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The primary pathological hallmark of Parkinson's disease (PD) is the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta, a critical midbrain region. In vitro models based on DA neurons provide a powerful platform for investigating the cellular and molecular mechanisms of PD and testing novel therapeutic strategies. A deep understanding of DA neuron development, including the signalling pathways and transcription factors involved, is essential for advancing PD research. This article first explores the differentiation and maturation processes of DA neurons in the midbrain, detailing the relevant signalling pathways. It then compares various in vitro models, including primary cells, immortalized cell lines, and stem cell‐based models, focusing on the advantages and limitations of each. Special attention is given to the role of immortalized and stem cell models in PD research. This review aims to guide researchers in selecting the most appropriate model for their specific research goals. Ethical considerations and clinical implications of using stem cells in PD research are also discussed. [ABSTRACT FROM AUTHOR]

Pseudomonas aeruginosa is an important opportunistic bacterium, which its resistant form can induce some complications in immunocompromised patients. The bacterium uses several mechanisms to overcome immune responses and makes a resistant form. Toll like receptors (TLRs) are the most well-known innate immune receptors that play key roles in the induction and stimulation of immune responses against bacteria. Accordingly, it has been hypothesised that Pseudomonas aeruginosa may cause significant interactions with the receptors to be resistance to immune responses and make persistence infection. Thus, the main aim of this review article is to discuss the roles played by toll like receptors in the induction of appropriate immune responses and also induction of the bacterium complications. [ABSTRACT FROM AUTHOR]

Bryophyllum pinnatum (Lam.) Oken, a multipurpose medicinal herb, has drawn much interest for its therapeutic qualities from both traditional and modern medicine systems. Many active secondary metabolites, such as bufadienolides, triterpenes, phenols, alkaloids, glycosides, lipids, flavonoids, and organic acids, are responsible for the plant's curative properties. B. pinnatum exhibits a noteworthy significance in oncological research by exhibiting its ability to modify numerous pathways, which may suggest a potential anticancer impact. The herb is recommended for treating lithiasis, a common cause of renal failure, due to its effectiveness in dissolving stones and avoiding crystal formation. The plant has a major impact on diabetes, especially type II diabetes. Moreover, the versatility of B. pinnatum extends to its examination in connection to COVID-19. However, caution is warranted, as B. pinnatum has been reported to possess toxicity attributed to the presence of bufadienolides in its metabolic profile. A comprehensive investigation is essential to thoroughly understand and confirm the synthesis of potentially hazardous compounds. This is crucial for minimizing their presence and ensuring the safe consumption of B. pinnatum among diverse populations of organisms. This review highlights the various medical uses of B. pinnatum, including its ability to effectively treat kidney and liver diseases, as well as its anti-leishmanial, neuropharmacological, antibacterial, immunosuppressive, anti-tumour, and cytotoxic effects. While extensively employed in both traditional and scientific domains, the plant's complete medicinal potential, molecular mechanisms, safety profile, and pharmacodynamics remain ambiguous, rendering it an ideal candidate for pioneering research endeavours. [ABSTRACT FROM AUTHOR]

In recent years, the growing public awareness of personal health has sparked a surge in interest in the beneficial effects of polyphenols on the human organism. Extensive research by domestic and international scholars has established that polyphenols, due to their unique chemical properties, exhibit remarkable anti-inflammatory and antioxidant properties, leading to improvements in various diseases, including cancer, diabetes, and colitis. Notably, China stands as one of the world’s largest producers and consumers of flax, a crop rich in lignans, a subclass of polyphenols. These flax lignans possess significant effects on the body, demonstrating immense potential for therapeutic applications. This paper delves into the origins, metabolic processes, and health benefits of flax lignans in China. It offers a comprehensive review of the mechanisms underlying flax lignans role in disease intervention, focusing on their interactions with relevant signalling pathways. Our findings suggest that flaxseed lignans can promote organismic health by either directly modulating gene expression or indirectly regulating signalling pathways. Furthermore, flaxseed lignans can exhibit diverse effects depending on specific physiological conditions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: This study aims to investigate the molecular mechanisms of Huangqi {Astragalus) in the treatment of premature ovarian insufficiency (POI) using network pharmacology and molecular docking methods. Methods: The active compounds and target proteins of Huangqi were screened from the TCMSP database, while the disease target proteins associated with POI were obtained from the Genecards database. The Venny online tool was used to identify the overlapping genes between the two datasets. Cytoscape software was used to construct a gene regulatory network for the active ingredients of Huangqi. The protein-protein interaction (PPI) network and core genes were selected based on the STRING database and CytoNCA plug-in of Cytoscape. GO (gene ontology) enrichment and KEGG (Kyoto encyclopedia of genes and genomes) pathway enrichment analyses of the overlapping genes were performed using the DAVID database. Molecular docking techniques were used to further elucidate the molecular mechanisms underlying the therapeutic effects. Human ovarian granulosa-like tumor cells (KGN) underwent serum starvation (SS) treatment to induce POI cell models and then received quercetin treatment, and experimentally validated the network pharmacology prediction results by TUNEL staining and Western blotting assay. Results: The TCMSP database provided 32 active compounds and 552 target genes associated with Huangqi, while totally 730 disease target genes associated with POI were screened out from the disease database. Of these, 62 genes were found to be shared between the two datasets. The top 6 compounds based on degree values were quercetin, isorhamnetin, kaempferol, mairin, formononetin and astragaloside IV. The 10 core genes identified were ALB, INS, AKT1, ACTB, TP53, TNF, ESR1, CASP3, STAT3 and PTEN. These potential targets were mainly involved in regulating the JAK2/STAT3 and PI3K/Akt signaling pathway. Molecular docking results revealed strong binding interactions between the compounds and the key proteins STAT3 and Akt1 in the JAK-STAT and PI3K-Akt signalling pathways. The results of in vitro experiments revealed that quercetin could activate the JAK2/STAT3 pathway and inhibit cell apoptosis. Conclusions: Network pharmacology and molecular docking analysis showed that Astragalus could regulate the response of ovarian cells to estradiol, inhibit apoptosis and regulate the JAK-STAT and PI3K-Akt signalling pathways in the treatment of early onset ovarian dysfunction. [ABSTRACT FROM AUTHOR]

Ali Attiq,1 Sheryar Afzal,2 Habibah A Wahab,1 Waqas Ahmad,1 Mahmoud Kandeel,2,3 Yassir A Almofti,2,4 Ahmed O Alameen,2,5 Yuan Seng Wu6,7 1School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, Penang, 11800, Malaysia; 2Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al Ahsa, 31982, Saudi Arabia; 3Department of Pharmacology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrel Sheikh, 6860404, Egypt; 4Department of Biochemistry, Molecular Biology and Bioinformatics, College of Veterinary Medicine, University of Bahri, Khartoum, 12217, Sudan; 5Department of Physiology, Faculty of Veterinary Medicine, University of Khartoum, Shambat, 13314, Sudan; 6Sunway Microbiome Centre, School of Medical and Life Sciences, Sunway University, Subang Jaya, Selangor, 47500, Malaysia; 7Department of Biological Sciences, School of Medical and Life Sciences, Sunway University, Subang Jaya, Selangor, 47500, MalaysiaCorrespondence: Sheryar Afzal, Department of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al Ahsa, 31982, Saudi Arabia, Email safzal@kfu.edu.sa Ali Attiq, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Gelugor, 11800, Penang, Malaysia, Email aliattiq@usm.myAbstract: Angiotensin-converting enzyme 2 receptors (ACE2R) are requisite to enter the host cells for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). ACE2R is constitutive and functions as a type I transmembrane metallo-carboxypeptidase in the renin-angiotensin system (RAS). On thyroid follicular cells, ACE2R allows SARS-CoV-2 to invade the thyroid gland, impose cytopathic effects and produce endocrine abnormalities, including stiff back, neck pain, muscle ache, lethargy, and enlarged, inflamed thyroid gland in COVID-19 patients. Further damage is perpetuated by the sudden bursts of pro-inflammatory cytokines, which is suggestive of a life-threatening syndrome known as a “cytokine storm”. IL-1β, IL-6, IFN-γ, and TNF-α are identified as the key orchestrators of the cytokine storm. These inflammatory mediators upregulate transcriptional turnover of nuclear factor-kappa B (NF-κB), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and mitogen-activated protein kinase (MAPK), paving the pathway for cytokine storm-induced thyroid dysfunctions including euthyroid sick syndrome, autoimmune thyroid diseases, and thyrotoxicosis in COVID-19 patients. Targeted therapies with corticosteroids (dexamethasone), JAK inhibitor (baricitinib), nucleotide analogue (remdesivir) and N-acetyl-cysteine have demonstrated effectiveness in terms of attenuating the severity and frequency of cytokine storm-induced thyroid dysfunctions, morbidity and mortality in severe COVID-19 patients. Here, we review the pathogenesis of cytokine storms and the mechanisms and pathways that establish the connection between thyroid disorder and COVID-19. Moreover, cross-talk interactions of signalling pathways and therapeutic strategies to address COVID-19-associated thyroid diseases are also discussed herein.Keywords: COVID-19, cytokine storm, signalling pathways, inflammation, thyroid disorders, cross talks

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.

Background Melasma is a common dyschromia, mainly found in women with darker skin types. Although asymptomatic, melasma significantly impacts patients’ quality of life. Due to this complex pathogenesis, melasma is difficult to treat. Plant and plant-derived products have been explored as alternatives for the treatment of melasma. Methods This study utilized network pharmacology coupled with molecular docking and molecular dynamics simulations to investigate the molecular mechanisms of three selected Cassipourea metabolites in the treatment of melasma. Results Of the 202 genes obtained from the 14 profiled metabolites, only PTGS2, TYR, ESR2, and ESR1 were common among metabolites and targets implicated in melasma. From this, The gene ontology highlighted the intracellular steroid hormone receptor, signalling pathway, macromolecular complex, and estrogen receptor activity as the top enriched functional annotations, while the KEGG pathway analysis identified five signalling pathways, from which the prolactin signalling pathway, endocrine resistance, and estrogen signalling pathway were implicated in the pathogenesis of melasma. These pathways were further connected by their linkage to ESR2 and ESR1., Of all Cassipourea metabolites and standards, with afzelechin having the highest docking score for both gens. Further binding interaction analysis showed that ESR2-bound tamoxifen had the highest binding free energy of -47.68 kcal/mol, however, among the interacting Cassipourea metabolites, sitosterol-glycoside exhibited the highest negative binding affinity for both ESR2 (-40.50 kcal/mol) and ESR1 (-78.97 kcal/mol) over 150 ns simulation, suggesting its potential as a dual modulator. Altogether, the metabolites presented remarkable binding stability and thermodynamic compactness with the apo-genes. Conclusion The finding that the selected Cassipourea metabolites are associated with the genes and enzymes implicated in melasma pathogenesis, together with their significant binding effects on the enriched genes, suggests their regulatory potential on the profiled targets and, consequently, in the treatment of melasma.

Ganoderma, a genus of mushrooms known for its long history of medicinal use, has gained increasing attention in recent years due to its potential health benefits. This review delves into the bioactive compounds found in Ganoderma and elucidates the intricate mechanisms underlying its immunomodulatory and anti-tumour activities. The diverse health-promoting effects of Ganoderma can be attributed to its decadent array of bioactive compounds, notably polysaccharides, and triterpenoids, which play a pivotal role. The ability of the mushroom to modulate the immune system, enhancing the activity of immune cells, such as natural killer cells and macrophages, is a central focus. Furthermore, we explore how Ganoderma exerts anti-tumour effects through the induction of apoptosis, inhibition of angiogenesis, and interference with various signalling pathways critical for cancer cell growth and metastasis. As research in this area continues to evolve, a comprehensive understanding of the potential of Ganoderma as a natural health supplement and its role in promoting well-being is emerging, offering promising avenues for further investigation and application in healthcare. [ABSTRACT FROM AUTHOR]

• Plants are constantly subjected to a number of abiotic stresses, such as moisture stress, soil salinity, heavy metal toxicity, and heat stress. • Abiotic stressors have the potential to disrupt cellular homeostasis, leading in oxidative damage, which changes gene expression and reduces photosynthetic efficiency. Melatonin is a pleiotropic factor that has emerged as a promising candidate for minimizing the impacts of abiotic stressors in crops. • In stressed plants, melatonin supplementation has been demonstrated to increase antioxidant defense mechanisms, stabilize membrane integrity, and promote osmotic correction. • This hormone also regulates the expression of genes that are susceptible to stress and signalling pathways, resulting in increased stress tolerance and positive results for agricultural quality and productivity in sustainable agriculture. • Understanding the precise mechanisms by which melatonin confers stress tolerance could provide vital insights for developing novel strategies to counteract abiotic stress and ensure global food security. Plants are continually subjected to a variety of climatic challenges, including moisture stress, soil salinity, toxicity of heavy metals and heat stress, all of which have a substantial impact on their development and productivity. Abiotic stressors have the potential to disturb cellular homeostasis resulting in oxidative damage thus altered the gene expression, and decreased photosynthetic efficiency. As a result, there is a rising need to investigate novel ways for increasing tolerance to abiotic stresses in plants. Melatonin is a pleiotropic hormone and has recently emerged as promising contender for reducing the effects of abiotic stresses in crops. Melatonin, in addition to its well-known role in regulating sleep and circadian rhythms in mammals, has been shown to have exceptional anti-inflammatory, anti-oxidant, as well as free radical neutralization activities in plants. Melatonin supplementation has been shown to boost antioxidant defense systems, stabilize membrane integrity, and induce osmotic correction in stressed plants. This hormone additionally influences the expression of genes sensitive to stress and signalling pathways, which leads to greater stress tolerance and has promising outcomes on agricultural quality and productivity for sustainable agriculture. To efficiently administer melatonin to plants, various agricultural practices such as seed priming, foliar spray, and root treatment have been investigated. However, further research is needed to optimize administration methods, dosage, and timing to attain the greatest effects. The present piece of review summarizes existing knowledge on the role of melatonin in enhancing plant environmental stress tolerance. Understanding the precise processes by which melatonin provides stress tolerance may provide important insights for establishing novel techniques to combat abiotic stress and secure global food security. [ABSTRACT FROM AUTHOR]

A model explaining the dietary-protein-driven post-natal skeletal muscle growth and protein turnover in the rat is updated, and the mechanisms involved are described, in this narrative review. Dietary protein controls both bone length and muscle growth, which are interrelated through mechanotransduction mechanisms with muscle growth induced both from stretching subsequent to bone length growth and from internal work against gravity. This induces satellite cell activation, myogenesis and remodelling of the extracellular matrix, establishing a growth capacity for myofibre length and cross-sectional area. Protein deposition within this capacity is enabled by adequate dietary protein and other key nutrients. After briefly reviewing the experimental animal origins of the growth model, key concepts and processes important for growth are reviewed. These include the growth in number and size of the myonuclear domain, satellite cell activity during post-natal development and the autocrine/paracrine action of IGF-1. Regulatory and signalling pathways reviewed include developmental mechanotransduction, signalling through the insulin/IGF-1–PI3K–Akt and the Ras–MAPK pathways in the myofibre and during mechanotransduction of satellite cells. Likely pathways activated by maximal-intensity muscle contractions are highlighted and the regulation of the capacity for protein synthesis in terms of ribosome assembly and the translational regulation of 5-TOPmRNA classes by mTORC1 and LARP1 are discussed. Evidence for and potential mechanisms by which volume limitation of muscle growth can occur which would limit protein deposition within the myofibre are reviewed. An understanding of how muscle growth is achieved allows better nutritional management of its growth in health and disease. [ABSTRACT FROM AUTHOR]

To investigate the effects and mechanisms of Mycobacterium avium MAV-5183 protein on apoptosis in mouse Ana-1 macrophages. A pET-21a-MAV-5183 recombinant plasmid was constructed. The recombinant MAV-5183 protein was cloned, expressed, purified, and identified using an anti-His-tagged antibody. Rabbits were immunized to obtain antiserum, and its potency and immunoreactivity were assessed through WB. Mouse Ana-1 macrophages were incubated with varying concentrations of MAV-5183 protein. Flow cytometry, following ANNEXIN V-FITC/PI double staining, detected apoptosis. Western Blot analysis was conducted to identify apoptosis-related molecules Caspase-9/8/3 and vesicle-related molecules ASC, NLRP3, and Cleaved-casp1. ELISA measured TNF-α and IL-6 levels in the culture supernatant. LDH activity and ROS levels were analyzed separately. RT-qPCR measured mRNA levels of Caspase-9/8/3, ASC, NLRP3, Caspase-1, IL-1β, Bax, MAPK-p38, Bcl-2, TNF-α, and IL-6. MAV-5183 protein was successfully cloned, purified, and identified. In in vitro studies on Ana-1 macrophages, MAV-5183 protein increased the expression of Caspase-9/8/3, ASC, NLRP3 (P < 0.01), induced ROS secretion (P < 0.05), and promoted inflammatory cytokine secretion (TNF-α, IL-6, P < 0.0001); however, it did not significantly affect LDH (P > 0.05). MAV-5183 also induced apoptosis in Ana-1 macrophages (P < 0.05). RT-qPCR results indicated a significant increase in mRNA expression of Caspase-9/8/3, ASC, NLRP3, TNF-α, IL-6, MAPK-p38, and pro-apoptotic factor Bax (P < 0.01), with no significant effect on Bcl-2 and IL-1β mRNA (P > 0.05). The data indicate that MAV-5183 induces macrophage apoptosis through a caspase-dependent pathway and promotes inflammatory cytokine secretion via ROS. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. However, and despite achieving initial remission, a significant portion of patients will relapse because of innate and acquired resistance, at which point the disease is considered incurable. In view of this, novel detection strategies and therapeutic approaches are needed to improve outcomes and survival of OC patients. In this review, we summarize our current knowledge of the genetic landscape and molecular pathways underpinning OC and its many subtypes. By examining therapeutic strategies explored in preclinical and clinical settings, we highlight the importance of decoding how single and convergent genetic alterations co-exist and drive OC progression and resistance to current treatments. We also propose that core signalling pathways such as the PI3K and MAPK pathways play critical roles in the origin of diverse OC subtypes and can become new targets in combination with known DNA damage repair pathways for the development of tailored and more effective anti-cancer treatments. [ABSTRACT FROM AUTHOR]

Cancer remains one of the leading causes of death worldwide. Despite advances in medical treatments, current therapeutic strategies, including radiotherapy, chemotherapy, targeted therapy, and surgical resection, have not significantly reduced the global incidence and mortality rates of cancer. Oncologists face considerable challenges in devising effective treatment plans due to the adverse side effects associated with standard therapies. Therefore, there is an urgent need for more effective and well-tolerated cancer treatments. Curcumin, a naturally occurring compound, has garnered significant attention for its diverse biological properties. Both preclinical studies and clinical trials have highlighted curcumin’s potential in cancer treatment, demonstrating its ability to inhibit the proliferation of various cancer cell types through multiple cellular and molecular pathways. This paper examines the antineoplastic properties, and the therapeutic mechanisms including cell signalling pathways targeted by curcumin that are implicated in cancer development and explores the challenges in advancing curcumin as a viable anticancer therapy.

IntroductionThis study addresses the rising cardiovascular disease (CVD) rates in the United Arab Emirates (UAE) by investigating the occurrence and impact of genetic variants in CVD-related genes.MethodsWe collected all genes linked to heritable CVD from public and diagnostic databases and mapped them to their corresponding biological processes and molecular pathways. We then evaluated the types and burden of genetic variants within these genes in 343 individuals from the Emirati Mendelian Study Cohort and 3,007 national electronic health records.ResultsWe identified a total of 735 genes associated with heritable CVD, covering a range of cardiovascular conditions. Enrichment analysis revealed key biological processes and pathways, including Apelin, FoxO, and Ras signaling, that are implicated across all forms of heritable CVD. Analysis of a UAE cohort of 3,350 individuals showed a predominance of rare and unique CVD variants specific to the population. The study found a significant burden of pathogenic variants in families with CVD within the Emirati Mendelian cohort and re-assessed the pathogenicity of 693 variants from national health records, leading to the discovery of new CVD-causing variants.DiscussionThis study underscores the importance of continuously updating our understanding of genes and pathways related to CVD. It also highlights the significant underrepresentation of the UAE population in public databases and clinical literature on CVD genetics, offering valuable insights that can inform future research and intervention strategies.

Hepatocellular carcinoma (HCC) is the most prevalent form of primary liver cancers with high mortality rate. Among its various etiological factors, one of the major risk factors for HCC is a chronic infection of hepatitis B virus (HBV). HBV X protein (HBx) has been identified to play an important role in the HBV-induced HCC pathogenesis since it may interfere with several key regulators of many cellular processes. HBx localization within the cells may be beneficial to HBx multiple functions at different phases of HBV infection and associated hepatocarcinogenesis. HBx as a regulatory protein modulates cellular transcription, molecular signal transduction, cell cycle, apoptosis, autophagy, protein degradation pathways, and host genetic stability via interaction with various factors, including its association with various non-coding RNAs. A better understanding on the regulatory mechanism of HBx on various characteristics of HCC would provide an overall picture of HBV-associated HCC. This article addresses recent data on HBx role in the HBV-associated hepatocarcinogenesis.

• Discovering putative biomarkers that point to the interaction between AUD and NDs. • To identify the synergistic effects and targets of AUD on the progression of NDs. • Exploring proinflammatory responses was the significant pathways in AUD and NDs. • Identifying hub proteins (CCL2, IL1B, and TH etc.) for therapeutic targets. • Determining several TFs and miRNAs to understand the gene regulation patterns. Clinical investigations showed that individuals with Alcohol Use Disorder (AUD) have worse Neurological Disease (ND) development, pointing to possible pathogenic relationships between AUD and NDs. It remains difficult to identify risk factors that are predisposing between AUD and NDs. In order to fix these issues, we created the bioinformatics pipeline and network-based approaches for employing unbiased methods to discover genes abnormally stated in both AUD and NDs and to pinpoint some of the common molecular pathways that might underlie AUD and ND interaction. We found 100 differentially expressed genes (DEGs) in both the AUD and ND patient's tissue samples. The most important Gene Ontology (GO) terms and metabolic pathways, including positive control of cytotoxicity caused by T cells, proinflammatory responses, antigen processing and presentation, and platelet-triggered interactions with vascular and circulating cell pathways were then extracted using the overlapped DEGs. Protein-protein interaction analysis was used to identify hub proteins, including CCL2, IL1B, TH, MYCN, HLA-DRB1, SLC17A7, and HNF4A, in the pathways that have been reported as playing a function in these disorders. We determined several TFs (HNF4A, C4A, HLA-B, SNCA, HLA-DMB, SLC17A7, HLA-DRB1, HLA-C, HLA-A, and HLA-DPB1) and potential miRNAs (hsa-mir-34a-5p, hsa-mir-34c-5p, hsa-mir-449a, hsa-mir-155-5p, and hsa-mir-1-3p) were crucial for regulating the expression of AUD and ND which could serve as prospective targets for treatment. Our methodologies discovered unique putative biomarkers that point to the interaction between AUD and various neurological disorders, as well as pathways that could one day be the focus of therapeutic intervention. [ABSTRACT FROM AUTHOR]

Cancer is a group of diseases characterized by uncontrolled cellular growth, abnormal morphology, and altered proliferation. Cancerous cells lose their ability to act as anchors, allowing them to spread throughout the body and infiltrate nearby cells, tissues, and organs. If these cells are not identified and treated promptly, they will likely spread. Around 70% of female breast cancers are caused by a mutation in the BRCA gene, specifically BRCA1. The absence of progesterone, oestrogen and HER2 receptors (human epidermal growth factor) distinguishes the TNBC subtype of breast cancer. There were approximately 6,85,000 deaths worldwide and 2.3 million new breast cancer cases in women in 2020. Breast cancer is the most common cancer globally, affecting 7.8 million people at the end of 2020. Compared to other cancer types, breast cancer causes more women to lose disability-adjusted life years (DALYs). Worldwide, women can develop breast cancer at any age after puberty, but rates increase with age. The maintenance of mammary stem cell stemness is disrupted in TNBC, governed by signalling cascades controlling healthy mammary gland growth and development. Interpreting these essential cascades may facilitate an in-depth understanding of TNBC cancer and the search for an appropriate therapeutic target. Its treatment remains challenging because it lacks specific receptors, which renders hormone therapy and medications ineffective. In addition to radiotherapy, numerous recognized chemotherapeutic medicines are available as inhibitors of signalling pathways, while others are currently undergoing clinical trials. This article summarizes the vital druggable targets, therapeutic approaches, and strategies associated with TNBC. [ABSTRACT FROM AUTHOR]

The chemopreventive and chemotherapeutic properties of soy and soy‐derived compounds, especially isoflavones, have been extensively studied in recent years. However, in contrast to their anticancer effects, such as cell growth inhibition, cell cycle arrest and apoptosis induction, isoflavones have also been found to promote the growth of cancer cells. Therefore, the aim of this comprehensive review article is to present the current state of knowledge regarding the molecular mechanisms by which soy‐derived isoflavones target multiple cellular signalling pathways in cancer cells. Our findings indicate that soy‐derived isoflavones act as, among other things, potent modulators of HOX transcript antisense RNA (HOTAIR)/SWI/SNF‐related matrix‐associated actin‐dependent regulator of chromatin subfamily B member 1 (SMARCB1), vascular endothelial growth factor (VEGF)/C–X–C motif chemokine ligand 12 (CXCL12)/C–X–C motif chemokine receptor type 4 (CXCR4), 17‐β‐oestradiol (E2)/oestrogen receptor‐α (ERα)/neuroglobin (NGB) and sonic hedgehog signalling pathways, epigenetic modulatory agents (i.a. miR‐155, miR‐34a and miR‐10a‐5p) and cancer stem cells and epithelial‐to‐mesenchymal transition inhibitors. The paper also discusses the latest epidemiological studies and clinical trials and provides an insight into recent extensive research on the chemo‐preventive and therapeutic potential of soy‐derived isoflavones. [ABSTRACT FROM AUTHOR]

Heat-shock proteins (HSPs), also known as stress proteins, are ubiquitously present in all forms of life. They play pivotal roles in protein folding and unfolding, the formation of multiprotein complexes, the transportation and sorting of proteins into their designated subcellular compartments, the regulation of the cell cycle, and signalling processes. These HSPs encompass HSP27, HSP40, HSP70, HSP60, and HSP90, each contributing to various cellular functions. In the context of cancer, HSPs exert influence by either inhibiting or activating diverse signalling pathways, thereby impacting growth, differentiation, and cell division. This article offers an extensive exploration of the functions of HSPs within the realms of pharmacology and cancer biology. HSPs are believed to play substantial roles in the mechanisms underlying the initiation and progression of cancer. They hold promise as valuable clinical markers for cancer diagnosis, potential targets for therapeutic interventions, and indicators of disease progression. In times of cellular stress, HSPs function as molecular chaperones, safeguarding the structural and functional integrity of proteins and aiding in their proper folding. Moreover, HSPs play a crucial role in cancer growth, by regulating processes such as angiogenesis, cell proliferation, migration, invasion, and metastasis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. • Insects' regenerative capabilities is governed at molecular level. • Phases of regeneration: Wound healing/blastema formation, growth, re-patterning. • Signalling pathways such as JNK , JAK/STAT, Wnt etc. are involved in regeneration. • Epigenetics also plays a vital role in regeneration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Nanoparticles are an essential aspect of current scientific evolution, offering several potential applications in a number of fields. Particularly, in the therapeutic field such as in wound healing, the unique physical and chemical properties of silica nanoparticles (SiNPs) have attracted attention to it. In this study, we intend to investigate the relationship between silica nanoparticles and wound healing by analyzing altered gene expression before and after the treatment with (SiNPs), of 40 tissue repair related genes, giving special attention to (Matrix Metalloproteinase-9 (MMP-9), hyaluronan synthase 2 (HAS-2), integrin subunit alpha X (ITGA-X), integrin subunit alpha V (ITGA-V), integrin subunit alpha 5 (ITGA-5), S100 calcium binding protein A4 (S100A4), and vascular endothelial growth factor A (VEGFA)), to study the implications of these findings for better wound healing and to provide better insight into how SiNPs might be used to regenerate tissues and repair wounds. Our results showed that silica nanoparticles can significantly enhance wound healing by upregulating the expression of these key genes involved in the process. [ABSTRACT FROM AUTHOR]

Traditional agriculture relies heavily on chemical inputs, which pose significant threats to the environment and deplete natural resources. The environmental challenges posed by chemical-based agriculture and emphasizes the urgent need for sustainable alternatives in the face of climate change. Acknowledging the detrimental impact of environmental stressors on global agriculture sets the stage for exploration of PGPR as a promising solution. Plant Growth-Promoting Rhizobacteria (PGPR) have emerged as a sustainable alternative, fostering plant development, and enhancing stress resilience. A comprehensive understanding of the underlying signalling pathways and stress management mechanisms is essential to maximizing their potential. Plant health has been demonstrated, nutrient uptake has improved, and environmental stress has been reduced with the help of PGPR. Identifying the specific plant signalling pathways that are impacted by PGPR and comprehending their function in stress mitigation are critical to creating efficient and sustainable farming practises. Utilizing PGPR-mediated stress control may reduce the need for chemical inputs, encouraging environmentally friendly farming methods. By creating genetically engineered crops with increased stress tolerance, the knowledge gathered in this review can help ensure food security in the face of climate change. The signalling pathways involved, the processes underpinning PGPR-plant interactions, and the responses of plants to diverse stressors when PGPR is present have been explored. This review offers helpful insights into the intricate link between PGPR and plants, putting light on the uncertainties that beg for additional research by critically analysing the present literature and highlighting knowledge gaps.

Introduction: Catharanthus roseus, commonly known as Vinca Rosea or Madagascar periwinkle, is a significant plant species within the Apocynaceae family, known for its diverse medicinal properties and ornamental attributes, long embraced by Chinese traditional medicine practices. Methodology: Electronic records of papers published in various databases like Scopus, Pubmed, and Google scholar were searched from 2011 onwards and compiled to give a comprehensive overview of the pharmacological significance of C. roseus in Cancer management. This paper provides a comprehensive overview of traditional uses and pharmacological importance of various alkaloids obtained from C. roseus against Cancer and Diabetes mellitus. Results: The alkaloids derived from C. roseus exhibit a wide range of medicinal importance, including antihypertensive, antimicrobial, anti-inflammatory, and anticancer properties. Specifically, Vinblastine and Vincristine, derived from C. roseus, have shown significant efficacy in the treatment of various cancers, including Hodgkin's lymphoma and leukemia, which along with vindesine and vinorelbine are known anti-tumor drugs derived from Chinese traditional medicine. Treatment of inflammations, skin conditions, excretions, respiratory symptoms and elevated blood sugar levels are other uses of C. roseus in Chinese traditional medicine. This paper covers strategies for enhancement of Alkaloids production from C. roseus and highlights their drug delivery systems. Discussion: This paper elucidates various important alkaloids obtained from C. roseus and their biological role. Further, it highlights the signaling pathways effected by Vinca alkaloids found in C. roseus and provides in-depth insights on MiRNA activity and nuclear pathways of Cancer.

ABSTRACTShenling Baizhu Powder is a traditional Chinese medicine formula that has been used for thousands of years to invigorate spleen, nourish stomach and regulate immune function. The multi-herbal extracts, an improved formular from Shenling Baizhu Powder, were used in our study to investigate its immune-enhancing effects and underling mechanisms. Based on UPLC-Q-TOF-MS and SPME-GC-MS analysis, 106 chemical compounds were identified from the extracts. In vitro assays indicated that the extracts could promote cell proliferation and NO secretion of RAW264.7 cells. RNA-seq and RT-qPCR showed that RAW264.7 cells treated with extracts increased the expression of pro-inflammatory factors IL-1β, iNOS, TNF-α, and TGF-β. Western-Blot revealed that the extracts could significantly enhance ERK phosphorylation level, and slightly increased JNK and p38 phosphorylation levels. These data suggest that multi-herbal extracts have a potential of regulating immune response via the JNK/p38/ERK signalling of MAPK pathways in RAW264.7 cells.

Abstract G protein-coupled receptors (GPCRs) play a key role in regulating the homeostasis of the internal environment and are closely associated with tumour progression as major mediators of cellular signalling. As a diverse and multifunctional group of proteins, the G protein signalling regulator (RGS) family was proven to be involved in the cellular transduction of GPCRs. Growing evidence has revealed dysregulation of RGS proteins as a common phenomenon and highlighted the key roles of these proteins in human cancers. Furthermore, their differential expression may be a potential biomarker for tumour diagnosis, treatment and prognosis. Most importantly, there are few systematic reviews on the functional/mechanistic characteristics and clinical application of RGS family members at present. In this review, we focus on the G-protein signalling regulator (RGS) family, which includes more than 20 family members. We analysed the classification, basic structure, and major functions of the RGS family members. Moreover, we summarize the expression changes of each RGS family member in various human cancers and their important roles in regulating cancer cell proliferation, stem cell maintenance, tumorigenesis and cancer metastasis. On this basis, we outline the molecular signalling pathways in which some RGS family members are involved in tumour progression. Finally, their potential application in the precise diagnosis, prognosis and treatment of different types of cancers and the main possible problems for clinical application at present are discussed. Our review provides a comprehensive understanding of the role and potential mechanisms of RGS in regulating tumour progression. Video Abstract

Abstract Duck Tembusu virus (DTMUV) is a neurotropic virus in the genus Flavivirus that causes massive economic losses to the poultry industry in China and neighbouring countries. Autophagy is pivotal in cellular responses to pathogens and in viral pathogenesis. However, little is known about the roles of autophagy in DTMUV replication and viral pathogenesis, especially in neuropathogenesis. In this study, mouse neuroblastoma cells (Neuro-2a) were used to establish a cell model of DTMUV infection. Our experiments indicated that DTMUV infection induced incomplete autophagy in Neuro-2a cells. Then, we used different autophagy regulators to alter the autophagy induced by DTMUV and found that incomplete autophagy promoted DTMUV replication. Furthermore, we showed that DTMUV infection activated the ERK and AMPK pathways, resulting in decreased phosphorylation of the autophagy repressor mTOR, subsequently leading to autophagic induction. In addition, we utilized ICR mice in an animal model of DTMUV infection to evaluate the autophagic responses in brain tissues and investigate the effects of autophagy on viral replication and tissue lesions. Our results confirmed that DTMUV induced incomplete autophagy in mouse brain tissues and that autophagy inducer treatment promoted DTMUV replication and aggravated DTMUV-induced lesions, whereas autophagy inhibitor treatment had the opposite effects. In summary, DTMUV infection induced incomplete autophagy through the ERK/mTOR and AMPK/mTOR signalling pathways to promote viral replication in mouse neuronal cells, and DTMUV-induced incomplete autophagy contributed to the neuropathogenesis of DTMUV.

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. [ABSTRACT FROM AUTHOR]

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)/β-catenin, transforming growth factor-β (TGF-β), 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. [ABSTRACT FROM AUTHOR]

Epstein‐Barr virus, a human gamma‐herpesvirus, has a close connection to the pathogenesis of cancers and other diseases, which are a burden for public health worldwide. So far, several drugs or biomolecules have been discovered that can target EBV‐encoded products for treatment, such as Silvestrol, affinity toxin, roscovitine, H20, H31, curcumin, thymoquinone, and ribosomal protein L22. These drugs activate or inhibit the function of some biomolecules, affecting subsequent signalling pathways by acting on the products of EBV. These drugs usually target LMP1, LMP2; EBNA1, EBNA2, EBNA3; EBER1, EBER2; Bam‐HI A rightward transcript and BHRF1. Additionally, some promising findings in the fields of vaccines, immunological, and cellular therapies have been established. In this review, we mainly summarise the function of drugs mentioned above and unique mechanisms, hoping that we can help giving insight to the design of drugs for the treatment of EBV‐associated diseases. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a highly prevalent chronic joint disease and the leading cause of disability. Currently, no drugs are available to control joint damage or ease the associated pain. The wingless-type (WNT) signalling pathway is vital in OA progression. Excessive activation of the WNT signalling pathway is pertinent to OA progression and severity. Therefore, agonists and antagonists of the WNT pathway are considered potential drug candidates for OA treatment. For example, SM04690, a novel small molecule inhibitor of WNT signalling, has demonstrated its potential in a recent phase III clinical trial as a disease-modifying osteoarthritis drug (DMOAD). Therefore, targeting the WNT signalling pathway may be a distinctive approach to developing particular agents helpful in treating OA. This review aims to update the most recent progress in OA drug development by targeting the WNT pathway. In this, we introduce WNT pathways and their crosstalk with other signalling pathways in OA development and highlight the role of the WNT signalling pathway as a key regulator in OA development. Several articles have reviewed the Wnt pathway from different aspects. This candid review provides an introduction to WNT pathways and their crosstalk with other signalling pathways in OA development, highlighting the role of the WNT signalling pathway as a key regulator in OA development with the latest research. Particularly, we emphasise the state-of-the-art in targeting the WNT pathway as a promising therapeutic approach for OA and challenges in their development and the nanocarrier-based delivery of WNT modulators for treating OA. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is a common malignant tumour in the digestive system. Due to the lack of sensitive diagnostic markers, strong metastasis ability, and resistance to anti-cancer drugs, the prognosis of PC is inferior. In the past decades, increasing evidence has indicated that the development of PC is closely related to various signalling pathways. With the exploration of RAS-driven, epidermal growth factor receptor, Hedgehog, NF-κB, TGF-ß, and NOTC H signalling pathways, breakthroughs have been made to explore the mechanism of pancreatic carcinogenesis, as well as the novel therapies. In this review, we discussed the signalling pathways involved in PC and summarised current targeted agents in the treatment of PC. Furthermore, opportunities and challenges in the exploration of potential therapies targeting signalling pathways were also highlighted. [ABSTRACT FROM AUTHOR]

Duck Tembusu virus (DTMUV) is a neurotropic virus in the genus Flavivirus that causes massive economic losses to the poultry industry in China and neighbouring countries. Autophagy is pivotal in cellular responses to pathogens and in viral pathogenesis. However, little is known about the roles of autophagy in DTMUV replication and viral pathogenesis, especially in neuropathogenesis. In this study, mouse neuroblastoma cells (Neuro-2a) were used to establish a cell model of DTMUV infection. Our experiments indicated that DTMUV infection induced incomplete autophagy in Neuro-2a cells. Then, we used different autophagy regulators to alter the autophagy induced by DTMUV and found that incomplete autophagy promoted DTMUV replication. Furthermore, we showed that DTMUV infection activated the ERK and AMPK pathways, resulting in decreased phosphorylation of the autophagy repressor mTOR, subsequently leading to autophagic induction. In addition, we utilized ICR mice in an animal model of DTMUV infection to evaluate the autophagic responses in brain tissues and investigate the effects of autophagy on viral replication and tissue lesions. Our results confirmed that DTMUV induced incomplete autophagy in mouse brain tissues and that autophagy inducer treatment promoted DTMUV replication and aggravated DTMUV-induced lesions, whereas autophagy inhibitor treatment had the opposite effects. In summary, DTMUV infection induced incomplete autophagy through the ERK/mTOR and AMPK/mTOR signalling pathways to promote viral replication in mouse neuronal cells, and DTMUV-induced incomplete autophagy contributed to the neuropathogenesis of DTMUV. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) play a key role in regulating the homeostasis of the internal environment and are closely associated with tumour progression as major mediators of cellular signalling. As a diverse and multifunctional group of proteins, the G protein signalling regulator (RGS) family was proven to be involved in the cellular transduction of GPCRs. Growing evidence has revealed dysregulation of RGS proteins as a common phenomenon and highlighted the key roles of these proteins in human cancers. Furthermore, their differential expression may be a potential biomarker for tumour diagnosis, treatment and prognosis. Most importantly, there are few systematic reviews on the functional/mechanistic characteristics and clinical application of RGS family members at present. In this review, we focus on the G-protein signalling regulator (RGS) family, which includes more than 20 family members. We analysed the classification, basic structure, and major functions of the RGS family members. Moreover, we summarize the expression changes of each RGS family member in various human cancers and their important roles in regulating cancer cell proliferation, stem cell maintenance, tumorigenesis and cancer metastasis. On this basis, we outline the molecular signalling pathways in which some RGS family members are involved in tumour progression. Finally, their potential application in the precise diagnosis, prognosis and treatment of different types of cancers and the main possible problems for clinical application at present are discussed. Our review provides a comprehensive understanding of the role and potential mechanisms of RGS in regulating tumour progression. 74jjuBYfA2H5q1bTR1jC4p Video Abstract [ABSTRACT FROM AUTHOR]

Abstract The musculoskeletal system supports the movement of the entire body and provides blood production while acting as an endocrine organ. With aging, the balance of bone homeostasis is disrupted, leading to bone loss and degenerative diseases, such as osteoporosis, osteoarthritis, and intervertebral disc degeneration. Skeletal diseases have a profound impact on the motor and cognitive abilities of the elderly, thus creating a major challenge for both global health and the economy. Cellular senescence is caused by various genotoxic stressors and results in permanent cell cycle arrest, which is considered to be the underlying mechanism of aging. During aging, senescent cells (SnCs) tend to aggregate in the bone and trigger chronic inflammation by releasing senescence-associated secretory phenotypic factors. Multiple signalling pathways are involved in regulating cellular senescence in bone and bone marrow microenvironments. Targeted SnCs alleviate age-related degenerative diseases. However, the association between senescence and age-related diseases remains unclear. This review summarises the fundamental role of senescence in age-related skeletal diseases, highlights the signalling pathways that mediate senescence, and discusses potential therapeutic strategies for targeting SnCs. Graphical Abstract

PDLSCs possess multidirectional differentiation potential and self-renewal ability. In the inflammatory environment, signalling pathways, such as Wnt/β-catenin, Wnt/Ca2+, Wnt/PCP, NF-κB, MAPK, BMPs, and PI3K/AKT, are involved in regulating the osteogenic differentiation of PDLSCs. In addition, multiple signalling pathways that interact with microRNAs play crucial roles in the osteogenic differentiation of PDLSCs.

Abstract With an average incidence of 1 in every 18,000 live births, retinoblastoma is a rare type of intraocular tumour found to affect patients during their early childhood. It is curable if diagnosed at earlier stages but can become life-threateningly malignant if not treated timely. With no racial or gender predisposition, or even environmental factors known to have been involved in the incidence of the disease, retinoblastoma is often considered a clinical success story in pediatric oncology. The survival rate in highly developed countries is higher than 95% and they have achieved this because of the advancement in the development of diagnostics and treatment techniques. This includes developing the already existing techniques like chemotherapy and embarking on new strategies like enucleation, thermotherapy, cryotherapy, etc. Early diagnosis, studies on the etiopathogenesis and genetics of the disease are the need of the hour for improving the survival rates. According to the Knudson hypothesis, also known as the two hit hypothesis, two hits on the retinoblastoma susceptibility (RB) gene is often considered as the initiating event in the development of the disease. Studies on the molecular basis of the disease have also led to deciphering the downstream events and thus in the discovery of biomarkers and related targeted therapies. Furthermore, improvements in molecular biology techniques enhanced the development of efficient methods for early diagnosis, genetic counseling, and prevention of the disease. In this review, we discuss the genetic and molecular features of retinoblastoma with a special emphasis on the mutation leading to the dysregulation of key signaling pathways involved in cell proliferation, DNA repair, and cellular plasticity. Also, we describe the classification, clinical and epidemiological relevance of the disease, with an emphasis on both the traditional and innovative treatments to tackle retinoblastoma. Video Abstract

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. However, and despite achieving initial remission, a significant portion of patients will relapse because of innate and acquired resistance, at which point the disease is considered incurable. In view of this, novel detection strategies and therapeutic approaches are needed to improve outcomes and survival of OC patients. In this review, we summarize our current knowledge of the genetic landscape and molecular pathways underpinning OC and its many subtypes. By examining therapeutic strategies explored in preclinical and clinical settings, we highlight the importance of decoding how single and convergent genetic alterations co-exist and drive OC progression and resistance to current treatments. We also propose that core signalling pathways such as the PI3K and MAPK pathways play critical roles in the origin of diverse OC subtypes and can become new targets in combination with known DNA damage repair pathways for the development of tailored and more effective anti-cancer treatments.