Molecular aspects of regeneration in insects.

Regeneration is a fascinating phenomenon observed in various organisms across the animal kingdom. Different orders of class Insecta are reported to possess comprehensive regeneration abilities. Several signalling molecules, such as morphogens, growth factors, and others trigger a cascade of events that promote wound healing, blastema formation, growth, and repatterning. Furthermore, epigenetic regulation has emerged as a critical player in regulating the process of regeneration. This report highlights the major breakthrough research on wound healing and tissue regeneration. Exploring and reviewing the molecular basis of regeneration can be helpful in the area of regenerative medicine advancements. The understanding gathered from this framework can potentially contribute to hypothesis designing with implications in the field of synthetic biology and human health.

Dichotomous role of the serine/threonine kinase MAP4K4 in pancreatic ductal adenocarcinoma onset and metastasis through control of AKT and ERK pathways.

MAP4K4 is a serine/threonine kinase of the STE20 family involved in the regulation of actin cytoskeleton dynamics and cell motility. It has been proposed as a target of angiogenesis and inhibitors show potential in cardioprotection. MAP4K4 also mediates cell invasion in vitro, is overexpressed in various types of cancer, and is associated with poor patient prognosis. Recently, MAP4K4 has been shown to be overexpressed in pancreatic cancer, but its role in tumour initiation, progression, and metastasis is unknown. Here, using the KrasG12D Trp53R172H Pdx1-Cre (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC), we show that deletion of Map4k4 drives tumour initiation and progression. Moreover, we report that the acceleration of tumour onset is also associated with an overactivation of ERK and AKT, two major downstream effectors of KRAS, in vitro and in vivo. In contrast to the accelerated tumour onset caused by loss of MAP4K4, we observed a reduction in metastatic burden with both the KPC model and in an intraperitoneal transplant assay indicating a major role of MAP4K4 in metastatic seeding. In summary, our study sheds light on the dichotomous role of MAP4K4 in the initiation of PDAC onset, progression, and metastatic dissemination. It also identifies MAP4K4 as a possible druggable target against pancreatic cancer spread, but with the caveat that targeting MAP4K4 might accelerate early tumorigenesis. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Unravelling the Mysteries of the Sonic Hedgehog Pathway in Cancer Stem Cells: Activity, Crosstalk and Regulation.

The Sonic Hedgehog (Shh) signalling pathway plays a critical role in normal development and tissue homeostasis, guiding cell differentiation, proliferation, and survival. Aberrant activation of this pathway, however, has been implicated in the pathogenesis of various cancers, largely due to its role in regulating cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells with the ability to self-renew, differentiate, and initiate tumour growth, contributing significantly to tumorigenesis, recurrence, and resistance to therapy. This review focuses on the intricate activity of the Shh pathway within the context of CSCs, detailing the molecular mechanisms through which Shh signalling influences CSC properties, including self-renewal, differentiation, and survival. It further explores the regulatory crosstalk between the Shh pathway and other signalling pathways in CSCs, highlighting the complexity of this regulatory network. Here, we delve into the upstream regulators and downstream effectors that modulate Shh pathway activity in CSCs. This review aims to cast a specific focus on the role of the Shh pathway in CSCs, provide a detailed exploration of molecular mechanisms and regulatory crosstalk, and discuss current and developing inhibitors. By summarising key findings and insights gained, we wish to emphasise the importance of further elucidating the interplay between the Shh pathway and CSCs to develop more effective cancer therapies.

The Jasmonic Acid Biosynthetic Genes SmLOX4 and SmLOX5 are Involved in Heat Tolerance in Eggplant.

High temperature stress (HTS) affects the growth and production of vegetable crops, including eggplant (Solanum melongena L.). Jasmonic acid (JA) plays key roles in regulating resistance to biotic and abiotic stresses in plants. Nonetheless, reports on the role of JA in heat tolerance in eggplant are rare. Herein, the effects of JA on heat tolerance in eggplant and the functions of the JA biosynthetic genes SmLOX4 and SmLOX5 were analysed. The results showed that the JA content increased under high temperature treatment (HTT) and that exogenous methyl jasmonate (MeJA) treatment reduced the damage caused by HTT to eggplant. The expression of SmLOX4 and SmLOX5 was induced by HTT and was significantly positively correlated with JA biosynthesis. SmLOX4 and SmLOX5 were localized in chloroplasts. The silencing of SmLOX4 and SmLOX5 by virus-induced gene silencing (VIGS) suppressed the heat tolerance of eggplant plants, whereas the overexpression of SmLOX4 and SmLOX5 enhanced the heat tolerance of Arabidopsis thaliana plants. JA content and the expression of JA signalling-related genes decreased in the SmLOX4- and SmLOX5-silenced plants but increased in the OE-SmLOX4 and OE-SmLOX5 transgenic plants. These results revealed that SmLOX4 and SmLOX5 improved eggplant heat tolerance by mediating JA biosynthesis and JA signalling pathways.

Cracking the code of Annexin A1-mediated chemoresistance.

The annexin superfamily protein, Annexin A1, initially recognized for its glucocorticoid-induced phospholipase A2-inhibitory activities, has emerged as a crucial player in diverse cellular processes, including cancer. This review explores the multifaceted roles of Anx-A1 in cancer chemoresistance, an area largely unexplored. Anx-A1's involvement in anti-inflammatory processes, its complex phosphorylation patterns, and its context-dependent switch from anti-to pro-inflammatory in cancer highlights its intricate regulatory mechanisms. Recent studies highlight Anx-A1's paradoxical roles in different cancers, exhibiting both up- and down-regulation in a tissue-specific manner, impacting different hallmark features of cancer. Mechanistically, Anx-A1 modulates drug efflux transporters, influences cancer stem cell populations, DNA damages and participates in epithelial-mesenchymal transition. This review aims to explore Anx-A1's role in chemoresistance-associated pathways across various cancers, elucidating its impact on survival signaling cascades including PI3K/AKT, MAPK/ERK, PKC/JNK/P-gp pathways and NFκ-B signalling. This review also reveals the clinical implications of Anx-A1 dysregulation in treatment response, its potential as a prognostic biomarker, and therapeutic targeting strategies, including the promising Anx-A1 N-terminal mimetic peptide Ac2-26. Understanding Anx-A1's intricate involvement in chemoresistance offers exciting prospects for refining cancer therapies and improving treatment outcomes.

Deletion of PTP4A3 phosphatase in high grade serous ovarian cancer cells decreases tumorigenicity and produces marked changes in intracellular signaling pathways and cytokine release.

The oncogenic protein tyrosine phosphatase PTP4A3 is frequently overexpressed in human ovarian cancers and is associated with poor patient prognosis. PTP4A3 is thought to regulate multiple oncogenic signaling pathways, including STAT3, SRC, and ERK. The objective of this study was to generate ovarian cancer cells with genetically depleted PTP4A3; to assess their tumorigenicity; to examine their cellular phenotype; and to uncover changes in their intracellular signaling pathways and cytokine release profiles. Genetic deletion of PTP4A3 using CRISPR/Cas9 enabled the generation of individual clones derived from single cells isolated from the polyclonal knockout population. We observed a >90% depletion of PTP4A3 protein levels by Western blotting in the clonal cell lines compared to the sham transfected wildtype population. The wildtype and polyclonal knockout cell lines shared similar monolayer growth rates, while the isolated clonal populations 2B4, 3C9, and 3C12 exhibited significantly lower monolayer growth characteristics consistent with their lower PTP4A3 levels. The clonal PTP4A3 knockout cell lines also had substantially lower in vitro colony formation efficiencies compared to the wildtype cells and were less tumorigenic in vivo The clonal knockout cells were markedly less responsive to IL-6-stimulated migration in a scratch wound assay compared to the wildtype cells. Antibody microarray assays documented differences in cytokine release and intracellular phosphorylation patterns in the PTP4A3 deleted clones. Bioinformatic network analyses indicated alterations in cellular signaling nodes. These biochemical changes could ultimately form the foundation for pharmacodynamic endpoints useful for emerging anti-PTP4A3 therapeutics. Significance Statement Clones of high grade serous ovarian cancer cells were isolated in which the oncogenic phosphatase PTP4A3 was deleted using CRISPR/Cas9 methodologies. The PTP4A3 null cells exhibited loss of in vitro proliferation, colony formation, and migration, and reduced in vivo tumorigenesis. Marked differences in intracellular protein phosphorylation and cytokine release were seen. The newly developed PTP4A3 knockout cells should provide useful tools to probe the role of PTP4A3 phosphatase in ovarian cancer cell survival, tumorigenicity and cell signaling.

Aloperine Attenuates Hepatic Ischemia/Reperfusion-Induced Liver Injury via STAT-3 Signaling in a Murine Model.

Hepatic ischemia/reperfusion (I/R) damage is one of the most common side effects of liver surgery. This pathophysiological process may lead to excessive hepatic damage. Aloperine is an active ingredient isolated from Sophora alopecuroides Linn and has a variety of therapeutic effects, including organ protection. However, the hepatoprotective effect of aloperine against hepatic I/R damage has not yet been determined. C57BL/6 mice were allocated to the sham-operated (sham), hepatic ischemia/reperfusion (I/R), and aloperine (ALO) groups. The mice were exposed to 30 min of hepatic hilum occlusion. Then a 3-hour reperfusion was performed. Mice in the sham group underwent sham surgery. Hepatic injury was evaluated by plasma aspartate aminotransferase (AST) and transaminase alanine aminotransferase (ALT) levels, histological evaluation, cell apoptosis, the number of activated inflammatory cells, and the expression levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The protein phosphorylation status of the reperfusion-associated survival pathways was evaluated. Mice with hepatic I/R injury presented increased plasma ALT and AST levels, increased hepatic apoptosis, abnormal histological structure, and elevated inflammatory responses. However, aloperine ameliorated hepatic I/R-induced injury. Moreover, aloperine enhanced the level of signal transducer and activator of transcription (STAT)-3 phosphorylation after I/R. Ag490, an agent that inhibits STAT-3 activity, abolished aloperine-induced STAT-3 phosphorylation and liver protection. Aloperine ameliorates hepatic I/R-induced liver injury via a STAT-3-mediated protective mechanism. Patients with hepatic I/R injury may benefit from aloperine treatment. Significance Statement Hepatic ischemia/reperfusion (I/R) can cause excessive liver damage. This study revealed that aloperine, an active component isolated from Sophora alopecuroides Linn., ameliorates hepatic I/R injury and related liver damage in vivo The underlying protective mechanism may involve the STAT-3 signaling pathway. These findings may lead to the development of a novel approach for treating hepatic I/R damage in clinical practice.

Inroads into saline-alkaline stress response in plants: unravelling morphological, physiological, biochemical, and molecular mechanisms.

MAIN CONCLUSION: This article discusses the complex network of ion transporters, genes, microRNAs, and transcription factors that regulate crop tolerance to saline-alkaline stress. The framework aids scientists produce stress-tolerant crops for smart agriculture. Salinity and alkalinity are frequently coexisting abiotic limitations that have emerged as archetypal mediators of low yield in many semi-arid and arid regions throughout the world. Saline-alkaline stress, which occurs in an environment with high concentrations of salts and a high pH, negatively impacts plant metabolism to a greater extent than either stress alone. Of late, saline stress has been the focus of the majority of investigations, and saline-alkaline mixed studies are largely lacking. Therefore, a thorough understanding and integration of how plants and crops rewire metabolic pathways to repair damage caused by saline-alkaline stress is of particular interest. This review discusses the multitude of resistance mechanisms that plants develop to cope with saline-alkaline stress, including morphological and physiological adaptations as well as molecular regulation. We examine the role of various ion transporters, transcription factors (TFs), differentially expressed genes (DEGs), microRNAs (miRNAs), or quantitative trait loci (QTLs) activated under saline-alkaline stress in achieving opportunistic modes of growth, development, and survival. The review provides a background for understanding the transport of micronutrients, specifically iron (Fe), in conditions of iron deficiency produced by high pH. Additionally, it discusses the role of calcium in enhancing stress tolerance. The review highlights that to encourage biomolecular architects to reconsider molecular responses as auxiliary for developing tolerant crops and raising crop production, it is essential to (a) close the major gaps in our understanding of saline-alkaline resistance genes, (b) identify and take into account crop-specific responses, and (c) target stress-tolerant genes to specific crops.

Cholesteryl ester transfer protein knock-down in conjunction with a cholesterol-depleting agent decreases tamoxifen resistance in breast cancer cells.

The cholesterogenic phenotype, encompassing de novo biosynthesis and accumulation of cholesterol, aids cancer cell proliferation and survival. Previously, the role of cholesteryl ester (CE) transfer protein (CETP) has been implicated in breast cancer aggressiveness, but the molecular basis of this observation is not clearly understood, which this study aims to elucidate. CETP knock-down resulted in a >50% decrease in cell proliferation in both 'estrogen receptor-positive' (ER+; Michigan Cancer Foundation-7 (MCF7) breast cancer cells) and 'triple-negative' breast cancer (TNBC; MDA-MB-231) cell lines. Intriguingly, the abrogation of CETP together with the combination treatment of tamoxifen (5 µM) and acetyl plumbagin (a cholesterol-depleting agent) (5 µM) resulted in twofold to threefold increase in apoptosis in both cell lines. CETP knockdown also showed decreased intracellular CE levels, lipid raft and lipid droplets in both cell lines. In addition, RT2 Profiler PCR array (Qiagen, Germany)-based gene expression analysis revealed an overall downregulation of genes associated in cholesterol biosynthesis, lipid signalling and drug resistance in MCF7 cells post-CETP knock-down. On the contrary, resistance in MDA-MB-231 cells was reduced through increased expression in cholesterol efflux genes and the expression of targetable surface receptors by endocrine therapy. The pilot xenograft mice study substantiated CETP's role as a cancer survival gene as knock-down of CETP stunted the growth of TNBC tumour by 86%. The principal findings of this study potentiate CETP as a driver in breast cancer growth and aggressiveness and thus targeting CETP could limit drug resistance via the reduction in cholesterol accumulation in breast cancer cells, thereby reducing cancer aggressiveness.

The role of IL-2 cytokine family in asthma.

BACKGROUND: The interleukin-2 (IL-2) family of cytokines, including IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, are pivotal regulators of the immune response, impacting both innate and adaptive immunity. Understanding their molecular characteristics, receptor interactions, and signalling pathways is essential for elucidating their roles in health and disease. OBJECTIVES: This review provides a comprehensive overview of the IL-2 family of cytokines, highlighting their molecular biology, receptor interactions, and signalling mechanisms. Furthermore, it explores the involvement of IL-2 family cytokines in the pathogenesis of chronic respiratory diseases, with a specific focus on chronic obstructive pulmonary disease (COPD) and asthma. METHODS: A thorough literature review was conducted to gather insights into the molecular biology, receptor interactions, and signalling pathways of IL-2 family cytokines. Additionally, studies investigating the roles of these cytokines in chronic respiratory diseases, particularly COPD and asthma, were analysed to discern their implications in wider pathophysiology of disease. RESULTS: IL-2 family cytokines exert pleiotropic effects on immune cells, modulating cellular proliferation, differentiation, and survival. Dysregulation of IL-2 family cytokines has been implicated in the pathogenesis of chronic respiratory illnesses, including COPD and asthma. Elevated levels of IL-2 and IL-9 have been associated with disease severity in COPD, while IL-4 and IL-9 play crucial roles in asthma pathogenesis by promoting airway inflammation and remodelling. CONCLUSION: Understanding the intricate roles of IL-2 family cytokines in chronic respiratory diseases provides valuable insights into potential therapeutic targets for these conditions. Targeting specific cytokines or their receptors may offer novel treatment modalities to attenuate disease progression and improve clinical outcomes in patients with COPD and asthma.

Vincristine attenuates isoprenaline-induced cardiac hypertrophy in male Wistar rats via suppression of ROS/NO/NF-қB signalling pathways.

Vincristine (VCR), a vinca alkaloid with anti-tumor and anti-oxidant properties, is acclaimed to possess cardioprotective action. However, the molecular mechanism underlying this protective effect remains unknown. This study investigated the effects of VCR on isoprenaline (ISO), a beta-adrenergic receptor agonist, induced cardiac hypertrophy in male Wistar rats. Animals were pre-treated with ISO (1 mg/kg) intraperitoneally for 14 days before VCR (25 µg/kg) intraperitoneal injection from days 1 to 28. Thereafter, mechanical, and electrical activities of the hearts of the rats were measured using a non-invasive blood pressure monitor and an electrocardiograph, respectively. After which, the heart was homogenized, and supernatants were assayed for contractile proteins: endothelin-1, cardiac troponin-1, angiotensin-II, and creatine kinase-MB, with markers of oxidative/nitrergic stress (SOD, CAT, MDA, GSH, and NO), inflammation (TNF-a and IL-6, NF-kB), and caspase-3 indicative of VCR reduced elevated blood pressure and reversed the abnormal electrocardiogram. ISO-induced increased endothelin-1, cardiac troponin-1, angiotensin-II, and creatine phosphokinase-MB, which were reversed by VCR. ISO also increased TNF-α, IL-6, NF-kB expression with increased caspase-3-mediated apoptosis in the heart. However, VCR reduced ISO-induced inflammation and apoptosis, with improved endogenous antioxidant agents (GSH, SOD, CAT) relative to ISO controls. Moreso, VCR, protected against ISO-induced histoarchitectural degeneration of cardiac myofibre. The result of this study revealed that VCR treatment significantly reverses ISO-induced cardiac hypertrophic phenotypes, via mechanisms connected to improved levels of proteins involved in excitation-contraction, and suppression of oxido-inflammatory and apoptotic pathways.

Cell-type specific molecular expression levels by restricted-dimensional cytometry.

BACKGROUND: Cytometric analysis has been commonly used to delineate distinct cell subpopulations among peripheral blood mononuclear cells by the differential expression of surface receptors. This capability has reached its apogee with high-dimensional approaches such as mass cytometry and spectral cytometry that include simultaneous assessment of 20-50 analytes. Unfortunately, this approach also engenders significant complexity with analytical and interpretational pitfalls. METHODS: Here, we demonstrate a complementary approach with restricted-dimensionality to assess cell-type specific intracellular molecular expression levels at exceptional levels of precision. The expression of five analytes was individually assessed in four mononuclear cell-types from peripheral blood. RESULTS: Distinctions in expression levels were seen between cell-types and between samples from different donor groups. Mononuclear cell-type specific molecular expression levels distinguished pregnant from nonpregnant women and G-CSF-treated from untreated persons. Additionally, the precision of our analysis was sufficient to quantify a novel relationship between two molecules-Rel A and translocator protein-by correlational analysis. CONCLUSIONS: Restricted-dimensional cytometry can provide a complementary approach to define characteristics of cell-type specific intracellular protein and phosphoantigen expression in mononuclear cells.

Clinical relevance of glycosylation in triple negative breast cancer: a review.

Glycosylation alterations in TNBC have significant implications for tumor behavior, diagnosis, prognosis, and therapeutic strategies. Dysregulated glycosylation affects cell adhesion, signaling, immune recognition, and response to therapy in TNBC. Different types of glycosylation, including N-linked glycosylation, O-linked glycosylation, glycosphingolipid glycosylation, mucin-type glycosylation, and sialylation, play distinct roles in TNBC. The "barcoding" method based on glycosylation sites of the membrane type mannose receptor (MR) shows promise in accurately distinguishing breast cancer subtypes, including TNBC. Alpha-L-fucosidase 1 (FUCA1) and Monocarboxylate transporter 4 (MCT4) have been identified as potential diagnostic and prognostic markers for TNBC. The glycosylation status of PD-L1 impacts the response to immune checkpoint blockade therapy in TNBC. Inhibiting fucosylation of B7H3 enhances immune responses and improves anti-tumor effects. Targeting glycosylated B7H4 and modulating estrogen metabolism through glycosylation-related mechanisms are potential therapeutic strategies for TNBC. Understanding the role of glycosylation in TNBC provides insights into disease mechanisms, diagnosis, and potential therapeutic targets. Further research in this field may lead to personalized treatment approaches and improved outcomes for TNBC patients.

Natural products and diet for the prevention of oral cancer: Research from south and southeast Asia.

Medicinal plants are of prime importance in the discovery of drugs. They are an inherent source of naturally available phytochemicals that can help in the prevention and treatment of several diseases including cancer. This article reviews the experimental and clinical evidence of phytochemicals available in natural dietary products that are used in everyday life across South Asia and South-East Asia for their perceived effectiveness in the management of Potentially Malignant Disorders and prevention of Oral Cancer. The review also highlights the active phytometabolites, their in vitro anti-proliferative properties and targeted signalling pathways, biological activities in in vivo models and translative potential for clinical trials in humans.

Visfatin Affects the Transcriptome of Porcine Luteal Cells during Early Pregnancy.

Visfatin/NAMPT (VIS), the hormone exerting a pleiotropic effect, is also perceived as an important factor in the regulation of reproductive processes and pregnancy maintenance. Previous studies confirmed its involvement in the control of porcine pituitary and ovary function. In this study, we hypothesized that VIS may affect the global transcriptome of luteal cells and thus regulate the functioning of the ovaries. Illumina's NovaSeq 6000 RNA sequencing was performed to investigate the differentially expressed genes (DEGs) and long non-coding RNAs (DELs) as well as the occurrence of differential alternative splicing events (DASs) in the porcine luteal cells exposed to VIS (100 ng/mL) during the implantation period. The obtained results revealed 170 DEGs (99 up- and 71 downregulated) assigned to 45 functional annotations. Moreover, we revealed 40 DELs, of which 3 were known and 37 were described for the first time. We identified 169 DASs events. The obtained results confirmed a significant effect of VIS on the transcriptome and spliceosome of luteal cells, including the genes involved in the processes crucial for successful implantation and pregnancy maintenance as angiogenesis, steroidogenesis, inflammation, cell development, migration, and proliferation.

Expression of RASSF1A, DIRAS3, and AKAP9 Genes in Thyroid Lesions: Implications for Differential Diagnosis and Prognosis of Thyroid Carcinomas.

Thyroid carcinoma is the primary endocrine malignancy worldwide. The preoperative examination of thyroid tissue lesion is often unclear. Approximately 25% of thyroid cancers cannot be diagnosed definitively without post-surgery histopathological examination. The assessment of diagnostic and differential markers of thyroid cancers is needed to improve preoperative diagnosis and reduce unnecessary treatments. Here, we assessed the expression of RASSF1A, DIRAS3, and AKAP9 genes, and the presence of BRAF V600E point mutation in benign and malignant thyroid lesions in a Polish cohort (120 patients). We have also performed a comparative analysis of gene expression using data obtained from the Gene Expression Omnibus (GEO) database (307 samples). The expression of RASSF1A and DIRAS3 was decreased, whereas AKAP9's was increased in pathologically changed thyroid compared with normal thyroid tissue, and significantly correlated with e.g., histopathological type of lesion papillary thyroid cancer (PTC) vs follicular thyroid cancer (FTC), patient's age, tumour stage, or its encapsulation. The receiver operating characteristic (ROC) analysis for the more aggressive FTC subtype differential marker suggests value in estimating RASSF1A and AKAP9 expression, with their area under curve (AUC), specificity, and sensitivity at 0.743 (95% CI: 0.548-0.938), 82.2%, and 66.7%; for RASSF1A, and 0.848 (95% CI: 0.698-0.998), 54.8%, and 100%, for AKAP9. Our research gives new insight into the basis of the aggressiveness and progression of thyroid cancers, and provides information on potential differential markers that may improve preoperative diagnosis.

Hydrolyzed conchiolin protein inhibits melanogenesis through PKA/CREB and MEK/ERK signalling pathways.

OBJECTIVE: Hydrolyzed conchiolin protein (HCP) derived from pearl and nacre extracts exerts skin-lightening effects; however, the underlying molecular mechanisms are not fully understood. Herein, we investigated the effect of HCP on melanogenesis and the signalling pathways involved. METHODS: B16F10 cells and PIG cells were treated with HCP to verify its ability to inhibit melanin. Western Blot, immunofluorescence, and flow cytometry methods were performed to investigate the effect of HCP on melanogenesis signalling pathway proteins. The inhibitors were used to further validate the effect of HCP on PKA/CREB and MEK/ERK signalling pathways. To further evaluate the whitening ability of HCP, changes in melanin were detected using 3D melanin skin model and zebrafish model. RESULTS: HCP was found to significantly inhibit melanin synthesis and decrease the expression of melanogenesis-related proteins, such as microphthalmia-associated transcription factor (MITF), tyrosinase, and tyrosinase-related protein-2, in a dose-dependent manner. Additionally, we revealed that HCP suppresses melanogenesis via the regulation of the PKA/cAMP response element-binding (CREB) and MEK/extracellular signalling-regulated kinase (ERK) signalling pathways. Using 3D melanin skin models, we demonstrated that HCP can achieve skin-lightening effects by improving apparent chroma, increasing apparent brightness, and inhibiting melanin synthesis. Furthermore, HCP exhibits skin-whitening effects in a zebrafish model. CONCLUSION: These results suggest that HCP suppresses the melanogenesis signalling cascade by inhibiting the PKA/CREB, MEK/ERK signalling pathway and downregulating MITF and its downstream signalling pathways, resulting in decreased melanin synthesis. In summary, HCP is a potential anti-pigmentation agent with promising applications in cosmetics and pharmaceutical products.

OBJECTIF: La protéine conchioline hydrolysée (HCP) dérivée des extraits de perle et de nacre exerce des effets éclaircissants sur la peau ; cependant, les mécanismes moléculaires sous­jacents ne sont pas entièrement compris. Dans cette étude, nous avons investigué l'effet de la HCP sur la mélanogenèse et les voies de signalisation impliquées. MÉTHODES: Les cellules B16F10 et PIG ont été traitées avec la HCP pour vérifier sa capacité à inhiber la mélanine. Des méthodes de Western Blot, d'immunofluorescence et de cytométrie en flux ont été réalisées pour étudier l'effet de la HCP sur les protéines des voies de signalisation de la mélanogenèse. Les inhibiteurs ont été utilisés pour valider davantage l'effet de la HCP sur les voies de signalisation PKA/CREB et MEK/ERK. Pour évaluer plus en détail la capacité éclaircissante de la HCP, les changements de mélanine ont été détectés en utilisant un modèle de peau en 3D de mélanine et un modèle de poisson­zèbre. RÉSULTATS: Il a été constaté que la HCP inhibe significativement la synthèse de la mélanine et diminue l'expression des protéines liées à la mélanogenèse, telles que le facteur de transcription associé à la microphthalmie (MITF), la tyrosinase et la protéine liée à la tyrosinase­2, de manière dose­dépendante. De plus, nous avons révélé que la HCP supprime la mélanogenèse via la régulation des voies de signalisation PKA/cAMP et MEK/ERK. En utilisant des modèles de peau en 3D de mélanine, nous avons démontré que la HCP peut atteindre des effets éclaircissants sur la peau en améliorant la chroma apparente, en augmentant la luminosité apparente et en inhibant la synthèse de la mélanine. En outre, la HCP présente des effets éclaircissants sur la peau dans un modèle de poisson­zèbre. CONCLUSION: Ces résultats suggèrent que la HCP supprime la cascade de signalisation de la mélanogenèse en inhibant les voies de signalisation PKA/CREB et MEK/ERK et en régulant à la baisse le MITF et ses voies de signalisation en aval, ce qui entraîne une diminution de la synthèse de la mélanine. En résumé, la HCP est un agent potentiel anti­pigmentation avec des applications prometteuses dans les produits cosmétiques et pharmaceutiques.

Targeting Signalling Pathways in Chronic Wound Healing.

Chronic wounds fail to achieve complete closure and are an economic burden to healthcare systems due to the limited treatment options and constant medical attention. Chronic wounds are characterised by dysregulated signalling pathways. Research has focused on naturally derived compounds, stem-cell-based therapy, small molecule drugs, oligonucleotide delivery nanoparticles, exosomes and peptide-based platforms. The phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT), Wingless-related integration (Wnt)/ß-catenin, transforming growth factor-ß (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), Notch and hypoxia-inducible factor 1 (HIF-1) signalling pathways have critical roles in wound healing by modulating the inflammatory, proliferative and remodelling phases. Moreover, several regulators of the signalling pathways were demonstrated to be potential treatment targets. In this review, the current research on targeting signalling pathways under chronic wound conditions will be discussed together with implications for future studies.

Exploration of gut microbiome and inflammation: A review on key signalling pathways.

The gut microbiome, a crucial component of the human system, is a diverse collection of microbes that belong to the gut of human beings as well as other animals. These microbial communities continue to coexist harmoniously with their host organisms and perform various functions that affect the host's general health. Each person's gut microbiota has a unique makeup. The gut microbiota is well acknowledged to have a part in the local as well as systemic inflammation that underlies a number of inflammatory disorders (e.g., atherosclerosis, diabetes mellitus, obesity, and inflammatory bowel disease).The gut microbiota's metabolic products, such as short-chain fatty acids (butyrate, propionate, and acetate) inhibit inflammation by preventing immune system cells like macrophages and neutrophils from producing pro-inflammatory factors, which are triggered by the structural elements of bacteria (like lipopolysaccharide). The review's primary goal is to provide comprehensive and compiled data regarding the contribution of gut microbiota to inflammation and the associated signalling pathways.

Atlanto-occipital assimilation: embryological basis and its clinical significance.

Atlanto-occipital assimilation is an osseous embryological anomaly of the craniovertebral junction in which the atlas (C1) is fused to the occiput of skull. Embryologically, this assimilation may happen due to failure of the segmentation and separation of the caudal occipital and the cranial cervical sclerotome. The segmentation clock is maintained by NOTCH and WNT signalling pathways along with Hox genes and retinoic acid. This condition is likely to be a consequence of mutation in above mentioned genes. The knowledge of this assimilation may be crucial for the clinicians as it may lead to various neurovascular symptoms. The present case report involves the analysis of atlanto-occipital assimilation with its clinical significance and embryological basis.