Cellular Signaling Pathways Research Articles

Unveiling the fibrotic puzzle of endometriosis: An overlooked concern calling for prompt action

Endometriosis is a benign, estrogen-dependent, persistent chronic inflammatory heterogeneous condition that features fibrotic adhesions caused by periodic bleeding. The characteristic ectopic lesions are marked by a widely spread dense fibrotic interstitium comprising of fibroblasts, myofibroblasts, collagen fibers, extracellular proteins, inflammatory cells, and active angiogenesis. Fibrosis is now recognized as a critical component of endometriosis because of which current treatments, such as hormonal therapy and surgical excision of lesions are largely ineffective with severe side effects, high recurrence rates, and significant morbidity. The symptoms include dysmenorrhea (cyclic or noncyclic), dyspareunia, abdominal discomfort, and infertility. The significant lack of knowledge regarding the underlying root causes, etiology, and complex pathogenesis of this debilitating condition, hinders early diagnosis and implement effective therapeutic approaches with minimal side effects presenting substantial hurdles in endometriosis management. Emerging research offer a close relationship between endometriosis and fibrosis, which is believed to be tightly linked to pain, a primary contributor to the deterioration of the patient’s quality of life. However, the underlying pathophysiological cellular and molecular signaling pathways behind endometriosis-associated fibrosis are poorly addressed. The available experimental disease models have tremendous challenges in reproducing the human characteristics of the disease limiting the treatment effectiveness. Future translational research on the topic has been hindered by the lack of an adequate fibrotic model of endometriosis emphasizing the necessity of etiological exploration. This review article focuses on recent developments in the field and highlight the necessity for novel fibrotic models for early diagnosis, a better understanding the disease’s etiology and develop effective anti-fibrotic treatments. By addressing these knowledge gaps, we want to open fresh avenues for a thorough investigation and extended research in the field of endometriosis.

Type A monoamine oxidase; its unique role in mood, behavior and neurodegeneration.

Monoamine oxidase catalyzes oxidative deamination of monoamine transmitters and plays a critical role in the pathogenesis of neuropsychiatric diseases. Monoamine oxidase is classified into type A and B (MAO-A, MAO-B) according to the substrate specificity and sensitivity to inhibitors. The isoenzymes are different proteins coded by different genes localized on the X-chromosome, but they have identical intron-exon organization, similar protein structure and enzymatic mechanism and are considered to be derived from the same ancestral gene. The isoform-specific transcription organization regulates expression and function of MAO-A in response to cellular signaling pathways and environmental factors. MAO-A shows distinct properties and functions: isoform-specified polymorphisms, localization in catecholamine neurons, expression during early embryonic stage, regulation of brain architecture development and mediation of death and survival of neuronal cells. MAO-A is more flexible to genetic and environmental changes than MAO-B. Defective MAO-A expression impairs embryonic brain development and causes adult abnormal mood and behavior, as shown by human male cases with MAO-A deletion. This paper presents the regulation of brain MAO-A expression epigenetically by interaction between genetic and environmental factors. Association of aberrant MAO-A expression and activity with aggression, asocial behaviors, depressive disorders, and neurodegenerative diseases is discussed. Novel therapeutic strategy for psychiatric diseases by intervention to the regulation of MAO-A expression and activity is proposed.

Role of chemokines in aging and age-related diseases

Chemokines (chemotactic cytokines) play essential roles in developmental process, immune cell trafficking, inflammation, immunity, angiogenesis, cellular homeostasis, aging, and tumorigenesis. Chemokines also modulate response to immunotherapy, and consequently influence the therapeutic outcome. The mechanisms underlying these processes are accomplished by interaction of chemokines with their cognate cell surface G protein-coupled receptors (GPCRs) and subsequent cellular signaling pathways. Chemokines play crucial role in influencing aging process and age-related diseases across various tissues and organs, primarialy through inflammatory responses (inflammaging), recruitment of macrophages, and orchestrated trafficking of other immune cells. Chemokines are categorized in four distinct groups based on the position and number of the N-terminal cysteine residues; namely, the CC, CXC, CX3C, and (X)C. They mediate inflammatory responses, and thereby considerably impact aging process across multiple organ-systems. Therefore, understanding the underlying mechanisms mediated by chemokines may be of crucial importance in delaying and/or modulating the aging process and preventing age-related diseases. In this review, we highlight recent progress accomplished in understanding the role of chemokines and their cellular signaling pathways involved in aging and age-relaed diseases of various organs. Moreover, we explore potential therapeutic strategies involving chemokines and chemokine receptor antagonists aimed at reducing aging and mitigating age-related diseases. One of the modern methods in this direction involves use of chemokine receptor antagonists and anti-chemokines, which suppress the pro-inflammatory response, thereby helping in resolution of inflammation. Considering the wide-spectrum of functional involvements of chemokines in aging and associated diseases, several clinical trials are being conducted to develop therapeutic approaches using chemokine receptor antagonists to improve life span and promote healthy aging.

The sensor protein AaSho1 regulates infection structures differentiation, osmotic stress tolerance and virulence via MAPK module AaSte11-AaPbs2-AaHog1 in Alternaria alternata

The high-osmolarity-sensitive protein Sho1 functions as a key membrane receptor in phytopathogenic fungi, which can sense and respond to external stimuli or stresses, and synergistically regulate diverse fungal biological processes through cellular signaling pathways. In this study, we investigated the biological functions of AaSho1 in Alternaria alternata, the causal agent of pear black spot. Targeted gene deletion revealed that AaSho1 is essential for infection structure differentiation, response to external stresses and synthesis of secondary metabolites. Compared to the wild-type (WT), the ∆AaSho1 mutant strain showed no significant difference in colony growth, morphology, conidial production and biomass accumulation. However, the mutant strain exhibited significantly reduced levels of melanin production, cellulase (CL) and ploygalacturonase (PG) activities, virulence, resistance to various exogenous stresses. Moreover, the appressorium and infection hyphae formation rates of the ∆AaSho1 mutant strain were significantly inhibited. RNA-Seq results showed that there were four branches including pheromone, cell wall stress, high osmolarity and starvation in the Mitogen-activated Protein Kinase (MAPK) cascade pathway. Furthermore, yeast two-hybrid experiments showed that AaSho1 activates the MAPK pathway via AaSte11-AaPbs2-AaHog1. These results suggest that AaSho1 of A. alternata is essential for fungal development, pathogenesis and osmotic stress response by activating the MAPK cascade pathway via Sho1-Ste11-Pbs2-Hog1.

Exploring the Role of Unconventional Post-Translational Modifications in Cancer Diagnostics and Therapy.

Unconventional Post-Translational Modifications (PTMs) have gained increasing attention as crucial players in cancer development and progression. Understanding the role of unconventional PTMs in cancer has the potential to revolutionize cancer diagnosis, prognosis, and therapeutic interventions. These modifications, which include O-GlcNAcylation, glutathionylation, crotonylation, including hundreds of others, have been implicated in the dysregulation of critical cellular processes and signaling pathways in cancer cells. This review paper aims to provide a comprehensive analysis of unconventional PTMs in cancer as diagnostic markers and therapeutic targets. The paper includes reviewing the current knowledge on the functional significance of various conventional and unconventional PTMs in cancer biology. Furthermore, the paper highlights the advancements in analytical techniques, such as biochemical analyses, mass spectrometry and bioinformatic tools etc., that have enabled the detection and characterization of unconventional PTMs in cancer. These techniques have contributed to the identification of specific PTMs associated with cancer subtypes. The potential use of Unconventional PTMs as biomarkers will further help in better diagnosis and aid in discovering potent therapeutics. The knowledge about the role of Unconventional PTMs in a vast and rapidly expanding field will help in detection and targeted therapy of cancer.

2-hydroxy-3-methyl anthraquinone promotes apoptosis and inhibits invasion of human hepatocellular carcinoma cells by targeting nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin-1/cellular tumor antigen p53 signaling pathway.

To investigate the anti-liver cancer effect of 2-hydroxy-3-methyl anthraquinone (HMA) and the specific mechanism based on nicotinamide adenine dinucleotide-dependent protein deacetylase sirtuin-1 (SIRT1)/cellular tumor antigen p53 (p53) pathway. Cell counting kit-8 method was used to observe the effect of HMA on the activity of human hepatocellular carcinoma cells (HepG2) cells. At 72 h and 80 μL HMA, the apoptosis rate of HepG2 cells in each group was measured by flow cytometry. Transwell was used to assay for cell invasion. The protein expression levels of SIRT1, p53, B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (Bax), caspase-9 (CASP9) and caspase-3 (CASP3) were detected by Western Blot. HMA significantly inhibited the proliferation of HepG2 cells, The half inhibiting concentration (IC50) of the HMA at 24, 48 and 72 h were examined and it were 126.3, 98.6, and 80.55 μM, respectively. Compared with the control group, the apoptosis rate of HMA, Selisistat (EX527), and HMA+ EX527 groups enhanced, while the apoptosis rate of SRT1720 diminished, demonstrating that inhibition of SIRT1 can lead to apoptosis of HepG2 cells. HMA+ EX527 group had the highest apoptosis rate, the lowest expression of SIRT1 and Bcl-2, and the highest expression of p53, Bax, CASP9 and CASP3. The number of invasions of HepG2 was significantly reduced after HMA and EX527 intervened. Western blot shows HMA could inhibit SIRT1, promote the expression of p53, and decrease the ratio of Bcl-2/Bax. HMA induced apoptosis in HepG2 cells, while inhibiting proliferation and invasion. The mechanism of HMA against HCC may be related to the SIRT1/p53 pathway.

Exosomes serve as a crucial mediator of epithelial–fibroblast communication during hair follicle morphogenesis in cashmere goats

The formation of dermal condensates (DCs) through fibroblasts is a pivotal event in hair follicle morphogenesis in cashmere goats, a process that intricately involves epithelial-fibroblast communication. Exosomes (Exos), as essential mediators of intercellular communication, have garnered increasing attention in recent years, yet their precise role in hair follicle morphogenesis remains largely unknown. In this study, we focused on isolating and identifying epithelial cell-derived exosomes (Epi-Exos) from Inner Mongolian cashmere goats. Our experiments demonstrated that Epi-Exos could efficiently enter fibroblasts within 12 h of co-culture. Both direct co-culture of epithelial cells with fibroblasts and co-culture with Epi-Exos alone revealed that Epi-Exos promoted fibroblast migration while inhibiting their proliferation, changes that mirror the cellular biological characteristics observed during DC formation. Furthermore, recognizing the abundance of miRNAs carried by Exos, we conducted small RNA sequencing (small RNA-seq) on Epi-Exos. This analysis identified a panel of 54 highly expressed miRNAs within the Epi-Exos, 34 of which were also found to be abundant in fetal skin tissues of Inner Mongolian cashmere goats. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that these miRNAs were significantly enriched in cellular processes and signaling pathways related to hair follicle morphogenesis. Notably, our findings offer new perspectives on the role of miRNAs in Epi-Exos regulating DC formation and hair follicle morphogenesis in cashmere goats, with significant implications for understanding hair follicle development mechanisms and potential clinical or production benefits, including improved cashmere quality and yield through targeted exosome-mediated signaling manipulation.

White spot syndrome virus IE1 protein blocks the integrin-FAK signaling to enhance viral infection in shrimp

DNA viruses commonly utilize immediate-early proteins to manipulate cellular signaling pathways in order to facilitate their infection. Our previous research has suggested that IE1, an immediate-early protein encoded by the white spot syndrome virus (WSSV), may modulate the shrimp integrin-FAK signaling pathway. However, the specific molecular mechanism and role of IE1 in regulating this signaling pathway remain unclear. In this study, we demonstrated that IE1 competes for binding to the cytoplasmic tail of Penaeus vannamei integrin-α5, resulting in the inhibition of the integrin-α5-FAK interaction, thereby suppressing FAK activation and cell adhesion. Furthermore, we observed a significant increase in the expression of P. vannamei integrin-α5 and FAK following WSSV infection. Additionally, knockdown of integrin-α5 or FAK through RNA interference has been shown to reduce cell adhesion and enhance WSSV infection. In conclusion, our findings reveal that IE1 disrupts integrin-FAK signaling to inhibit cell adhesion, ultimately promoting WSSV infection in shrimp.

The Influence and Mechanisms of Natural Plant Polysaccharides on Intestinal Microbiota-Mediated Metabolic Disorders

Natural plant polysaccharides are renowned for their broad spectrum of biological activities, making them invaluable in both the pharmaceutical and food industries. Their safety, characterized by low toxicity and minimal side effects, coupled with their potential therapeutic properties, positions them as crucial elements in health-related applications. The functional effectiveness of these polysaccharides is deeply connected to their structural attributes, including molecular weight, monosaccharide components, and types of glycosidic bonds. These structural elements influence how polysaccharides interact with the gut microbiota, potentially alleviating various metabolic and inflammatory disorders such as inflammatory bowel disease, diabetes, liver-associated pathologies, obesity, and kidney diseases. The polysaccharides operate through a range of biological mechanisms. They enhance the formation of short-chain fatty acids, which are pivotal in keeping intestinal health and metabolic balance. Additionally, they strengthen the intestinal mucosal barrier, crucial for deterring the ingress of pathogens and toxins into the host system. By modulating the immune responses within the gut, they help in managing immune-mediated disorders, and their role in activating specific cellular signaling pathways further underscores their therapeutic potential. The review delves into the intricate structure–activity relationships of various natural polysaccharides and their interactions with the intestinal flora. By understanding these relationships, the scientific community can develop targeted strategies for the use of polysaccharides in therapeutics, potentially leading to innovative treatments for a range of diseases. Furthermore, the insights gained can drive the advancement of research in natural polysaccharide applications, providing direction for novel dietary supplements and functional foods designed to support gut health and overall well-being.

Nuclear Factor I family members are key transcription factors regulating gene expression

The Nuclear Factor I (NFI) family of transcription factors (TFs) plays key roles in cellular differentiation, proliferation, and homeostasis. As such, NFI family members engage in large number of interactions with other proteins and the chromatin. However, despite their well-established significance, the NFIs interactomes, their dynamics, and their functions have not been comprehensively examined. Here, we employed complementary omics-level techniques, i.e. interactomics (affinity purification mass spectrometry (AP-MS) and proximity-dependent biotinylation (BioID)), and chromatin immunoprecipitation sequencing (ChIP-Seq), to obtain a comprehensive view of the NFI proteins and their interactions in different cell lines. Our analyses included all four NFI family members, and a less studied short isoform of NFIB (NFIB4), which lacks the DNA binding domain. We observed that, despite exhibiting redundancy, each family member had unique high-confidence interactors and target genes, suggesting distinct roles within the transcriptional regulatory networks. The study revealed that NFIs interact with other TFs to co-regulate a broad range of regulatory networks and cellular processes. Notably, time-dependent proximity-labeling unveiled a highly dynamic nature of NFI protein-protein interaction networks and hinted at temporal modulation of NFI interactions. Furthermore, gene ontology (GO) enrichment analysis of NFI interactome and targetome revealed the involvement of NFIs in transcriptional regulation, chromatin organization, and cellular signaling pathways, and pathways related with cancer. Additionally, we observed that NFIB4 engages with proteins associated with mRNA regulation, which suggests that NFIs have roles beyond traditional DNA binding and transcriptional modulation. We propose that NFIs may function as potential pioneering TFs, given their role in regulating the DNA binding ability of other TFs and their interactions with key chromatin remodeling complexes, thereby influencing a wide range of cellular processes. These insights into NFI protein-protein interactions and their dynamic, context-dependent nature provide a deeper understanding of gene regulation mechanisms and hint at the role of NFIs as master regulators.

Drosophila: An Important Model for Exploring the Pathways of Inflammatory Bowel Disease (IBD) in the Intestinal Tract

Inflammatory bowel disease (IBD) is a chronic and recurring lifelong condition, the exact etiology of which remains obscure. However, an increasing corpus of research underscores the pivotal role of cellular signaling pathways in both the instigation and management of intestinal inflammation. Drosophila, owing to its prodigious offspring, abbreviated life cycle, and the conservation of signaling pathways with mammals, among other advantages, has become a model organism for IBD research. This review will expound on the feasibility of utilizing Drosophila as an IBD model, comparing its intestinal architecture with that of mammals, its inflammatory responses, and signaling pathways. Furthermore, it will deliberate on the role of natural products across various biological models of IBD pathways, elucidating the viability of fruit flies as IBD models and the modus operandi of cellular signaling pathways in the context of IBD.

Biodistribution Analysis of Adeno-Associated Viral Vectors of Serotypes 9 and rh.10 Encoding Arylsulfatase A Following Prior Immunization with Serotype 9 in Pigs

Lysosomal storage diseases are a group of inherited disorders caused by lysosomal dysfunction, impairing cellular metabolic enzymes, signaling pathways, and other biological processes. Among them is metachromatic leukodystrophy (MLD) associated with arylsulfatase A (ARSA) deficiency, which leads to the accumulation of sulfatides and the destruction of myelin sheaths in the nervous system. This study evaluates the therapeutic efficacy of adeno-associated viruses (AAVs) in treating neurodegenerative diseases such as MLD. The biodistribution and safety of AAV9-ARSA and AAVrh.10-ARSA vectors following prior immunization in pigs were shown. The immune aspects of AAV-based gene therapy were outlined. Its potential efficacy and durability limitations were discussed.

Biosynthesis and Characterization of Silver Nanoparticles Using Cleistanthus collinus; Investigation on Molecular Mechanism of Apoptosis Cell Death Against Lung Cancer Cells

Background: The discovery of novel molecular and cellular signaling pathways for cancer medicines would enhance the efficacy of cancer therapy. In the current study, we made an effort to explore the mitochondrial-mediated apoptosis cell death signaling pathway in A549 lung cancer cells by silver nanoparticles (AgNPs) synthesized from leaf extract of Cleistanthus collinus. Methods: In-depth, A549 lung cancer cells were treated with AgNPs, and further studies such as HOECHST 33342, AO/EB, Rhodamine-123 staining, flowcytometry, RT-PCR, and Western blotting techniques (24, 48, and 72 h) evidenced apoptosis pathway in cancer cells. Results: Indeed, the microscopic studies proved that AgNPs-treated lung cancer cells appeared with cell shrinkage, membrane swelling, and apoptotic body formation whereas the untreated cells (control) failed to show any morphological consequences. The flow cytometry analysis revealed the G2/M phase of cell cycle arrest by cells were accumulated in large numbers. The RT-PCR data confirmed the expression (Bax and p53) and suppression (Bcl 2) apoptosis-responsive genes in cancer cells. Finally, immunoblotting proved the increased expression of cytochrome c, initiator caspase 9, and executioner caspase 3, which are effective proteins of intrinsic apoptosis activation. Conclusion: Ultimately, the overall present investigations confirmed the mitochondrial signaling pathway played a key role in inducing apoptosis in A549 cancer cell death and demonstrated that AgNPs are novel therapeutic agents for cancer nanomedicine

Carotenoids as modulators of the PI3K/Akt/mTOR pathway: innovative strategies in cancer therapy.

Cancer progression is primarily driven by the uncontrolled activation of cellular signaling pathways, with the PI3K/Akt/mTOR (PAMT) pathway playing a central role. This pathway significantly contributes to the proliferation and survival of cancer cells, and its hyperactivity is a major challenge in managing several types of malignancies. This article delves into the promising potential of carotenoids, natural pigments found in abundance in fruits and vegetables, as a novel therapeutic strategy for cancer treatment. By specifically targeting and inhibiting the PAMT pathway, carotenoids may effectively disrupt the growth and survival of cancer cells. The article examines the complex mechanisms underlying these interactions and highlights the obstacles faced in cancer treatment. It proposes a compelling approach to developing therapies that leverage natural products to target this critical pathway, offering a fresh perspective on cancer treatment. Further research is essential to enhance the therapeutic efficacy of these compounds.

L-aspartate ameliorates diet-induced obesity by increasing adipocyte energy expenditure.

Obesity always leads to profound perturbation of metabolome. Metabolome studies enrich the knowledge on associations between endogenous metabolites and obesity, potentially providing innovative strategies for the development of novel anti-obesity pharmacotherapy. This study aims to identify an endogenous metabolite that regulates energy expenditure and to explore its application for obesity treatment. C57BL/6 mice were fed with a high-fat and high-cholesterol (HFC) diet, comprising 60% fat and 1.2% cholesterol, for 12 weeks to induce obesity. Significant metabolites were identified in the livers of both health and obese mice through comparative hepatic metabolomics analysis. Correlation between serum or adipose L-aspartate level and body weight in obese mice, as well as human body mass index (BMI), was evaluated. In addition, saline or 200 mg/kg L-aspartate was orally administrated to HFC diet mice and HFC diet-induced obese mice for 6-7 weeks. Body weight, adipose tissue weight, glucose tolerance and liver damage were assessed to evaluate the effect on obesity prevention and treatment. Comprehensive lab animal monitoring system (CLAMS) and seahorse assay were employed to investigate the regulatory effect of L-aspartate on energy metabolism in vivo and in vitro, respectively. 3T3-L1 preadipocytes and murine white adipose tissue (WAT) were utilized to examine the impact of L-aspartate on adipocyte adipogenesis and lipogenesis and cellular signalling pathway in vitro and in vivo. L-aspartate, an approved drug for liver injury and chronic fatigue, was identified as an endogenous inducer of energy expenditure. Serum or adipose L-aspartate levels were found to be negatively correlated with the severity of obesity in both humans and mice. Administration of L-aspartate to HFC diet mice led to a significant reduction in body weight, with decreases of 14.5% in HFC diet mice and 8.5% in HFC diet-induced obese mice, respectively. In addition, the treatment improved related metabolic syndrome (Figure 2 and Figure S3). These therapeutics were associated with enhancements in whole-body energy expenditure and suppression of adipocyte adipogenesis along with activation of Adenosine 5'-monophosphate-activated protein kinase (AMPK) signalling pathway. L-aspartate may serve as a novel endogenous inducer of energy expenditure and suppressor of adipogenesis and lipogenesis along with activation of AMPK, thereby offering a promising therapeutic strategy for obesity prevention and treatment.

Topography-Mediated Induction of Epithelial Mesenchymal Transition via Alumina Textiles for Potential Wound Healing Applications.

Substrate topography is vital in determining cell growth and fate of cellular behavior. Although current invitro studies of the underlying cellular signaling pathways mostly rely on their induction by specific growth factors or chemicals, the influence of substrate topography on specific changes in cells has been explored less often. This study explores the impact of substrate topography, specifically the tricot knit microfibrous structure of alumina textiles, on cell behavior, focusing on fibroblasts and keratinocytes for potential wound healing applications. The textiles, studied for the first time as invitro substrates, demonstrated support for keratinocyte adhesion, leading to alterations in cell morphology and the expression of E-cadherin and fibronectin. These topography-induced changes resembled the epithelial-to-mesenchymal transition (EMT), crucial for wound healing, and were specific to keratinocytes and absent in identically treated fibroblasts. Biochemically induced EMT in keratinocytes cultured on flat alumina substrates mirrored the changes seen with alumina textiles alone, suggesting the tricot knit microfibrous topography could serve as an invitro model system to induce EMT-like mechanisms. These results enhance our understanding of how substrate topography influences EMT-related processes in wound healing, paving the way for further evaluation of microfibrous alumina textiles as innovative wound dressings.

Involvement of PDGFR-integrin interactions in the regulation of anoikis resistance in glioblastoma progression.

The interactions between platelet-derived growth factor/PDGF receptor and integrin signaling are crucial for cells to respond to extracellular stimuli. Integrin interactions with PDGFR within the lipid rafts activate downstream cellular signaling pathways that regulate cell proliferation, cell migration, cell differentiation, and cell death processes. The mechanisms underlying PDGFR activation mediated receptor internalization, interactions with other cell-surface receptors, particularly extracellular matrix receptors, integrins, and how these cellular mechanisms switch on anchorage-independent cell survival, leading to anoikis resistance are discussed. The role of regulatory molecules such as noncoding RNAs, that can modulate several molecular and cellular processes, including autophagy, in the acquisition of anoikis resistance is also discussed. Overall, the review provides a new perspective on a complex interplay of regulatory cellular machineries involving autophagy, noncoding RNAs and cellular mechanisms of PDGFR activation, PDGFR-integrin interactions, and involvement of lipids rafts in the acquisition of anoikis resistance that regulates glioblastoma progression along with potential future strategies to develop novel therapeutics for glioblastoma multiforme.

Dengue virus NS1 hits hard at the barrier integrity of human cerebral microvascular endothelial cells via cellular microRNA dysregulations

ABSTRACT Dengue virus (DENV) infections are commonly reported in the tropical and subtropical regions of the world. DENV is reported to exploit various strategies to cross the blood-brain barrier. The NS1 protein of DENV plays an important role in viral neuropathogenesis, resulting in endothelial hyperpermeability and cytokine-induced vascular leak. miRNAs are short non-coding RNAs that play an important role in post-transcriptional gene regulations. However, no comprehensive information about the involvement of miRNAs in DENV-NS1-mediated neuropathogenesis has been explored to date. We observed that DENV-NS1 significantly alters the cellular miRNome of human cerebral microvascular endothelial cells in a bystander fashion. Subsequent target prediction and pathway enrichment analysis indicated that these microRNAs and their corresponding target genes are involved in pathways associated with blood-brain barrier dysfunction such as “Adherens junction” and “Tight junction”. Additionally, several miRNA-mRNA pairs were also found to be involved in cellular signaling pathways related to cytokine production, for instance, “Jak-STAT signaling pathway”, “Chemokine signaling pathway”, “IL-17 signaling pathway”, “NF-κB signaling pathway”, and “Viral protein interaction with cytokine and cytokine receptor”. The dysregulated production of inflammatory cytokines is reported to compromise BBB permeability. This study is the first report to demonstrate that DENV-NS1-mediated miRNA perturbations are crucial in compromising endothelial barrier integrity. It also offers insights into potential therapeutic targets to mitigate DENV-NS1-induced vascular permeability and inflammation.

Therapeutic potential and agricultural benefits of curcumin: a comprehensive review of health and sustainability applications

AbstractTurmeric (Curcuma longa L.), the plant from which curcumin is derived, is renowned for its wide range of therapeutic and agricultural benefits. Curcumin, the key bioactive compound, is highly valued for its potent anti-provocative, antioxidant, and antimicrobial properties, which contribute to its effectiveness in treating various human diseases and improving plant resilience to environmental stresses. The therapeutics potential of curcumin is notable owing its abilities to combat microbes act as an oxidant and reduce inflammation. Its effectiveness in treating a range of human disease such as tumor, cardiac problems, and brain degenerative ailments stems from its ability to modulate various cellular process and signaling pathways. Despite its low bioavailability, innovations in delivery system such as nanoparticles and liposomal formulations, have enhanced its therapeutic efficacy by improving solubility and systemic absorption. In agriculture, curcumin's antimicrobial properties provide a natural alternative to chemical pesticides, offering protection against pathogens and enhancing plant resilience to specific environmental stresses such as drought, salinity, and oxidative stress. Nanotechnology applications have furthered these benefits by facilitating the efficient uptake and distribution of curcumin within plant tissues, promoting growth and stress tolerance. This review also highlights curcumin's nutritional benefits, including its impact on gut health and metabolic syndrome. Synergistic interactions with dietary nutrients can amplify its health benefits, making it a valuable dietary supplement. However, ongoing research is needed to fully understand curcumin's mechanisms of action and long-term safety. Overall, curcumin holds promise as a versatile agent in both medical and agricultural fields, supporting sustainable practices and advancing health outcomes. Future research should focus on optimizing curcumin formulations and translating preclinical findings into clinical successes. Graphical abstract

Renewed Insight into Cancer Mechanism and Therapy: Advances, Challenges, and Future Directions

Cancer remains a complex and multifactorial disease characterized by genetic mutations, epigenetic changes, and alterations in cellular signaling pathways. While traditional treatments such as surgery, chemotherapy, and radiation have been the backbone of cancer therapy, their limitations, including drug resistance, recurrence, and significant side effects, have driven the search for more targeted and personalized treatment approaches. This review provides an in-depth exploration of recent advances in cancer research and therapy, focusing on molecular mechanisms, genetic alterations, and the tumor microenvironment, all of which play pivotal roles in tumor initiation and progression. Key discoveries in oncogenes, tumor suppressor genes, and immune evasion strategies have led to the development of targeted therapies and immunotherapies. These advancements have revolutionized the treatment landscape, with therapies like immune checkpoint inhibitors, CAR T-cell therapy, and personalized medicine offering improved patient outcomes. However, challenges such as tumor heterogeneity, acquired drug resistance, therapy-related toxicities, and the high costs of these novel treatments continue to limit their effectiveness and accessibility. The review also delves into emerging therapeutic strategies, including next-generation immunotherapies, precision oncology enhanced by artificial intelligence, tumor vaccines, microbiome-based therapies, and the application of nanotechnology for drug delivery. As cancer therapies evolve, addressing these challenges is crucial for future breakthroughs. The review emphasizes the need for continued research into overcoming resistance mechanisms, reducing treatment-related side effects, and enhancing global access to cutting-edge treatments. Looking ahead, the integration of new technologies and the development of more equitable healthcare strategies will be essential to ensuring that advances in cancer therapy translate into improved survival and quality of life for patients worldwide. In conclusion, while remarkable progress has been made in cancer treatment, a multifaceted approach that blends scientific innovation, precision medicine, and healthcare accessibility will be key to overcoming the ongoing challenges in the fight against cancer. Keywords: Cancer Mechanism, Therapy, Advances, Challenges, Future Directions