IL-4Rα signalling in B cells and T cells play differential roles in acute and chronic atopic dermatitis.

Atopic dermatitis (AD) is a common pruritic inflammatory skin disease with complex environmental and genetic predisposing factors. Primary skin barrier dysfunction and aberrant T helper 2 (TH2) responses to common allergens, together with increased serum IgE antibodies, characterise the disease. B and T cells are essential in the disease manifestation, however, the exact mechanism of how these cells is involved is unclear. Targeting interleukin 4 receptor alpha (IL-4Rα), an IL-4/IL-13 signalling axis, with dupilumab shows efficacy in AD. We investigated the importance of IL-4Rα signalling specifically on B and T cells during acute and chronic models of AD. We used House dust mite (HDM) and Ovalbumin (OVA) in chronic models and a low-calcemic analog of vitamin D (MC903) for acute models of AD. We used mb1creIL-4Rα-/lox, iLCKcreIL-4Rα-/lox, LCKcreIL-4Rα-/lox, CD4creIL-4Rα-/lox, Foxp3creIL-4Rα-/lox and IL-4Rα-/lox littermate controls. IL-4Rα-responsive B cells were essential in serum IgE levels, but not in epidermal thickening in both chronic and acute models. IL-4Rα-responsive T cells were essential in epidermal thickening in the pan-T cell, but not CD4 or CD8 T cells suggesting the importance of γδT cells during acute AD. Our results suggest that IL-4Rα responsiveness on innate T cells regulates acute atopic dermatitis, while on B cells it regulates IgE.

Molecular interaction between small nuclear ribonucleoprotein polypeptide G and heat shock protein 70.14: a microscale thermophoresis exposition towards developing anti-cancer drugs.

BACKGROUND: Targeting protein-protein interactions (PPIs) linked to protein quality control (PQC) pathways as potential anti-cancer drug targets have unanimously widened biological insights and the therapeutic potential of PPIs as smart-drug discovery tools in cancer. PPIs between disease-relevant proteins associated with protein homeostasis in PQC pathways have been linked to improved mechanistic understanding associated with conformational abnormalities and impairment, cellular proteotoxicity, induced apoptosis, and pathogenesis in different types of cancers. In this context, PPIs between small nuclear ribonucleoprotein polypeptide G (SNRPG) and heat shock protein 70.14 (Hsp70.14) have attracted attention as potential smart drug discovery tools in cancer diagnostics and therapeutics. Validated evidence of high-quality biological data has shown the presence of the two proteins in different types of cancers including breast cancer. The links between SNRPG and Hsp70.14 in cancer-cell networks remain elusive, overlooked, and uncharacterized. METHODOLOGY: In this study, we explored the interaction between the two oncogenic proteins using the MST-based assays. RESULTS: The results revealed a low KD in the nanomolar concentration range of 2.4673 × 10-7 demonstrating a great affinity for SNRPG binding to Hsp70.14. CONCLUSIONS: The results suggest a possible involvement between the two proteins in hostile tumour microenvironments. Furthermore, these findings offer a different therapeutic perspective that could pave the way for the creation of novel small molecule inhibitors as drugs for the treatment of cancer.

The Practicality of the Use of Liquid Biopsy in Early Diagnosis and Treatment Monitoring of Oral Cancer in Resource-Limited Settings.

An important driving force for precision and individualized medicine is the provision of tailor-made care for patients on an individual basis, in accordance with best evidence practice. Liquid biopsy(LB) has emerged as a critical tool for the early diagnosis of cancer and for treatment monitoring, but its clinical utility for oral squamous cell carcinoma (OSCC) requires more research and validation. Hence, in this review, we have discussed the current applications of LB and the practicality of its routine use in Africa; the potential advantages of LB over the conventional "gold-standard" of tissue biopsy; and finally, practical considerations were discussed in three parts: pre-analytic, analytic processing, and the statistical quality and postprocessing phases. Although it is imperative to establish clinically validated and standardized working guidelines for various aspects of LB sample collection, processing, and analysis for optimal and reliable use, manpower and technological infrastructures may also be an important factor to consider for the routine clinical application of LB for OSCC. LB is poised as a non-invasive precision tool for personalized oral cancer medicine, particularly for OSCC in Africa, when fully embraced. The promising application of different LB approaches using various downstream analyses such as released circulating tumor cells (CTCs), cell free DNA (cfDNA), microRNA (miRNA), messenger RNA (mRNA), and salivary exosomes were discussed. A better understanding of the diagnostic and therapeutic biomarkers of OSCC, using LB applications, would significantly reduce the cost, provide an opportunity for prompt detection and early treatment, and a method to adequately monitor the effectiveness of the therapy for OSCC, which typically presents with ominous prognosis.

Respiratory Viral and Bacterial Factors That Influence Early Childhood Asthma.

Asthma is a chronic respiratory condition characterised by episodes of shortness of breath due to reduced airway flow. The disease is triggered by a hyperreactive immune response to innocuous allergens, leading to hyper inflammation, mucus production, changes in structural cells lining the airways, and airway hyperresponsiveness. Asthma, although present in adults, is considered as a childhood condition, with a total of about 6.2 million children aged 18 and below affected globally. There has been progress in understanding asthma heterogeneity in adults, which has led to better patient stratification and characterisation of multiple asthma endotypes with distinct, but overlapping inflammatory features. The asthma inflammatory profile in children is not well-defined and heterogeneity of the disease is less described. Although many factors such as genetics, food allergies, antibiotic usage, type of birth, and cigarette smoke exposure can influence asthma development particularly in children, respiratory infections are thought to be the major contributing factor in poor lung function and onset of the disease. In this review, we focus on viral and bacterial respiratory infections in the first 10 years of life that could influence development of asthma in children. We also review literature on inflammatory immune heterogeneity in asthmatic children and how this overlaps with early lung development, poor lung function and respiratory infections. Finally, we review animal studies that model early development of asthma and how these studies could inform future therapies and better understanding of this complex disease.

Interplay between heat shock proteins, inflammation and cancer: a potential cancer therapeutic target.

The historical relationship between cancer and inflammation has long been evaluated, and dates back to the early work of Virchow (1863), where he hypothesised that chronic inflammation as a direct cause of tissue injury and infection, could actually promote tissue proliferation. At that period in time however, the exact mechanisms that mediated this relationship were little understood. Subsequent studies have since then demonstrated that chronic inflammation plays significant roles in microenvironments, mostly in the progression of tumours, probably, through over-secretion of proinflammatory cytokines and other immune-killing apparatus such as reactive oxygen species (ROS) which cause damage to normal cells leading to DNA damage and increased cellular mutation rates. Recently, the identification of DNA lesion 5-chlorocytosine (5-CIC) created by hypochlorous acid (HOCl) secreted to nullify or kill infectious agents and toll-like receptor 4 (TLR4)-mediated chronic inflammation in the human gut, has become the latest evidence linking inflammation directly to cancer. The key to cellular survival and adaptation under unfavourable or pathological conditions is the expression of heat shock proteins (HSPs) also called molecular chaperones. These proteins play essential roles in DNA repair processes by maintaining membrane integrity, orderliness and stability of client proteins that play prominent roles in DNA repair mechanisms. More so, HSPs have also been shown to modulate the effects of pro-inflammatory/apoptotic cytokines through the inhibition of cascades leading to the generation of ROS-mediated DNA damage, while promoting the DNA repair mechanism, thus playing prominent roles in various stages of DNA repair and cancer progression. Hence, studies targeting HSPs and their inhibitors in inflammation, DNA damage, and repair, could improve current cancer therapeutic efficiency. Here the focus will be on the relationship between HSPs, inflammation and cancer, as well as roles of HSPs in DNA damage response (DDR).

Roles of Heat Shock Proteins in Apoptosis, Oxidative Stress, Human Inflammatory Diseases, and Cancer.

Heat shock proteins (HSPs) play cytoprotective activities under pathological conditions through the initiation of protein folding, repair, refolding of misfolded peptides, and possible degradation of irreparable proteins. Excessive apoptosis, resulting from increased reactive oxygen species (ROS) cellular levels and subsequent amplified inflammatory reactions, is well known in the pathogenesis and progression of several human inflammatory diseases (HIDs) and cancer. Under normal physiological conditions, ROS levels and inflammatory reactions are kept in check for the cellular benefits of fighting off infectious agents through antioxidant mechanisms; however, this balance can be disrupted under pathological conditions, thus leading to oxidative stress and massive cellular destruction. Therefore, it becomes apparent that the interplay between oxidant-apoptosis-inflammation is critical in the dysfunction of the antioxidant system and, most importantly, in the progression of HIDs. Hence, there is a need to maintain careful balance between the oxidant-antioxidant inflammatory status in the human body. HSPs are known to modulate the effects of inflammation cascades leading to the endogenous generation of ROS and intrinsic apoptosis through inhibition of pro-inflammatory factors, thereby playing crucial roles in the pathogenesis of HIDs and cancer. We propose that careful induction of HSPs in HIDs and cancer, especially prior to inflammation, will provide good therapeutics in the management and treatment of HIDs and cancer.