those who were TB-negative. Differentially expressed genes were mapped to various interlinked inflammatory signaling pathways, including mitogen-activated protein kinase (MAPK), Natural Killer (NK) cells, nuclear factor kappa-B (NF-kB), tumor necrosis factor (TNF), and Toll-like receptors (TLR) signaling. Inflammatory pathways and gene expression profiles add to the diagnostic tools to identify TB-positive women at an early stage. The results from this study are still experimental and large multi-centric studies are suggested before their recommendation in routine clinical practice.

Advances in Pigmentation Management: A Multipronged Approach.

Key cellular players regulating human skin pigmentation include melanocytes in the epidermis that synthesize melanin, neighboring keratinocytes that receive and distribute melanin in the upper layers, and fibroblasts in the dermis that affect overlying melanocytes and keratinocytes. In addition, endocrine factors from the blood supply (endothelial cells) and inflammation-related factors play a role. Thus, new strategies for affecting pigmentation need to consider these multiple cell lines to adequately cover various causes and disease processes associated with hyperpigmentation. Pathophysiologic mechanisms and cellular pathways involved in melanogenesis were thoroughly reviewed with particular emphasis on the cellular interplay involved in the process. A complex system of interlinking and independent pathways was defined and described demonstrating differing pathways for altered pigmentary disorders - melasma associated with endothelial cell interactions; post inflammatory hyperpigmentation associated with keratinocyte inflammatory mediators (PGE2 in particular); and photodamage involving all 4 cell types. In vitro validation studies were then undertaken to define differing cell group gene expression profiles with selected peptides and other active agents. Melanocytic production of pigment was then tested with these agents to identify key potential players capable of limiting pigmentation. Hexapeptide-12 and lactoferrin (melanocytes), Hexapeptide-11 (in keratinocytes), and phosphatidylserine (endothelial cells) were identified as major inhibitors of melanogenesis based on their gene expression profiles. This was confirmed by secondary melanin production tests performed on melanocytic lines. Additional active agents were also identified as inhibitors of melanocytic production of melanin, and together, these constituents formed the basis for a novel formulation for use in pigmentary disorders. A comprehensive scientific narrative of the various facets relating to pigmentation has been presented including differing pathways affecting varied cell lines that effect pigment production. Based on this concept, actives were tested using gene expression studies as well as in vitro melanogenic model testing in different cell lines. Using this novel multi-faceted approach, we have selected and validated a series of active agents to be used in a formulation targeting the complex problem of hyperpigmentation. J Drugs Dermatol. 2022;21(11):1206-1220. doi:10.36849/JDD.7013.

Combinatorial approaches of nanotherapeutics for inflammatory pathway targeted therapy of prostate cancer.

Prostate cancer (PC) is the most prevalent male urogenital cancer worldwide. PC patients presenting an advanced or metastatic cancer succumb to the disease, even after therapeutic interventions including radiotherapy, surgery, androgen deprivation therapy (ADT), and chemotherapy. One of the hallmarks of PC is evading immune surveillance and chronic inflammation, which is a major challenge towards designing effective therapeutic formulations against PC. Chronic inflammation in PC is often characterized by tumor microenvironment alterations, epithelial-mesenchymal transition and extracellular matrix modifications. The inflammatory events are modulated by reactive nitrogen and oxygen species, inflammatory cytokines and chemokines. Major signaling pathways in PC includes androgen receptor, PI3K and NF-κB pathways and targeting these inter-linked pathways poses a major therapeutic challenge. Notably, many conventional treatments are clinically unsuccessful, due to lack of targetability and poor bioavailability of the therapeutics, untoward toxicity and multidrug resistance. The past decade witnessed an advancement of nanotechnology as an excellent therapeutic paradigm for PC therapy. Modern nanovectorization strategies such as stimuli-responsive and active PC targeting carriers offer controlled release patterns and superior anti-cancer effects. The current review initially describes the classification, inflammatory triggers and major inflammatory pathways of PC, various PC treatment strategies and their limitations. Subsequently, recent advancement in combinatorial nanotherapeutic approaches, which target PC inflammatory pathways, and the mechanism of action are discussed. Besides, the current clinical status and prospects of PC homing nanovectorization, and major challenges to be addressed towards the advancement PC therapy are also addressed.

Ayurvedic Management of Diabetic Macular Oedema — DME (<i>Sannipataja timira</i>) — A Case Report

Background: Diabetic Macular Edema (DME) is the primary cause of visual loss in Diabetic Retinopathy (DR). The hyperglycemic state promotes the activation of multiple interlinked pathways leading to DME. The current guidelines in contemporary science recommend Anti VEG-F injections as the first line of treatment for this condition. Repeated Anti-VEG-F injections cause much financial burden on the patient and their family, at the cost of minimal visual outcome. From the signs and symptoms, it was diagnosed as Sannipataja timira according to Ayurveda. A 53-year-old male patient sought Ayurvedic treatment when his vision in the right eye did not improve after the injection of Accentrix for DME. His ophthalmologist advised him to repeat the injection after six months but did not assure him of complete resolution of edema. So, he opted for Ayurvedic treatment. His treatment comprised internal medicines consisting of Punarnavadi kashaya, Guduchyadi kashaya, Chandraprabha vati, Gomutra haritaki lehya; external treatments like Talpodichil with Punarnavadi churna and Pratimarsha nasya with Anu taila; Kriyakalpas (eye treatments) like Vidalaka and Anjana karma. At the end of 7.5 months of Ayurvedic treatment, his visual acuity improved from 6/60 to 6/6. Optical Coherence Tomography (OCT) affirmed the full resolution of DME. Ayurvedic treatment effectively reversed the process of macular edema, thereby bringing about marked visual outcomes in DME. Such patients shall be encouraged to go for Ayurvedic treatments, not the expensive and invasive Anti-VEGF injections.

ELF4 is a critical component of a miRNA-transcription factor network and is a bridge regulator of glioblastoma receptor signaling and lipid dynamics.

The loss of neurogenic tumor suppressor microRNAs miR-124, miR-128, and miR-137 is associated with glioblastoma's undifferentiated state. Most of their impact comes via the repression of a network of oncogenic transcription factors. We conducted a high-throughput functional siRNA screen in glioblastoma cells and identify E74 like ETS transcription factor 4 (ELF4) as the leading contributor to oncogenic phenotypes. In vitro and in vivo assays were used to assess ELF4 impact on cancer phenotypes. We characterized ELF4's mechanism of action via genomic and lipidomic analyses. AMAPK reporter assay verified ELF4's impact on MAPK signaling, and qRT-PCR and western blotting were used to corroborate ELF4 regulatory role on most relevant target genes. ELF4 knockdown resulted in significant proliferation delay and apoptosis in GBM cells and long-term growth delay and morphological changes in glioma stem cells (GSCs). Transcriptomic analyses revealed that ELF4 controls two interlinked pathways: 1)Receptor tyrosine kinase signaling and 2)Lipid dynamics. ELF4 modulation directly affected receptor tyrosine kinase (RTK) signaling, as mitogen-activated protein kinase (MAPK) activity was dependent upon ELF4 levels. Furthermore, shotgun lipidomics revealed that ELF4 depletion disrupted several phospholipid classes, highlighting ELF4's importance in lipid homeostasis. We found that ELF4 is critical for the GBM cell identity by controlling genes of two dependent pathways: RTK signaling (SRC, PTK2B, and TNK2) and lipid dynamics (LRP1, APOE, ABCA7, PLA2G6, and PITPNM2). Our data suggest that targeting these two pathways simultaneously may be therapeutically beneficial to GBM patients.